A sexually transmitted disease (STD), also known as a sexually transmitted infection (STI), or venereal disease (VD), is an illness that

has a significant probability of transmission between humans by means of human sexual behavior, including vaginal intercourse, oral sex, and anal sex. While in the past, these illnesses have mostly been referred to as STDs or VD, in recent years the term sexually transmitted infections (STIs) has been preferred, as it has a broader range of meaning; a person may be infected, and may potentially infect others, without having a disease. Some STIs can also be transmitted via the use of IV drug needles after its use by an infected person, as well as through childbirth or breastfeeding. Sexually transmitted infections have beClassification and terminology
Until the 1990s, STDs were commonly known as venereal diseases :Veneris is the Latin genitive form of the name Venus, the Roman goddess of love. Social disease was another euphemism. Sexually transmitted infection is a broader term than sexually transmitted disease.[1] An infection is a colonization by a parasitic species, which may not cause any adverse effects. In a disease the infection leads to impaired or abnormal function. In either case the condition may not exhibit signs or symptoms. Increased understanding of infections like HPV, which infects most sexually active individuals but cause disease in only a few has lead to increased use of the term STI. Public health officials originally introduced the term sexually transmitted infection, which clinicians are increasingly using alongside the term sexually transmitted disease in order to distinguish it from the former.[citation needed] STD may refer only to infections that are causing diseases, or it may be used more loosely as a synonym for STI. Because most of the time people do not know that they are infected with an STD until they are tested or start showing symptoms of disease, most people use the term STD, even though the term STI is also appropriate in many cases. Moreover, the term sexually transmissible disease is sometimes used since it is less restrictive in consideration of other factors or means of transmission. For instance, meningitis is transmissible by means of sexual contact but is not labeled as an STI because sexual contact is not the primary vector for the pathogens that cause meningitis. This discrepancy is addressed by the probability of infection by means other than sexual contact. In general, an STI is an infection that has a negligible probability of transmission by means other than sexual contact, but has a realistic means of transmission by sexual contact (more sophisticated meansblood transfusion, sharing

of hypodermic needlesare not taken into account). Thus, one may presume that, if a person is infected with an STI, e.g., chlamydia, gonorrhea, genital herpes, it was transmitted to him/her by means of sexual contact. The diseases on this list are most commonly transmitted solely by sexual activity. Many infectious diseases, including the common cold, influenza, pneumonia, and most others that are transmitted person-to-person can also be transmitted during sexual contact, if one person is infected, due to the close contact involved. However, even though these diseases may be transmitted during sex, they are not considered STDs.

en well known for hundreds of years. Cause

Bacterial

Chancroid (Haemophilus ducreyi) Chlamydia (Chlamydia trachomatis) Granuloma inguinale or (Klebsiella granulomatis) Gonorrhea (Neisseria gonorrhoeae) Syphilis (Treponema pallidum)

Fungal

Candidiasis (yeast infection)

Viral

Micrograph showing the viral cytopathic effect of herpes (ground glass nuclear inclusions, multinucleation). Pap test. Pap stain.

Viral hepatitis (Hepatitis B virus)saliva, venereal fluids. (Note: Hepatitis A and Hepatitis E are transmitted via the fecal-oral route; Hepatitis C is rarely sexually transmittable,[2] and the route of transmission of Hepatitis D (only if infected with B) is uncertain, but may include sexual transmission.[3][4][5]) Herpes simplex (Herpes simplex virus 1, 2) skin and mucosal, transmissible with or without visible blisters HIV (Human Immunodeficiency Virus) venereal fluids, semen, breast milk, blood

HPV (Human Papillomavirus) skin and mucosal contact. 'High risk' types of HPV cause almost all cervical cancers, as well as some anal, penile, and vulvar cancer. Some other types of HPV cause genital warts. Molluscum contagiosum (molluscum contagiosum virus MCV)close contact

Parasites

Crab louse, colloquially known as "crabs" or "pubic lice" (Pthirus pubis) Scabies (Sarcoptes scabiei)

Protozoal

Trichomoniasis (Trichomonas vaginalis)

Transmission probability

The risks and transmission probabilities of sexually transmitted diseases are summarized by act in the table below.[6][7][8][9][10][11][12]

Odds of transmission per unprotected sexual act with an infected person

Known risks Chlamydia Gonorrhea Herpes (rare) HPV [9] Syphilis (1%)

Possible or unknown risks

Performing oral sex on a man

With ass to mouth practices:

Hepatitis B (low risk)[11] HIV (very low risk; 0.01%)[7] Hepatitis C (unknown)

Hepatitis A Shigella Herpes (rare)

Performing oral sex on a woman

HPV

Receiving oral sex - man

Chlamydia Gonorrhea Non-gonococcal urethritis Herpes [9] Syphilis (1%)

HPV

Receiving oral sex - woman

Herpes

HPV

Vaginal sex - man

Chlamydia (30-50%)[11] Crabs Scabies [12] Gonorrhea (20%) Hepatitis B Herpes [7] HIV (0.05%) [10] HPV (at least 5%) Non-gonococcal urethritis Syphilis Trichomoniasis Chlamydia (3050%)[11] Crabs Scabies [12] Gonorrhea (50 to 90%) Hepatitis B Herpes [7] HIV (0.1%) [11] [10] HPV (high; at least 5%) Syphilis Trichomoniasis

Hepatitis C

Vaginal sex - woman

Hepatitis C

Chlamydia
Crabs Scabies

Anal sex - insertive

Gonorrhea Hepatitis B Herpes [8] HIV (0.62%) HPV Non-gonococcal urethritis [9] Syphilis (1.4%)

Hepatitis C

Chlamydia
Crabs Scabies

Anal sex - receptive

Gonorrhea Hepatitis B Herpes [8] HIV (1.7%) HPV [9] Syphilis (1.4%)

Hepatitis C

Oral-anal sex

Amebiasis Cryptosporidiosis Giardiasis Hepatitis A Shigellosis

HPV

Pathophysiology
Many STDs are (more easily) transmitted through the mucous membranes of the penis, vulva, rectum, urinary tract and (less oftendepending on type of infection)[citation needed] the mouth, throat, respiratory tract and eyes. The visible membrane covering the head of the penis is a mucous membrane, though it produces no mucus (similar to the lips of the mouth). Mucous membranes differ from skin in that they allow certain pathogens into the body.[13] Pathogens are also able to pass through breaks or abrasions of the skin, even minute ones. The shaft of the penis is particularly susceptible due to the friction caused during penetrative sex. The primary sources of infection in ascending order are venereal fluids, saliva, mucosal or skin (particularly the penis), infections may also be transmitted from feces, urine and sweat.[14][dubious discuss] The amount of contact with infective sources which causes infection varies with each pathogen but in all cases a disease may result from even light contact from fluid carriers like veneral fluids onto a mucous membrane. This is one reason that the probability of transmitting many infections is far higher from sex than by more casual means of transmission, such as non-sexual contacttouching, hugging, shaking handsbut it is not the only reason. Although mucous membranes exist in the mouth as in the genitals, many STIs seem to be easier to transmit through oral sex than through deep kissing. According to a safe sex chart, many infections that are easily transmitted from the mouth to the genitals or from the genitals to the mouth, are much harder to transmit from one mouth to another.[15] With HIV, genital fluids happen to contain much more of the pathogen than saliva. Some infections labeled as STIs can be transmitted by direct skin contact. Herpes simplex and HPV are both examples. KSHV, on the other hand, may be transmitted by deep-kissing but also when saliva is used as a sexual lubricant. Depending on the STD, a person may still be able to spread the infection if no signs of disease are present. For example, a person is much more likely to spread herpes infection when blisters are present (STD) than when they are absent (STI). However, a person can spread HIV infection (STI) at any time, even if he/she has not developed symptoms of AIDS (STD). All sexual behaviors that involve contact with the bodily fluids of another person should be considered to contain some risk of transmission of sexually transmitted diseases. Most attention has focused on controlling HIV, which causes AIDS, but each STD presents a different situation. As may be noted from the name, sexually transmitted diseases are transmitted from one person to another by certain sexual activities rather than being actually caused by those sexual activities. Bacteria, fungi, protozoa or viruses are still the causative agents. It is not possible to catch any sexually transmitted disease from a sexual activity with a person who is not carrying a disease;

