IMMUNODEFICIENCIES

ACQUIRED DEFICIENCIES
 Acquired Immunodeficiencies

Cause Mechanism

HIV Infection Decreased number of CD4+ T cells

Influenza virus infection Transient lymphocyte downregulation

Denutrition (low calories/proteins) Metabolic alterations can inhibit maturation

Malnutrition (low micronutrients) and functions of lymphocytes

Radio- and chemio-therapy for cancer Decreased number of BM precursors

treatment

Metastases and leukemias involving BM Reduction of the tissue where lymphocyte

development occurs

Pharmacological immunosuppression for Reduced lymphocyte activation

allografts or autoimmune diseases

Asplenia for sickle cell disease, or splenectomy Reduced phagocytosis of bacteria in

bloodstream
AIDS- Acquired Immunodeficiency Syndrome
• beginning of XX century: the virus likely passed from apes to man.
• 1981- first cases reported in US (S. FRANCISCO, LOS ANGELES) among gay
communities and persons receiving blood transfusions. Atypical pneumonia
(sustained by pneumocystis jirovecii), diffused candidiasis, B cell lymphomas and
rare tumors (Kaposi’s sarcoma) triggered by oncogenic viruses.
• 1983- Discovery of HIV by Luc Montagnier (Pasteur Institute) – Nobel Prize in
Medicine (2008)
• two main strains of HIV have been detected:
• HIV-1: more virulent, worldwide diffused, originating from Common chimpanzee
• HIV-2: less virulent, diffused in West Africa, orignating from Sooty mangabey (monkey)
 Global HIV & AIDS statistics — 2019 fact sheet UN-AIDS
In 2018 (the latest data available)...

• 37.9 million [32.7 million–44.0 million] people globally were living with HIV.

• 23.3 million [20.5 million–24.3 million] people were accessing antiretroviral

therapy.

• 1.7 million [1.4 million–2.3 million] people became newly infected with HIV.

• 770 000 [570 000–1.1 million] people died from AIDS-related illnesses.

• 74.9 million [58.3 million–98.1 million] people have become infected with HIV
since the start of the epidemic.

• 32.0 million [23.6 million–43.8 million] people have died from AIDS-related
illnesses since the start of the epidemic.
HIV: a retrovirus, of the genus
LENTIVIRUS

Two copies of the genome (RNA)

Proteic capsid (p24 protein)
External envelope (lipid bilayer
deriving from the infected cell)
17 trimeric clover-like receptors
(gp41-gp120) through which the
virus binds to the target cell
Molecular cell target: CD4, CCR5,
CXCR4
 HIV genome (9749 bp, 9 genes, partially overlapping)

LTR
Long Terminal Repeat

Structural genes:
Group Specific Antigen (gag)
Envelope (env)
Polymerase (pol)

Regulatory genes:
vif, vpr, tat, rev, vpu, nef
VIRUS ENTRY
 HIV life cycle

Vpr Pol-integrase

RNApol
Crm1

LTR contain TATA boxes, which are Transcription Starting Site able to bind NFkB and SP1- Replication rate:
109/1010 per day; transcription is error-prone: 3/105 nucleotides: high mutational rate
HIV particle budding from a CD4 Th. This is a lytic cycle leading to
cell death. Estimated destruction of 1-2 109 Th/day
 HIV can have different tropism

• R5 (Mø-tropic): the targeted co-receptor is CCR5

(CCL3, CCL4, CCL5) Mø and other cell types can be
infected (including epithelial mucosa of rectum and
vagina)  first stages of infection
• X4 (T-tropic): the targeted co-receptor is CXCR4
(CCL12)  late stages of infection. It kills T cells.
• R5X4 (double tropism)
Target cells
Th cells/activated (CD4; CXCR4; CCR5 – memory)
Monocytes/Mø (CD4; CCR5)
Microglial cells (CD4)
Dendritic cells (DC_SIGN, CCR5, CD4dim)
Transmission routes: sexual,
parenteral (blood exchange), vertical
(mother-son).

FASE ACUTA INIZIALE

(T della memoria con
CCR5)
SEGUITA DA UNA
FASE CRONICA

DC: C_type lectin

receptors
 ACUTE PHASE: viremia and marked decrease of CD4 T cells (mediated by CD8),
seroconversion. Flu-like symptoms (fever, headache, sore throat with pharyngitis,
lymphoadenopathy, cutaneous rash)
 LATENCY PHASE: persistent viral replication and progressive decrease of CD4 T cells. In some
patients there is a strong proliferative response of CD4 (long term progressors) associated to the
anti-retroviral therapy
 SYMPTOMATIC PHASE: chronic diarrhea, severe bacterial infections
 OPEN DISEASE PHASE (AIDS): atypical pneumonia, brain toxoplasmosis; candidiasis of
bronchi, lungs and esophagus, cancer like Kaposi’s sarcoma; HIV wasting syndrome.
 The Responses of the Immune system to HIV Infection

 Decrease in total CD4 T cells

 Non-infected T cells can fuse with infected ones through gp120 and gp40 (induction of apoptosis).
 Activation of inflammasome - pyroptosis. Activated T cells are prone to cell death also via caspase
activation by the inflammasome – Increased inflammatory state.
 CD8 T cells increase and are responsible for the direct cytotoxicity of infected or opsinized T CD4+
 Ab against viral Ag are produced (seroconversion), but usually they are not effective (high
mutation rate of viral Ag, native structure hidden by other proteins/glycans). B cells have a
decreased function due to the block of B-T cooperation.
 Treg increase, even though their contribution to the immunodeficiency is not known
Some persons convert to disease much later

- 1% of infected people do not convert to overt disease for

at least 10-15 years. They are indicated as Long term non
progressors
They can be subdivided into:
• Controllers: (7% of infected persons) with low viremia
(<2,000 copies/ml)
 these persons have genetic variants of CCR5 (variant
with gene deleted in homozygosis), HLA-B (B*27 and
B*57, and KIR receptors.

• Elite controllers (1:300 infected persons) <50

copies/ml. They produce neutralizing Ab.
 ANTIRETROVIRAL THERAPY:

fusion
inhibitors (T-
20 or
Enfuvirtide)

Antiviral drugs:
1. NUCLEOSIDIC ANALOGUES (e.g. AZT, no longer used); analogues of
deossicitidine and deossiadenosine): they inhibit viral Retrotranscriptase;
2. NON-NUCLEOSIDIC ANALOGUES (same action: they block RT);
3. PROTEASE INHIBITORS;
4. INTEGRASE INHIBITORS.
Today a combination of these drugs is used to overcome the rapid acquisition of drug
resistance by the virus: HAART- Highly Active anti-retroviral therapy
Elite Controllers develop
NEUTRALIZING ABS towards a
wide spectrum of conserved epitopes
Conserved regions V1 and
V2 of gp120
glycans of gp120 binding site to CD4

gp41
Toward Engineering HIV-1-Specific Neutralizing
Monoclonal Antibodies
Anti-HIV VACCINES – issues:
• Many HIV variants
• Ideally, the vaccine should work also in infected people,
most of them have an already compromised immune
system, with presence of other infections
• The vaccine should be able to induce the production of
broad-range neutralizing Ab (anti-gp41; anti-gp120)
• Another possible strategy is the development of vaccine
using viral vectors (canary pox) to elicit a cell-mediated
response.
• 2018: a new vaccine based on different HIV Ag is in trial in
2600 women at risk of infection (south Africa)