Introduction
Viruses and their hosts have coevolved for millions
of years. During this coevolution, the hosts have equipped themselves with an
elaborate immune system to defend themselves from the invading viruses and
other pathogens. The viruses, on their part, have developed many strategies to
evade host’s antiviral immune responses. These strategies, which have allowed
viruses to replicate and persist successfully in the host, will be discussed in
this article. We will begin this discussion with a brief overview of the
antiviral immune responses of the host.
Viral Immune Evasion Strategies
The purpose of an elaborate system of innate and
adaptive antiviral immune mechanisms is to seek out and destroy viruses and
virus-infected host cells. Viruses have developed various strategies to subvert
host’s antiviral responses to ensure their own replication and survival. In
recent years, a lot of new information has become available about the biology
of many different viruses.
Immune evasion through latency
The state of a reversible, nonproductive viral
infection in the host cells is called latency. Viruses may evade immune
responses of the host by becoming “latent” and invisible to the immune system.
During latency, viruses may infect nonpermissive or semipermissive cells of the
host and express only a minimum number of viral genes, which are just necessary
to maintain the virus in the cells. The ubiquitous human pathogen EBV
represents a classic example of viral latency. The virus only expresses one
protein EBNA-1 and two nonpolyadenylated, short RNA molecules (EBV-encoded
small RNA or EBER-1 and -2) in certain latently infected host cells. The virus
becomes active and replicates only when the cell becomes activated. The newly
produced virions then infect another lot of host cells. Some viruses may
persist in immuneprivileged tissues of the host, e.g., brain, retina, and
kidney. For example, HSV-1 infects and replicates in epithelial cells but persists
as latent infection with little gene expression in sensory neurons of
Trigeminal ganglia, which do not express MHC antigens. The virus expresses only
one gene, the latency-associated transcript gene, which inhibits viral
replication. Upon proper stimuli, such as immunosuppression, trauma, or
exposure to sun or ultraviolet radiation, the virus may activate itself and
descend down axons of the neurons and infect epithelial cells. Similarly,
Herpes zoster virus becomes latent in dorsal root ganglions of the spinal cord.
Another herpesvirus, HCMV, persists for long periods of time in kidney, retina,
and bone marrow. HIV-1 is known to persist as a latent transcriptionally
inactive provirus in the host cell’s genome in long-lived, resting CD4_ memory
T cells. These cells may lack virus-needed transcription factors. The virus may
also persist in the brain, which is protected by blood brain barrier from
infiltration of lymphocytes. These cells and tissues serve as reservoirs of the
virus, which are resistant to chemotherapy and represent a real challenge for a
complete elimination of the virus from the infected host.
Targeting immune cells
Many viruses have developed the strategy of
infecting immune cells, which play a key role in orchestrating antiviral immune
responses. For example, HIV-1 infects CD4+ T cells. The depletion of these
cells is a hallmark of HIV-induced AIDS. It has been shown that HIV-specific
CD4+ T cells are more susceptible to HIV infection than HCMV-specific CD4+ T cells,
as the former cells preferentially migrate to the sites of HIV infection. CD4+
T cells play an important role in the generation of virus-specific CTL and
antibodies. The lack of help from CD4+ T cells is probably one of the reasons
for incomplete differentiation of HIV-specific CTL in HIV-infected individuals.
Consequently, these CTL are compromised in their cytotoxic abilities and are
unable to clear the infection. Many viruses, e.g., the reovirus and measles virus,
infect DC and induce the expression of TRAIL and FasL on their surface. Such DC
cannot present antigens and prime T cells for the generation of virus-specific
CTL. Instead, they kill interacting T, B, and NK cells via Fas/FasL and
TRAIL/DR interactions. The virus-infected DC may in fact induce
immunosuppression instead of an antiviral immune response. The human pathogen
HSV-1 infects and induces apoptosis in immature DC by decreasing the expression
of cellular Fas-associated death domain-like IL-1-converting enzyme
(FLICE)-inhibitory proteins (cFLIP) at the mRNA level. The virus also increases
the expression of TNF-and TRAIL in these cells. These ligands induce
apoptosis in the virus-infected DC. The HIV protein Nef was shown to bind CXC
chemokine receptor 4 and induce apoptosis of CD4+ T cells. Another HIV protein
Vpr inhibits DC maturation and impairs their ability to activate virus-specific
CTL and memory T cell.
Interference with apoptosis of the
virus-infected host cells
Apoptosis or programmed cell death is a
physiological process, whereby the cell causes its own death through a
regulated and controlled process of degradation of its protein and DNA contents
by its own enzymes. It is a relatively silent and noninflammatory process. The
cells may undergo apoptosis through an extrinsic or intrinsic pathway. The
extrinsic pathway is activated when external factors such as TNF FasL, or TRAIL
bind to their specific receptors, so-called death receptors or DR, a family of
TNFR-related proteins expressed on the cell surface. The oligomerized DR
recruit the adapter Fasassociated death domain (FADD) via their death domains
(DD). The death effector domain (DED) of FADD interacts with the DED of
procaspase 8 or 10 (also called FLICE). This results in the proteolytic
cleavage and activation of these caspases. The intrinsic pathway is activated
upon the release of cytochrome c, direct inhibitors of apoptosis proteases
(IAP)-binding protein (DIABLO), and other proapoptotic factors from
mitochondria. The cytochrome c forms a complex, the death-inducing signaling complex
(DISC), with apoptosis protease-activating factor-1 and procaspase-9, resulting
in the activation of the latter. DIABLO binds and inhibits cellular IAP and
allows activated caspases to mediate their effects. Cells may undergo apoptosis
through this pathway when subjected to irreparable DNA damage, viral
infections, or physical and chemical insults
Conclusions
Viruses have evolved a diverse array of strategies
to evade host’s immune responses. These strategies are as diverse as the viruses
themselves. In general, each virus uses multiple strategies for immune evasion.
Large DNA viruses can afford to encode multiple proteins that target different
aspects of the immune response. Small RNA viruses mainly rely on antigenic variability
as the principal immune evasion mechanism. The down-regulation of MHC antigens
on the surface of virus infected cells is a strategy used by many diverse
viruses, suggesting the importance of virus-specific CTL in controlling the
replication of these viruses in the infected host. However, as exemplified by
HIV-1, HCV, HCMV, and MCMV, the viruses also have to develop mechanisms to
avoid being killed by NK cells. In fact, we are only beginning to understand
the immunology of these cells. As many viruses differentially down-regulate HLA
(-A and -B but not -C) molecules to simultaneously evade killing of the
virus-infected cells by CTL and NK cells, the viral epitopes presented by HLA-C
may be used for vaccine purposes. Efforts should be directed at developing reagents,
which could block the action of the viral proteins involved in the degradation
of the host MHC antigens. The viral proteins, which increase resistance of the
virusinfected cells to NK and CTL-mediated killing, may represent ideal
molecular targets for developing novel antiviral drugs. Understanding viral
immune evasion mechanisms allows us a better understanding of the host parasite
interactions and their coevolution. This knowledge may also enable us to devise
rational strategies for countering these evasion mechanisms.
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