conversely, a person who has an STD got it from contact (sexual or otherwise) with someone who had it, or his/her bodily fluids. Some STDs such as HIV can be transmitted from mother to child either during pregnancy or breastfeeding. Although the likelihood of transmitting various diseases by various sexual activities varies a great deal, in general, all sexual activities between two (or more) people should be considered as being a two-way route for the transmission of STDs, i.e., "giving" or "receiving" are both risky although receiving carries a higher risk. Healthcare professionals suggest safer sex, such as the use of condoms, as the most reliable way of decreasing the risk of contracting sexually transmitted diseases during sexual activity, but safer sex should by no means be considered an absolute safeguard. The transfer of and exposure to bodily fluids, such as blood transfusions and other blood products, sharing injection needles, needle-stick injuries (when medical staff are inadvertently jabbed or pricked with needles during medical procedures), sharing tattoo needles, and childbirth are other avenues of transmission. These different means put certain groups, such as medical workers, and haemophiliacs and drug users, particularly at risk. Recent epidemiological studies have investigated the networks that are defined by sexual relationships between individuals, and discovered that the properties of sexual networks are crucial to the spread of sexually transmitted diseases. In particular, assortative mixing between people with large numbers of sexual partners seems to be an important factor. It is possible to be an asymptomatic carrier of sexually transmitted diseases. In particular, sexually transmitted diseases in women often cause the serious condition of pelvic inflammatory disease.

Prevention

San Francisco City Clinic a municipal STD testing center in San Francisco. Main article: Safe sex

Prevention is key in addressing incurable STIs, such as HIV & herpes. Sexual health clinics fight to promote the use of condoms and provide outreach for at-risk communities. The most effective way to prevent sexual transmission of STIs is to avoid contact of body parts or fluids which can lead to transfer with an infected partner. Not all sexual activities involve contact: cybersex, phonesex or masturbation from a distance are methods of avoiding contact. Proper use of condoms reduces contact and risk. Although a condom is effective in limiting exposure, some disease transmission may occur even with a condom.[16] Ideally, both partners should get tested for STIs before initiating sexual contact, or before resuming contact if a partner engaged in contact with someone else. Many infections are not detectable immediately after exposure, so enough time must be allowed between possible exposures and testing for the tests to be accurate. Certain STIs, particularly certain persistent viruses like HPV, may be impossible to detect with current medical procedures. Many diseases that establish permanent infections can so occupy the immune system that other diseases become more easily transmitted. The innate immune system led by defensins against HIV can prevent transmission of HIV when viral counts are very low, but if busy with other viruses or overwhelmed, HIV can establish itself. Certain viral STI's also greatly increase the risk of death for HIV infected patients.
Vaccines

Vaccines are available that protect against some viral STIs, such as Hepatitis A, Hepatitis B, and some types of HPV. Vaccination before initiation of sexual contact is advised to assure maximal protection.
Condoms

Condoms and female condoms only provide protection when used properly as a barrier, and only to and from the area that it covers. Uncovered areas are still susceptible to many STDs. In the case of HIV, sexual transmission routes almost always involve the penis, as HIV cannot spread through unbroken skin, thus properly shielding the insertive penis with a properly worn condom from the vagina or anus effectively stops HIV transmission. An infected fluid to broken skin borne direct transmission of HIV would not be considered "sexually transmitted", but can still theoretically occur during sexual contact, this can be avoided simply by not engaging in sexual contact when having open bleeding wounds. Other STDs, even viral infections, can be prevented with the use of latex, polyurethane or polyisoprene condoms as a barrier. Some microorganisms and viruses are small enough to pass through the pores in natural skin condoms, but are still too large to pass through latex or synthetic condoms.

Proper usage entails:

Not putting the condom on too tight at the end, and leaving 1.5 cm (3/4 inch) room at the tip for ejaculation. Putting the condom on snug can and often does lead to failure. Wearing a condom too loose can defeat the barrier. Avoiding inverting, spilling a condom once worn, whether it has ejaculate in it or not. Avoiding condoms made of substances other than latex, polyisoprene or polyurethane that do not protect against HIV. Avoiding the use of oil based lubricants (or anything with oil in it) with latex condoms, as oil can eat holes into them. Using flavored condoms for oral sex only, as the sugar in the flavoring can lead to yeast infections if used to penetrate.

Not following the first five guidelines above perpetuates the common misconception that condoms are not tested or designed properly.[citation needed] In order to best protect oneself and the partner from STIs, the old condom and its contents should be assumed to be infectious. Therefore the old condom must be properly disposed of. A new condom should be used for each act of intercourse, as multiple usage increases the chance of breakage, defeating the effectiveness as a barrier.
Nonoxynol-9

Researchers had hoped that nonoxynol-9, a vaginal microbicide would help decrease STD rates. Trials, however, have found it ineffective.[17] In fact, the use of nonoxynol-9 can put women at a higher risk of HIV infection.[18]

Diagnosis
STI tests may test for a single infection, or consist of a number of individual tests for any of a wide range of STIs, including tests for syphilis, trichomonas, gonorrhea, chlamydia, herpes, hepatitis and HIV tests. No procedure tests for all infectious agents. STI tests may be used for a number of reasons:

as a diagnostic test to determine the cause of symptoms or illness as a screening test to detect asymptomatic or presymptomatic infections as a check that prospective sexual partners are free of disease before they engage in sex without safer sex precautions (for example, when starting a long term mutually monogamous sexual relationship, in fluid bonding, or for procreation). as a check prior to or during pregnancy, to prevent harm to the baby as a check after birth, to check that the baby has not caught an STI from the mother to prevent the use of infected donated blood or organs as part of the process of contact tracing from a known infected individual as part of mass epidemiological surveillance

Not all STIs are symptomatic, and symptoms may not appear immediately after infection. In some instances a disease can be carried with no symptoms, which leaves a greater risk of passing the disease on to others. Depending on the disease, some untreated STIs can lead to infertility, chronic pain or even death.[19] Early identification and treatment results in less chance to spread disease, and for some conditions may improve the outcomes of treatment. There is often a window period after initial infection during which an STI test will be negative. During this period the infection may be transmissible. The duration of this period varies depending on the infection and the test. Diagnosis may also be delayed by reluctance of the infected person to seek a medical professional. One report indicated that afflicted people turn to the Internet rather than to a medical professional for information on STIs to a higher degree than for other sexual problems.[20]
STD Wizard

The STD Wizard is a publicly available expert system for determining which screening tests, vaccinations, and evaluations are recommended, related to sexually transmitted diseases. The information included within the STD Wizard is based on the Centers for Disease Control and Prevention "Sexually Transmitted Diseases Treatment Guidelines - 2006". The system has English and Spanish language interfaces. The STD Wizard runs in a web browser. The program asks a series of questions, related to demographics, behaviors, and symptoms. There are potentially over 100 questions, but most users get asked about 20. The exact questions asked depend on the user's responses. Typical questions include:

Demographics - How old are you, in years? Behaviors - Have you had more than one sex partner within the past six months? Symptoms - Are you having a discharge from your penis or burning during urination?

