Immunity to Viruses

Wasista Hanung Pujangga

Pendahuluan
• Viruses are obligatory intracellular microorganisms
• infect various cell types by receptor-mediated endocytosis after binding to
normal cell surface molecules.
• use components of the nucleic acid and protein synthetic machinery of the
host to replicate.
• Viral replication leads to injury and ultimately death of the infected
cell (the infected cell is lysed) This result is one type of cytopathic
effect of viruses.
• Viruses can stimulate inflammatory responses that cause damage to
tissues
• Innate and adaptive immune responses to viruses are aimed at
blocking infection and eliminating infected cells
Innate Immunity to Viruses
• The principal mechanisms of innate immunity against viruses are
inhibition of infection by type I interferons and NK cell mediated
killing of infected cells.
• Infection by many viruses is associated with production of type I interferons
(IFNs) by infected cells, and by dendritic cells, especially of the plasmacytoid
type, responding to viral products.
• NK cells kill virus-infected cells and are an important mechanism of immunity
against viruses early in the course of infection, before adaptive immune
responses have developed.
• Protection against viruses  activation of intrinsic apoptotic death
pathways in infected cells and enhance sensitivity to extrinsic
inducers of apoptosis.
 Type I Interferon

• Type I interferons increase the

cytotoxicity of NK cells and CD8+
CTLs and promote the
differentiation of naive T cells to
the Th1 subset of helper T cells.
• Type I interferons upregulate
expression of class I MHC
molecules and thereby increase
the probability that virally infected
cells will be recognized and killed
by CD8+ CTLs.
 NK cells
• Class I MHC expression is often
shut off in virus-infected cells as
an escape mechanism from CTLs

B, Activating receptors of NK cells recognize ligands on target cells and activate protein tyrosine
kinases (PTKs), whose activities are inhibited by inhibitory receptors that recognize class I MHC
molecules and activate protein tyrosine phosphatases (PTP). NK cells do not efficiently kill class I
MHC– expressing healthy cells.
C, If a virus infection or other stress inhibits class I MHC expression on infected cells and induces
expression of additional activating ligands, the NK cell inhibitory receptor is not engaged and the
activating receptor is unopposed to trigger responses of NK cells, including killing of target cells and
cytokine secretion.
Structure and ligands of activating and inhibitory receptors of NK cells.

• CD16 and the NCRs associate with ζ

chain homodimers, FcεRIγ
homodimers, or ζ-FcεRIγ
heterodimers.
• There are multiple different KIRs, with
different ligand specificities.
• KIR, killer cell immunoglobulin (Ig) like
receptors; MIC, MHC class I
polypeptide-related sequence; NCR,
natural cytotoxicity receptor. ULBP,
UL-16 binding protein.

Abbas AK, et al. Cellular and Molecular Immunology, 9ed. 2018

Adaptive Immunity to Viruses
• Adaptive immunity against viral infections is mediated by
antibodies, which block virus binding and entry into host cells, and
by CTLs, which eliminate the infection by killing infected cells
• In latent infections, viral DNA persists in host cells, but the virus
does not replicate or kill infected cells.
Antibodies
• Antibodies are effective against viruses only during the extracellular stage of
the lives of these microbes.
• Antiviral antibodies bind to viral envelope or capsid antigens and function
mainly as neutralizing antibodies to prevent virus attachment and entry into
host cells
• Antibodies prevent both initial infection and cell-to-cell spread  but after the
viruses enter cells and begin to replicate intracellularly, they are inaccessible to
antibodies.
• Secreted antibodies, especially of the IgA isotype, are important for neutralizing
viruses within the respiratory and intestinal tracts.
• Complement activation may also participate in antibody-mediated viral
immunity, mainly by promoting phagocytosis and possibly by direct lysis of
viruses with lipid envelopes.
CTLs
• Most virus-specific CTLs are CD8+ T cells that recognize cytosolic, usually
endogenously synthesized, viral peptides presented by class I MHC
molecules.
• If the infected cell is a tissue cell and not an antigen-presenting cell (APC),
such as a dendritic cell, the infected cell may be phagocytosed by the
dendritic cell, which processes the viral antigens and presents them to naive
CD8+ T cells.
• CD8+ T cells undergo massive proliferation during viral infection, and most of
the proliferating cells are specific for a few viral peptides.
• The antiviral effects of CTLs are to
• kill infected cells
• activation of nucleases within infected cells that degrade viral genomes
• secretion of cytokines, such as IFN-γ, which activates phagocytes and may have
some antiviral activity
 Innate and Adaptive Immune Responses Against Viruses

A, Kinetics of innate and adaptive immune responses to a virus infection.

B, Mechanisms by which innate and adaptive immunity prevent and eradicate virus infections. Innate immunity is
mediated by type I IFN, which prevent infection, and NK cells, which eliminate infected cells. Adaptive immunity is
mediated by antibodies and CTLs, which block infection and kill infected cells, respectively.