Typical recommendations include:

Screening tests - e.g., HIV screening test Vaccinations - e.g., Hepatitis B vaccination Evaluations - e.g., Seek medical attention in the next week for rash

Management
High risk exposure such as that which occurs in rape cases may be treated prophylacticly using antibiotic combinations such as azithromycin, cefixime, and metronidazole. An option for treating partners of patients (index cases) diagnosed with chlamydia or gonorrhea is patient-delivered partner therapy, which is the clinical practice of treating the sex partners of

index cases by providing prescriptions or medications to the patient to take to his/her partner without the health care provider first examining the partner.[21]

Epidemiology

Age-standardized, disability-adjusted life years for STDs (excluding HIV) per 100,000 inhabitants in 2004.[22] no data < 60 60-120 120-180 180-240 240-300 300-360 360-420 420-480 480-540 540-600 600-1000 > 1000

STD incidence rates remain high in most of the world, despite diagnostic and therapeutic advances that can rapidly render patients with many STDs noninfectious and cure most. In many cultures, changing sexual morals and oral contraceptive use have eliminated traditional sexual restraints, especially for women, and both physicians and patients have difficulty dealing openly and candidly with sexual issues. Additionally, development and spread of drug-resistant bacteria (e.g., penicillin-resistant gonococci) makes some STDs harder to cure. The effect of travel is

most dramatically illustrated by the rapid spread of the AIDS virus (HIV-1) from Africa to Europe and the Americas in the late 1970s.[23] In 1996, the World Health Organization estimated that more than 1 million people were being infected daily. About 60% of these infections occur in young people <25 years of age, and of these 30% are <20 years. Between the ages of 14 and 19, STDs occur more frequently in girls than boys by a ratio of nearly 2:1; this equalizes by age 20. An estimated 340 million new cases of syphilis, gonorrhea, chlamydia and trichomoniasis occurred throughout the world in 1999.[24][25] Commonly reported prevalences of STIs among sexually active adolescent girls both with and without lower genital tract symptoms include chlamydia (1025%), gonorrhea (318%), syphilis (03%), Trichomonas vaginalis (816%), and herpes simplex virus (212%).[citation needed] Among adolescent boys with no symptoms of urethritis, isolation rates include chlamydia (911%) and gonorrhea (23%).[citation needed] At least one in four U.S. teenage girls has a sexually transmitted disease,[26] a CDC study found.[27] Among girls who admitted ever having sex, the rate was 40%.[28] AIDS is the single largest cause of mortality in present-day Sub-Saharan Africa.[29] The majority of HIV infections are acquired through unprotected sexual relations between partners, one of whom has HIV. Approximately 1.1 million persons are living with HIV/AIDS in the United States,[30] and AIDS remains the leading cause of death among African American women between ages 25 and 34.[31] Hepatitis B is also classed as a sexually transmitted disease because it can be passed on sexually.[32] The disease is found globally, with the highest rates in Asia and Africa and lower rates in the Americas and Europe.[33] Worldwide, an estimated two billion people have been infected with the hepatitis B virus.[34]

History

1930s Works Progress Administration poster

The first well-recorded European outbreak of what is now known as syphilis occurred in 1494 when it broke out among French troops besieging Naples.[35] From this centre, the disease swept across Europe, killing more than five million people.[36] As Jared Diamond describes it, "[W]hen syphilis was first definitely recorded in Europe in 1495, its pustules often covered the body from the head to the knees, caused flesh to fall from people's faces, and led to death within a few months," rendering it far more fatal than it is today. Diamond concludes,"[B]y 1546, the disease had evolved into the disease with the symptoms so well known to us today."[37] Prior to the invention of modern medicines, sexually transmitted diseases were generally incurable, and treatment was limited to treating the symptoms of the disease. The first voluntary hospital for venereal diseases was founded in 1746 at London Lock Hospital.[38] Treatment was not always voluntary: in the second half of the 19th century, the Contagious Diseases Act was used to arrest suspected prostitutes. The first effective treatment for a sexually transmitted disease was salvarsan, a treatment for syphilis. With the discovery of antibiotics, a large number of sexually transmitted diseases became easily curable, and this, combined with effective public health campaigns against STDs, led to a public perception during the 1960s and 1970s that they have ceased to be a serious medical threat. During this period, the importance of contact tracing in treating STIs was recognized. By tracing the sexual partners of infected individuals, testing them for infection, treating the infected and

tracing their contacts in turn, STI clinics could be very effective at suppressing infections in the general population. In the 1980s, first genital herpes and then AIDS emerged into the public consciousness as sexually transmitted diseases that could not be cured by modern medicine. AIDS in particular has a long asymptomatic periodduring which time HIV (the human immunodeficiency virus, which causes AIDS) can replicate and the disease can be transmitted to othersfollowed by a symptomatic period, which leads rapidly to death unless treated. HIV/AIDS entered the United States in about 1969 likely through a single infected immigrant from Haiti.[39] Recognition that AIDS threatened a global pandemic led to public information campaigns and the development of treatments that allow AIDS to be managed by suppressing the replication of HIV for as long as possible. Contact tracing continues to be an important measure, even when diseases are incurable, as it helps to contain infection. Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS),[1][2] a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The four major routes of transmission are unsafe sex, contaminated needles, breast milk, and transmission from an infected mother to her baby at birth (perinatal transmission). Screening of blood products for HIV has largely eliminated transmission through blood transfusions or infected blood products in the developed world. HIV infection in humans is considered pandemic by the World Health Organization (WHO). Nevertheless, complacency about HIV may play a key role in HIV risk.[3][4] From its discovery in 1981 to 2006, AIDS killed more than 25 million people.[5] HIV infects about 0.6% of the world's population.[5] In 2009, AIDS claimed an estimated 1.8 million lives, down from a global peak of 2.1 million in 2004.[6] Approximately 260,000 children died of AIDS in 2009.[6] A disproportionate number of AIDS deaths occur in Sub-Saharan Africa, retarding economic growth and exacerbating the burden of poverty.[7] In 2005, it was estimated that HIV would infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans.[8] Treatment with antiretroviral drugs reduces both the mortality and the morbidity of HIV infection.[9] Although antiretroviral medication is still not universally available, expansion of antiretroviral therapy programs since 2004 has helped to turn the tide of AIDS deaths and new infections in many parts of the world.[6] Intensified awareness and preventive measures, as well as the natural course of the epidemic, have also played a role. Nevertheless, an estimated 2.6 million people were newly infected in 2009.[6] HIV infects vital cells in the human immune system such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells.[10] HIV infection leads to low levels of CD4+ T cells through three main mechanisms: First, direct viral killing of infected cells; second, increased rates of apoptosis in infected cells; and third, killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.

Most untreated people infected with HIV-1 eventually develop AIDS.

[11]

These individuals

mostly die from opportunistic infections or malignancies associated with the progressive [12] failure of the immune system. HIV progresses to AIDS at a variable rate affected by viral, host, and environmental factors; most will progress to AIDS within 10 years of HIV infection: [13][14] some will have progressed much sooner, and some will take much longer. Treatment with anti-retrovirals increases the life expectancy of people infected with HIV. Even after HIV has progressed to diagnosable AIDS, the average survival time with antiretroviral therapy was [15] estimated to be more than 5 years as of 2005. Without antiretroviral therapy, someone who [16] has AIDS typically dies within a year. HIV is a member of the genus Lentivirus,[17] part of [18] the family of Retroviridae. Lentiviruses have many morphologies and biological properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period.[19] Lentiviruses are transmitted as singlestranded, positive-sense, enveloped RNA viruses. Upon entry into the target cell, the viral RNA genome is converted (reverse transcribed) into double-stranded DNA by a virally encoded reverse transcriptase that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded integrase and host co-factors.[20] Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system. Alternatively, the virus may be transcribed, producing new RNA genomes and viral proteins that are packaged and released from the cell as new virus particles that begin the replication cycle anew. Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both LAV and HTLV-III. It is more virulent, more infective,[21] and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2 compared to HIV-1 implies that fewer of those exposed to HIV-2 will be infected per exposure. Because of its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.[22]

Signs and symptoms

A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably. CD4+ T cell count (cells per L) HIV RNA copies per mL of plasma

Infection with HIV-1 is associated with a progressive decrease of the CD4+ T cell count and an increase in viral load, the level of HIV in the blood. The stage of infection can be determined by measuring the patient's CD4+ T cell count and viral load. The stages of HIV infection are acute infection (also known as primary infection), latency and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, lymphadenopathy (swollen lymph nodes), pharyngitis (sore throat), rash, myalgia (muscle pain), malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts (fewer than 200 per microliter), various opportunistic infections, cancers and other conditions. A small percentage of HIV-1 infected individuals retain high levels of CD4+ T-cells without antiretroviral therapy. However, most have detectable viral load and will eventually progress to AIDS without treatment, albeit more slowly than others. These individuals are classified as HIV controllers or long-term nonprogressors (LTNP). People who maintain CD4+ T cell counts and also have low or clinically undetectable viral load without anti-retroviral treatment are known as elite controllers or elite suppressors (ES).[23][24]
Acute infection Main article: Acute HIV infection

Main symptoms of acute HIV infection.

Infection with HIV generally occurs by introduction of bodily fluids from an infected person into the body of an uninfected person. A period of rapid viral replication ensues, leading to an

abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood.[25] This response is accompanied by a marked drop in the numbers of circulating CD4+ T cells. This acute viremia is associated in virtually all patients with the activation of CD8+ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts rebound. A good CD8+ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus.[26] During this period (usually 24 weeks post-exposure) most individuals (80 to 90%) develop an influenza or mononucleosis-like illness called acute HIV infection, the most common symptoms of which may include fever, lymphadenopathy, pharyngitis, rash, myalgia, malaise, mouth and esophageal sores, and may also include, but less commonly, headache, nausea and vomiting, enlarged liver/spleen, weight loss, thrush, and neurological symptoms. Infected individuals may experience all, some, or none of these symptoms. The duration of symptoms varies, averaging 28 days and usually lasting at least a week.[27] Because of the nonspecific nature of these symptoms, they are often not recognized as signs of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. As a consequence, these primary symptoms are not used to diagnose HIV infection, as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome can be important because the patient is much more infectious during this period.[28]
Chronic infection

A strong immune defense reduces the number of viral particles in the blood stream, marking the start of secondary or chronic HIV infection. The secondary stage of HIV infection can vary between two weeks and 20 years. During this phase of infection, HIV is active within lymph nodes, which typically become persistently swollen, in response to large amounts of virus that become trapped in the follicular dendritic cells (FDC) network.[29] The surrounding tissues that are rich in CD4+ T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, CD4+ CD45RO+ T cells carry most of the proviral load.[30] During this stage of infection early initiation of antiretroviral therapy significantly improves survival, as compared with deferred therapy.[31]
AIDS Main article: AIDS For more details on this topic, see AIDS Diagnosis, AIDS Symptoms and WHO Disease Staging System for HIV Infection and Disease

When CD4+ T cell numbers decline below a critical level of 200 cells per L, cell-mediated immunity is lost, and infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained weight loss, recurring respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis), prostatitis, skin rashes, and oral ulcerations. Common opportunistic infections and tumors, most of which are normally controlled by robust CD4+ T cell-mediated immunity then start to affect the patient. Typically, resistance is lost early on to oral Candida species and to Mycobacterium tuberculosis, which leads to an increased susceptibility to oral candidiasis (thrush) and tuberculosis. Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles, Epstein-Barr virus-induced B-cell lymphomas, or Kaposi's sarcoma. Pneumonia caused by the fungus Pneumocystis jirovecii is common and often fatal. In the final stages of AIDS, infection with cytomegalovirus (another herpes virus) or Mycobacterium avium complex is more prominent. Not all patients with AIDS get all these infections or tumors, and there are other tumors and infections that are less prominent but still significant.

Transmission
Estimated per-act risk for acquisition of HIV by exposure route[32][33] Exposure Route Blood transfusion Mother-to-child, including pregnancy, childbirth and breastfeeding (without treatment) Mother-to-child, including pregnancy, childbirth and breastfeeding (with optimal treatment) Needle-sharing injection drug use Percutaneous needle stick Receptive anal intercourse (2009 and 2010 studies) Receptive anal intercourse (based on data of a 1992 study) Insertive anal intercourse for uncircumcised men (2010 study) Insertive anal intercourse for circumcised men (2010 study) Estimated infections per 10,000 exposures to an infected source 9,000 (90%)[34] 2,500 (25%)[35] 100-200 (1%-2%)[35] 67 (.67%)[36] 30 (.30%)[37] 170 (1.7%) [30890][38] / 143 [48285][33] 50 (.5%)[39][40] 62 (.62%)a [7-168][33] 11 (.11%)a [224][33]

Insertive anal intercourse (based on data of a 1992 study) Low-income country female-to-male Low-income country male-to-female Receptive penile-vaginal intercourse Insertive penile-vaginal intercourse Fellating a man Man being fellated

6.5(.065%)[39][40] 38 (.38%) [13110][38] 30 (.3%) [1463][38] 10 (.1%)[39][40][41] 5 (.05%)[39][40] 1 (.01%)b[40] 0.5 (.005%)b[40]