Abbas AK, et al. Cellular and Molecular Immunology, 9ed. 2018; p.362-6
Latent infections
• Latency is often a state of balance between infection and the immune
response.
• CTLs generated in response to the virus can control the infection but are
unable to eradicate it  As a result, the virus persists in infected cells.
• Such latent infections are common with Epstein-Barr virus and several other
DNA viruses of the herpesvirus family.
• Reactivation of the infection is associated with expression of viral genes that
are responsible for cytopathic effects and for spread of the virus. These
cytopathic effects may include lysis of infected cells or uncontrolled
proliferation of the cells
• Any deficiency in the host immune response can result in failure to control
reactivated latent infection.
 Immune Evasion by Viruses

• Viruses can alter their antigens and are thus no

longer targets of immune responses.
• The principal mechanisms of antigenic variation
are point mutations and reassortment of RNA
genomes (in RNA viruses), leading to antigenic
drift and antigenic shift.
• Viral genomes undergo mutations in the genes that
encode these surface proteins, and the variation
that occurs as a result is called antigenic drift.
• Reassortment of viral genes results in major changes
in antigenic structure called antigenic shift, which
creates distinct viruses such as the avian flu or the
swine flu viruses.
• Some viruses inhibit class I MHC–associated presentation of cytosolic protein
antigens.
• Inhibition of antigen presentation blocks the assembly and expression of stable class I
MHC molecules and the display of viral peptides  viruses cannot be recognized or
killed by CD8+ CTLs.
• Some viruses produce molecules that inhibit the immune response.
• Epstein-Barr virus produces a protein that is homologous to the cytokine IL-10, which
inhibits activation of macrophages and dendritic cells and may thus suppress cell-
mediated immunity.
• Some chronic viral infections are associated with failure of CTL responses,
called exhaustion
• The type of immune deficit may result from persistent antigen stimulation leading to
upregulation of T cell inhibitory receptors, such as PD-1 (programmed death 1) HIV
or Hepatitis virus infection
• Viruses may infect and either kill or inactivate immunocompetent cells.
• The obvious example is HIV, which survives by infecting and eliminating CD4+ T cells,
the key inducers of immune responses to protein antigens.
 Poliovirus
• After fecal-oral transmission, the major site of replication is the intestinal tract
(epithelia and Peyer’s patches).
• After a mean incubation time of 7 d, influenza-like symptoms develop, from
which the patient recovers within a few days.
• Fecal excretion of PV occurs shortly after infection and persists for
approximately 7 wk, and a short viremic phase appears between 3 to 7 d after
infection.
• Besides this abortive poliomyelitis, nonparalytic poliomyelitis may occur in 1%-
2% of the infections with viral invasion of the CNS leading to meningitis and
muscle spasm.
• The illness lasts for approximately 6 d. In up to 2% of the cases paralytic
poliomyelitis occurs, and in 80% of these patients residual paralysis persists.
• The host fights virus infections by employing various mechanisms, including
cytokine release, antibody production and cytotoxic T cell (CTL) activation.
Dotzauer A and Kraemer L. Innate and adaptive immune responses against picornaviruses and their counteractions: An overview. World J Virol 2012 June 12; 1(3): 91-107
 Innate Immunity
• The innate immune system responds within minutes after viral entry
into host cells, is able to block viral replication to a certain degree.
• Sensing of specific structures of the viral nucleic acid like double-
stranded RNAs (which occur as replicative intermediates and are
recognized as pathogen associated molecular patterns) is accomplished
in the cytoplasm by Toll-like receptor (TLR)3, which is associated with
intracellular vesicles, or by the sensors retinoic acid-inducible gene I
(RIG-I) and melanoma differentiation-associated gene 5 (MDA-5)
resulting in synthesis of cytokines with strong antiviral activity, like type
interferon (IFN).
• After primary infection, antibodies seem to be important to control viral
viremic spread to distant organs, and to retard the severity of the
disease.

Dotzauer A and Kraemer L. Innate and adaptive immune responses against picornaviruses and their counteractions: An overview. World J Virol 2012 June 12; 1(3): 91-107
 Adaptive immunity
Antibodies
• Neutralizing anti-PV IgM antibodies appear 3 d after infection, reach their peak
titer after 9 d and disappear in the course of 4 wk.
• The anti-PV IgG response is also briskly appearing 3-4 d after exposure. These
antibodies reach the peak titer 3-4 wk after infection and persist for years, perhaps
lifelong. The antibodies seem to be responsible for controlling viremia, as the
termination of viremia immediately follows the detection of neutralizing
antibodies.
• Low levels of circulating anti-PV antibody, including passively given immune
globulin, are able to prevent the paralytic disease.
• Virus excretion continues for about 1 mo  it is not clear why shedding is going on
for so long, the termination of shedding and final viral clearance seem also to be
mediated by antibodies because hypogammaglobulinemia may result in
persistent excretion for years but T-cell deficiency does not result in persistent
viral excretion.
Dotzauer A and Kraemer L. Innate and adaptive immune responses against picornaviruses and their counteractions: An overview. World J Virol 2012 June 12; 1(3): 91-107
 T-cells
• In contrast to the neutralizing antibody response to PV, much less is known about
the adaptive T-cell responses and their probable role in PV infections.
• PV-specific CD4+ T cells are induced in vaccinated individuals, and epitopes have
been identified.
• The induction may occur by dendritic cells and macrophages infected with PV.
• This also shows that HLA class Ⅱ presentation remains intact in infected antigen
presenting cells.
• The resultant CD4+ T cells were also able to produce IFN-γ and lyse infected target
cells  The cytolytic ability together with the ability to secrete IFN-γ allows the
assumption that PV-specific CD4+ T cells may play a role in virus clearance.
• Furthermore, stimulation of PV-specific cytotoxic CD8+ T-cell (CTL) responses by
infected macrophages could be demonstrated, and these CTLs secreted IFN-γ 
This implies that virus clearance is not only due to the CD4+ T-cell/antibody
response, but that the CTL response might also play a role.
Dotzauer A and Kraemer L. Innate and adaptive immune responses against picornaviruses and their counteractions: An overview. World J Virol 2012 June 12; 1(3): 91-107
 Time courses of viral excretion, viremia and of the antibody
responses after infection with poliovirus

SIgA: Secretory IgA; sIgA: Serum IgA.

Dotzauer A and Kraemer L. Innate and adaptive immune responses against picornaviruses and their counteractions: An overview. World J Virol 2012 June 12; 1(3): 91-107