The data shown represents transmission without the use of condoms. Risk increases substantially in the presence of genital ulcers, mucosal lacerations, concurrent sexually transmitted infections, or a partner with a high viral load of HIV.[42] Commercial sex exposure and national income levels may also impact risk.[38]
Bracketed values represent 95% confidence interval "best-guess estimate" Pooled transmission probability estimate
a

Other studies found insufficient evidence that male circumcision protects against HIV infection among men who have sex with men[43][44]
b

Oral trauma, sores, inflammation, concomitant sexually transmitted infections, ejaculation in the mouth, and systemic immune suppression may increase HIV transmission rate.[45]

Three main transmission routes for HIV have been identified. HIV-2 is transmitted much less frequently by the mother-to-child and sexual route than HIV-1.
Sexual

The majority of HIV infections are acquired through unprotected sexual relations. Complacency about HIV plays a key role in HIV risk.[3][4] Sexual transmission can occur when infected sexual secretions of one partner come into contact with the genital, oral, or rectal mucous membranes of another. In high-income countries, the risk of female-to-male transmission is 0.04% per act and male-to-female transmission is 0.08% per act. For various reasons, these rates are 4 to 10 times higher in low-income countries.[38] The rate for receptive anal intercourse is much higher, 1.7% per act.[38] A 1999 meta-analysis of studies of condom use showed that the consistent use of latex condoms reduces the risk of sexual transmission of HIV by about 85%.[46] However, spermicide may actually increase the transmission rate.[47][48][49]

Randomized, controlled trials in which uncircumcised men were randomly assigned to be medically circumcised in sterile conditions and given counseling and other men were not circumcised have been conducted in South Africa,[50] Kenya,[51] and Uganda[52] showing reductions in female-to-male sexual HIV transmission of 60%, 53%, and 51%, respectively. As a result, a panel of experts convened by WHO and the UNAIDS Secretariat has "recommended that male circumcision now be recognized as an additional important intervention to reduce the risk of heterosexually acquired HIV infection in men."[53] Among men who have sex with men, there is insufficient evidence that male circumcision protects against HIV infection or other Sexually Transmitted Infections.[43] Studies of HIV among women having undergone female genital cutting (FGC) have reported mixed results, but with some evidence of increased risk of transmission.[54][55][56][57] Programmes that aim to encourage sexual abstinence while also encouraging and teaching safer sex strategies for those who are sexually active can reduce short- and long-term HIV risk behaviour among young people in high-income countries, according to a 2007 Cochrane Review of studies.[58]
Blood products

In general, if infected blood comes into contact with any open wound, HIV may be transmitted. This transmission route can account for infections in intravenous drug users, hemophiliacs, and recipients of blood transfusions (though most transfusions are checked for HIV in the developed world) and blood products. It is also of concern for persons receiving medical care in regions where there is prevalent substandard hygiene in the use of injection equipment, such as the reuse of needles in Third World countries. Health care workers such as nurses, laboratory workers, and doctors have also been infected, although this occurs more rarely. Since transmission of HIV by blood became known medical personnel are required to protect themselves from contact with blood by the use of universal precautions. People giving and receiving tattoos, piercings, and scarification procedures can also be at risk of infection. HIV has been found at low concentrations in the saliva, tears, and urine of infected individuals, but there are no recorded cases of infection by these secretions and the potential risk of transmission is negligible.[59] It is not possible for mosquitoes to transmit HIV.[60]
Mother-to-child

The transmission of the virus from the mother to the child can occur in utero (during pregnancy), intrapartum (at childbirth), or via breast feeding. In the absence of treatment, the transmission rate up to birth between the mother and child is around 25%.[35] However, where combination antiretroviral drug treatment and Cesarian section are available, this risk can be reduced to as low as one percent.[35] Postnatal mother-to-child transmission may be largely prevented by complete avoidance of breast feeding; however, this has significant associated morbidity. Exclusive breast feeding and the provision of extended antiretroviral prophylaxis to the infant are also efficacious in avoiding transmission.[61] UNAIDS estimate that 430,000 children were infected worldwide in 2008 (19% of all new infections), primarily by this route, and that a further 65,000 infections were averted through the provision of antiretroviral prophylaxis to HIV-positive women.[62]

Multiple infection Main article: HIV superinfection

Unlike some other viruses, infection with HIV does not provide immunity against additional infections, in particular, in the case of more genetically distant viruses. Both inter- and intraclade multiple infections have been reported,[63] and even associated with more rapid disease progression.[64] Multiple infections are divided into two categories depending on the timing of the acquisition of the second strain. Coinfection refers to two strains that appear to have been acquired at the same time (or too close to distinguish). Reinfection (or superinfection) is infection with a second strain at a measurable time after the first. Both forms of dual infection have been reported for HIV in both acute and chronic infection around the world.[65][66][67][68]
Prevention

There is currently no publicly available vaccine for HIV or AIDS.[69][70][71] However, a vaccine that is a combination of two previously unsuccessful vaccine candidates (ALVAC-HIV and AIDSVAX) was reported in September 2009 to have resulted in a 30% reduction in infections in a trial conducted in Thailand.[72][73] Further trials of the vaccine are ongoing.[74][75] Additionally, a course of antiretroviral treatment administered immediately after exposure, referred to as postexposure prophylaxis, is believed to reduce the risk of infection if begun as quickly as possible.[76] In July 2010, a vaginal gel containing tenofovir, a reverse transcriptase inhibitor, was shown to reduce HIV infection rates by 39 percent in a trial conducted in South Africa.[77] Early treatment of HIV-infected people with antiretrovirals protected 96% of partners from infection.[78]

Virology
Structure and genome Main article: Structure and genome of HIV Human immunodeficiency virus

Scanning electron micrograph of HIV-1 (in green) budding from cultured lymphocyte. Multiple round bumps on cell surface represent sites of assembly and

budding of virions.

Virus classification Group: Family: Genus: Group VI (ssRNA-RT) Retroviridae Lentivirus Species

Human immunodeficiency virus 1 Human immunodeficiency virus 2

HIV is different in structure from other retroviruses. It is roughly spherical[79] with a diameter of about 120 nm, around 60 times smaller than a red blood cell, yet large for a virus.[80] It is composed of two copies of positive single-stranded RNA that codes for the virus's nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein p24.[81] The singlestranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as reverse transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.[81] This is, in turn, surrounded by the viral envelope that is composed of two layers of fatty molecules called phospholipids taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and about 70 copies of a complex HIV protein that protrudes through the surface of the virus particle.[81] This protein, known as Env, consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure into the viral envelope.[82] This glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the infectious cycle.[82] Both these surface proteins, especially gp120, have been considered as targets of future treatments or vaccines against HIV.[83] The RNA genome consists of at least seven structural landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS), and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat env and rev), encoding 19 proteins. Three of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles.[81] For example, env codes for a protein called gp160 that is broken down by a viral enzyme to form gp120 and gp41. The six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.[81]

The two Tat proteins (p16 and p14) are transcriptional transactivators for the LTR promoter acting by binding the TAR RNA element. The TAR may also be processed into microRNAs that regulate the apoptosis genes ERCC1 and IER3.[84][85] The Rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the RRE RNA element. The Vif protein (p23) prevents the action of APOBEC3G (a cell protein that deaminates DNA:RNA hybrids and/or interferes with the Pol protein). The Vpr protein (p14) arrests cell division at G2/M. The Nef protein (p27) down-regulates CD4 (the major viral receptor), as well as the MHC class I and class II molecules.[86][87][88] Nef also interacts with SH3 domains. The Vpu protein (p16) influences the release of new virus particles from infected cells.[81] The ends of each strand of HIV RNA contain an RNA sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell. The Psi element is involved in viral genome packaging and recognized by Gag and Rev proteins. The SLIP element (TTTTTT) is involved in the frameshift in the Gag-Pol reading frame required to make functional Pol.[81]
Tropism Main article: HIV tropism

Diagram of the immature and mature forms of HIV

The term viral tropism refers to which cell types HIV infects. HIV can infect a variety of immune cells such as CD4+ T cells, macrophages, and microglial cells. HIV-1 entry to macrophages and CD4+ T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells and also with chemokine coreceptors.[82]

Macrophage (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the chemokine receptor CCR5 for entry and are, thus, able to replicate in macrophages and CD4+ T cells.[89] This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4+ cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the central nervous system. In tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce huge amounts of virus. T-tropic isolates, or syncitia-inducing (SI) strains replicate in primary CD4+ T cells as well as in macrophages and use the -chemokine receptor, CXCR4, for entry.[89][90][91] Dual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry. The -chemokine SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down-regulating the expression of CXCR4 on the surface of these cells. HIV that use only the CCR5 receptor are termed R5; those that use only CXCR4 are termed X4, and those that use both, X4R5. However, the use of coreceptor alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection[89] and HIV can also infect a subtype of myeloid dendritic cells,[92] which probably constitute a reservoir that maintains infection when CD4+ T cell numbers have declined to extremely low levels. Some people are resistant to certain strains of HIV.[93] For example, people with the CCR5-32 mutation are resistant to infection with R5 virus, as the mutation stops HIV from binding to this coreceptor, reducing its ability to infect target cells. Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal fluid, which is passed from a male to his sexual partner. The virions can then infect numerous cellular targets and disseminate into the whole organism. However, a selection process leads to a predominant transmission of the R5 virus through this pathway.[94][95][96] How this selective process works is still under investigation, but one model is that spermatozoa may selectively carry R5 HIV as they possess both CCR3 and CCR5 but not CXCR4 on their surface[97] and that genital epithelial cells preferentially sequester X4 virus.[98] In patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and Ttropic variants appear that can infect a variety of T cells through CXCR4.[99] These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS.[100] Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of studies with subtype B-infected individuals have determined that between 40 and 50% of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes.[101][102] HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution. The adoption of "accessory genes" by HIV-2 and its more promiscuous pattern of coreceptor usage (including CD4-independence) may assist the virus in its adaptation to avoid innate restriction factors present in host cells. Adaptation to use normal cellular machinery to enable transmission

and productive infection has also aided the establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host but ultimately become a commensal organism. Having achieved a low pathogenicity, over time, variants more successful at transmission will be selected.[103]
Replication cycle

The HIV replication cycle

Entry to the cell HIV enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.[104][105] Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface.[104][105] gp120 binds to integrin 47 activating LFA-1 the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-

cell spreading of HIV-1.[106] The gp160 spike contains binding domains for both CD4 and chemokine receptors.[104][105] The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor.[104][105] This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.[104][105] Repeat sequences in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.[104][105] After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell.[104] During the microtubule-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome. HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannosespecific C-type lectin receptors such as DC-SIGN can also be used.[107] DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T-cells when the virus is captured in the mucosa by DCs.[107] The presence of FEZ-1, which occurs naturally in neurons, is believed to prevent the infection of cells by HIV.[108] Replication and transcription Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule.[109] The process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or allow the virus to evade the body's immune system. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a sense DNA from the antisense cDNA.[110] Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by another viral enzyme called integrase.[109]

Reverse transcription of the HIV genome into double strand DNA

This integrated viral DNA may then lie dormant, in the latent stage of HIV infection.[109] To actively produce the virus, certain cellular transcription factors need to be present, the most important of which is NF-B (NF kappa B), which is upregulated when T-cells become activated.[111] This means that those cells most likely to be killed by HIV are those currently fighting infection. During viral replication, the integrated DNA provirus is transcribed into mRNA, which is then spliced into smaller pieces. These small pieces are exported from the nucleus into the cytoplasm, where they are translated into the regulatory proteins Tat (which encourages new virus production) and Rev. As the newly produced Rev protein accumulates in the nucleus, it binds to viral mRNAs and allows unspliced RNAs to leave the nucleus, where they are otherwise retained until spliced.[112] At this stage, the structural proteins Gag and Env are produced from the fulllength mRNA. The full-length RNA is actually the virus genome; it binds to the Gag protein and is packaged into new virus particles. HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will bind to any appropriate RNA, whereas HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself. This may mean that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global infections). Assembly and release The final step of the viral cycle, assembly of new HIV-1 virons, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is cleaved by protease and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors the gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. Maturation occurs either in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion.[113]

This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.
Genetic variability Further information: Subtypes of HIV

The phylogenetic tree of the SIV and HIV.

HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of about 1010 virions every day, coupled with a high mutation rate of approximately 3 x 105 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase.[114][115][116] This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.[114] This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes.[114] This recombination is most obvious when it occurs between subtypes.[114] The closely related simian immunodeficiency virus (SIV) has evolved into many strains, classified by the natural host species. SIV strains of the African green monkey (SIVagm) and sooty mangabey (SIVsmm) are thought to have a long evolutionary history with their hosts. These hosts have adapted to the presence of the virus,[117] which is present at high levels in the host's blood but evokes only a mild immune response,[118] does not cause the development of simian AIDS,[119] and does not undergo the extensive mutation and recombination typical of HIV infection in humans.[120] In contrast, when these strains infect species that have not adapted to SIV ("heterologous" hosts such as rhesus or cynomologus macaques), the animals develop AIDS and the virus generates genetic diversity similar to what is seen in human HIV infection.[121] Chimpanzee SIV (SIVcpz),

the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host.[122] SIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus.[117] This virus has also lost a function of the Nef gene that is present in most SIVs; without this function, T cell depletion is more likely, leading to immunodeficiency.[122] Three groups of HIV-1 have been identified on the basis of differences in the envelope (env) region: M, N, and O.[123] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct.[124] The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Coinfection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs.[125] Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.[126] The existence of a fourth group, "P", has been hypothesised based on a virus isolated in 2009.[127][128][129] The strain is apparently derived from gorilla SIV (SIVgor), first isolated from western lowland gorillas in 2006.[127] The genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsmm.

Diagnosis
Main article: HIV test

Many HIV-positive people are unaware that they are infected with the virus.[130] For example, less than 1% of the sexually active urban population in Africa have been tested and this proportion is even lower in rural populations.[130] Furthermore, only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results.[130] Again, this proportion is even lower in rural health facilities.[130] Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine and medical research are routinely screened for HIV.[131] HIV-1 testing consists of initial screening with an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a nonreactive result from the initial ELISA are considered HIV-negative unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate.[132] If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., Western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or reactive by Western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide

an indeterminate Western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person.[133] Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. In general, a second specimen should be collected more than a month later and retested for persons with indeterminate Western blot results. Although much less commonly available, nucleic acid testing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations.[132] In addition, a few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection. Modern HIV testing is extremely accurate. The chance of a false-positive result in the two-step testing protocol is estimated to be 0.0004% to 0.0007% in the general U.S. population.[134][135][136][137]
Screening at schools

The South African government announced a plan to start HIV testing in secondary schools by March 2011[138] but this plan was eventually scrapped because doing so would invade pupil's privacy at schools, schools typically don't have the facilities to securely store such information, and schools generally do not have the capacity to provide counselling for HIV positive pupils. In South Africa, anyone over the age of 12 may request an HIV test without parental knowledge or consent. Some 80,000 pupils in three provinces were tested under this programme before it was cancelled.[139]

Treatment
Further information: Antiretroviral drug and Post-exposure prophylaxis

Abacavir a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)

There is currently no cure for HIV infection. Treatment consists of highly active antiretroviral therapy, or HAART.[140] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available.[141] Current HAART options are combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral agents. Typically, these classes are two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). There is no empirical evidence for withholding treatment at any stage of HIV infection,[142] and death rates are almost twice as high when therapy is deferred (until the CD4 count falls below 500) compared to starting therapy when the CD4 count is above 500.[31] However, the timing for starting HIV treatment is still subject to debate.[143] The United States Panel on Antiretroviral Guidelines for Adults and Adolescents in 2009 recommended that antiretroviral therapy should be initiated in all patients with a CD4 count less than 350, with treatment also recommended for patients with CD4 counts between 350 and 500. However, for patients with CD4 counts over 500, the expert Panel was evenly divided, with 50% in favor of starting antiretroviral therapy at this stage of HIV disease, and 50% viewing initiating therapy at this stage as optional. They noted that "Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence".[144] New classes of drugs such as entry inhibitors provide treatment options for patients infected with viruses already resistant to common therapies, although they are not widely available and not typically accessible in resource-limited settings. Because AIDS progression in children is more rapid and less predictable than in adults, in particular, in young infants, more aggressive treatment is recommended for children than adults.[145] In developed countries where HAART is available, doctors assess their patients thoroughly: measuring the viral load, how fast CD4 declines, and patient readiness. They then decide when to recommend starting treatment.[146] HAART neither cures the patient nor uniformly removes all symptoms; high levels of HIV-1, often HAART-resistant, return if treatment is stopped.[147][148] Moreover, it would take more than a lifetime for HIV infection to be cleared using HAART.[149] Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to a large reduction in HIV-associated morbidity and mortality in the developed world.[141][150][151] One study suggests the average life expectancy of an HIV infected individual is 32 years from the time of infection if treatment is started when the CD4 count is 350/L.[152] Life expectancy is further enhanced if antiretroviral therapy is initiated before the CD4 count falls below 500/L.[31] In the absence of HAART, progression from HIV infection to AIDS has been observed to occur at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months.[16] However, HAART sometimes achieves far less than optimal results, in some circumstances being effective in less than fifty percent of patients.[citation needed] This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. However, non-adherence and non-

persistence with antiretroviral therapy is the major reason most individuals fail to benefit from HAART.[153] The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues along with side effects that create intentional non-adherence also contribute to this problem.[154][155][156] The side effects include lipodystrophy, dyslipidemia, insulin resistance, an increase in cardiovascular risks, and birth defects.[157][158] Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.[159] Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. Unfortunately, only a vaccine is thought to be able to halt the pandemic. This is because a vaccine would cost less, thus being affordable for developing countries, and would not require daily treatment.[159] However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.[159]
HIV latent reservoir

Despite the success of highly active antiretroviral therapy (HAART) in controlling HIV infection and reducing HIV-associated mortality, current drug regimens are unable to completely eradicate HIV infection. Many people on HAART achieve suppression of HIV to levels below the limit of detection of standard clinical assays for many years. However, upon withdrawal of HAART, HIV viral loads rebound quickly with a concomitant decline in CD4+ T-Cells, which, in most cases, without a resumption of treatment, leads to AIDS. To successfully reproduce itself, HIV must convert its RNA genome to DNA, which is then imported into the host cell's nucleus and inserted into the host genome through the action of HIV integrase. Because HIV's primary cellular target, CD4+ T-Cells, function as the memory cells of the immune system, integrated HIV can remain dormant for the duration of these cells' lifetime. Memory T-Cells may survive for many years and possibly for decades. The latent HIV reservoir can be measured by co-culturing CD4+ T-Cells from infected patients with CD4+ T-Cells from uninfected donors and measuring HIV protein or RNA.[160] The failure of vaccine candidates to protect against HIV infection and progression to AIDS has led to a renewed focus on the biological mechanisms responsible for HIV latency. A limited period of therapy combining anti-retrovirals with drugs targeting the latent reservoir may one day allow for total eradication of HIV infection.[161]

Prognosis
Without treatment, the net median survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype,[162] and the median survival rate after diagnosis of

AIDS in resource-limited settings where treatment is not available ranges between 6 and 19 months, depending on the study.[163] In areas where it is widely available, the development of HAART as effective therapy for HIV infection and AIDS reduced the death rate from this disease by 80%, and raised the life expectancy for a newly diagnosed HIV-infected person to 20 50 years.[164][165] As new treatments continue to be developed and because HIV continues to evolve resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year after the individual progresses to AIDS.[16] Most patients die from opportunistic infections or malignancies associated with the progressive failure of the immune system.[12] The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility and immune function[93][166][167] health care and co-infections,[12][16] as well as which particular strain of the virus is involved.[168][169][170]

Epidemiology
Main article: AIDS pandemic

Estimated prevalence of HIV among young adults (1549) per country at the end of 2005.

Numbers of people living with, newly infected with, and killed by HIV (19902008)[171]

UNAIDS and the WHO estimated that AIDS killed more than 25 million people between 1981, when it was first recognized, and 2005, making it one of the most destructive pandemics in recorded history. Despite improved access to antiretroviral treatment and care in many regions of the world, the AIDS pandemic claimed an estimated 2.8 million (between 2.4 and 3.3 million) lives in 2005 of which more than half a million (570,000) were children.[5] UNAIDS estimated that 33.3 million people were living with HIV at the end of 2009, up from 26.2 million people in 1999. They also estimated AIDS-related deaths in 2009 at 1.8 million people, down from a peak of 2.1 million in 2004, new infections at 2.6 million, down from a peak of 3.2 million in 1997, and the number of people in low- or middle-income countries receiving antiretroviral therapy in 2009 at 5.2 million, up from 4.0 million in 2008.[6] Sub-Saharan Africa remains by far the worst-affected region, with an estimated 22.5 million people currently living with HIV (67% of the global total), 1.3 million deaths (72% of the global

total) and 1.8 million new infections (69% of the global total). However, the number of new infections declined by 19% across the region between 2001 and 2009, and by more than 25% in 22 sub-Saharan African countries during this period. Asia is the second-worst affected region, with 4.9 million people living with HIV (15% of the global total).[6] The latest evaluation report of the World Bank's Operations Evaluation Department assesses the development effectiveness of the World Bank's country-level HIV/AIDS assistance defined as policy dialogue, analytic work, and lending with the explicit objective of reducing the scope or impact of the AIDS epidemic.[172] This is the first comprehensive evaluation of the World Bank's HIV/AIDS support to countries, from the beginning of the epidemic through mid-2004. Because the Bank aims to assist in implementation of national government programmes, their experience provides important insights on how national AIDS programmes can be made more effective. The development of HAART as effective therapy for HIV infection has substantially reduced the death rate from this disease in those areas where these drugs are widely available.[141] As the life expectancy of persons with HIV has increased in countries where HAART is widely used, the continuing spread of the disease has caused the number of persons living with HIV to increase substantially. In Africa, the number of mother-to-child-transmission (MTCT) cases and the prevalence of AIDS is beginning to reverse decades of steady progress in child survival. Countries such as Uganda are attempting to curb the MTCT epidemic by offering VCT (voluntary counselling and testing), PMTCT (prevention of mother-to-child transmission) and ANC (ante-natal care) services, which include the distribution of antiretroviral therapy.

History
Origins Main article: Origin of AIDS See History of known cases and spread for early cases of HIV / AIDS

HIV is thought to have originated in non-human primates in sub-Saharan Africa and was transferred to humans late in the 19th or early in the 20th century.[173][174][175] The first paper recognizing a pattern of opportunistic infections characteristic of AIDS was published in 1981.[176] Both HIV-1 and HIV-2 are believed to have originated in West-Central Africa and to have jumped species (a process known as zoonosis) from non-human primates to humans. HIV-1 appears to have originated in southern Cameroon through the evolution of SIV(cpz), a simian immunodeficiency virus (SIV) that infects wild chimpanzees (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies Pan troglodytes troglodytes).[177][178] The closest relative of HIV-2 is SIV(smm), a virus of the sooty mangabey (Cercocebus atys atys), an Old World monkey living in litoral West Africa (from southern Senegal to western Ivory Coast.[22] New World monkeys such as the owl monkey are resistant to HIV-1 infection, possibly because of a genomic fusion of two viral resistance genes.[179] HIV-1 is thought to have jumped the species

barrier on at least three separate occasions, giving rise to the three groups of the virus, M, N, and O.[180] There is evidence that humans who participate in bushmeat activities, either as hunters or as bushmeat vendors, commonly acquire SIV.[181] However, SIV is a weak virus, it is typically suppressed by the human immune system within weeks of infection. It is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough time to mutate into HIV.[182] Furthermore, due to its relatively low person-toperson transmission rate, it can only spread throughout the population in the presence of one or more of high-risk transmission channels, which are thought to have been absent in Africa prior to the 20h century. Specific proposed high-risk transmission channels, allowing the virus to adapt to humans and spread throughout the society, depend on the proposed timing of the animal-to-human crossing. Genetic studies of the virus suggest that the most recent common ancestor of the HIV-1 M group dates back to circa 1910.[183] Proponents of this dating link the HIV epidemic with the emergence of colonialism and growth of large colonial African cities, leading to social changes, including a higher degree of sexual promiscuity, the spread of prostitution, and the concomitant high frequency of genital ulcer diseases (such as syphilis) in nascent colonial cities.[184] There is evidence that transmission rates of HIV during vaginal intercourse, while quite low under regular circumstances, may be increased tens, if not hundreds of times, if one of the partners suffers from a STD resulting in genital ulcers. Early 1900's colonial cities were notable due to their high prevalence of prostitution and genital ulcer STD's, to the degree that, as of 1928, as many as 45% of female residents of eastern Kinshasa were thought to have been prostitutes, and, as of 1933, around 15% of all residents of the same city were infected by one of the forms of syphilis.[184] An alternative view holds that unsafe medical practices in Africa during years following World War II, such as unsterile reuse of single use syringes during mass vaccination, antibiotic and anti-malaria treatment campaigns, were the initial vector that allowed the virus to adapt to humans and spread.[182][185][186] The earliest well documented case of HIV in a human dates back to 1959.[187] The virus may have been present in the United States as early as 1966,[188] but the vast majority of infections occurring outside sub-Saharan Africa (including the U.S.) can be traced back to a single unknown individual who got infected with HIV in Haiti and then brought the infection to the United States some time around 1969.[189] The epidemic then rapidly spread among high-risk groups (initially, sexually promiscuous gay men). By 1978, the prevalence of HIV-1 among gay male residents of New York and San Francisco was estimated at 5%, suggesting that several thousand individuals in the country had been infected by then.[189]
Discovery

AIDS was first clinically observed between late 1980 and early 1981.[190] Injection drug users and gay men with no known cause of impaired immunity showed symptoms of Pneumocystis carinii pneumonia (PCP), a rare opportunistic infection that was known to present itself in people with very compromised immune systems.[191][192][193] Soon thereafter, additional gay men

developed a previously-rare skin cancer called Kaposis sarcoma (KS).[194][195] Many more cases of PCP and KS quickly emerged, alerting U.S. Centers for Disease Control and Prevention (CDC). A CDC task force was formed to monitor the outbreak. After recognizing a pattern of anomalous symptoms presenting themselves in patients, the task force named the condition acquired immune deficiency syndrome (AIDS).[196] In 1983, two separate research groups led by Robert Gallo and Luc Montagnier independently declared that a novel retrovirus may have been infecting AIDS patients, and published their findings in the same issue of the journal Science.[197][198] Gallo claimed that a virus his group had isolated from an AIDS patient was strikingly similar in shape to other human T-lymphotropic viruses (HTLVs) his group had been the first to isolate. Gallo's group called their newly isolated virus HTLV-III. At the same time, Montagnier's group isolated a virus from a patient presenting lymphadenopathy (swelling of the lymph nodes) of the neck and physical weakness, two classic symptoms of AIDS. Contradicting the report from Gallo's group, Montagnier and his colleagues showed that core proteins of this virus were immunologically different from those of HTLV-I. Montagnier's group named their isolated virus lymphadenopathy-associated virus (LAV).[196] HIV was chosen as a compromise between the two claims (LAV and HTLV-III). Whether Gallo or Montagnier deserve more credit for the discovery of the virus that causes AIDS has been a matter of considerable controversy. Together with his colleague Franoise Barr-Sinoussi, Montagnier was awarded one half of the 2008 Nobel Prize in Physiology or Medicine for his "discovery of human immunodeficiency virus".[199] Harald zur Hausen also shared the Prize for his discovery that human papilloma virus leads to cervical cancer, but Gallo was left out.[200] Gallo said that it was "a disappointment" that he was not named a corecipient.[201] Montagnier said he was "surprised" Gallo was not recognized by the Nobel Committee: "It was important to prove that HIV was the cause of AIDS, and Gallo had a very important role in that. I'm very sorry for Robert Gallo."[200]

AIDS denialism
Main article: AIDS denialism

A small group of individuals continue to dispute the connection between HIV and AIDS,[202] the existence of HIV itself, or the validity of HIV testing and treatment methods.[203][204] These claims, known as AIDS denialism, have been examined and rejected by the scientific community.[205] However, they have had a significant political impact, particularly in South Africa, where the government's official embrace of AIDS denialism was responsible for its ineffective response to that country's AIDS epidemic, and has been blamed for hundreds of thousands of avoidable deaths and HIV infections.[206][207][208]