Page 573 - Clinical Immunology_ Principles and Practice ( PDFDrive )

550 ParT fOur Immunological Deficiencies

Anti-HIV Cellular Immunity INNATE IMMUNITY
In individuals with HIV infection, the initial control of viremia Innate immunity mechanisms are characterized by their lack of
occurs with the initial expansion of HIV-specific CD8 T cells. antigen specificity and include epithelial barriers, the complement
The importance of anti-HIV cytotoxic T cells is suggested by system, phagocytes, and antigen-presenting cells (APCs). Their
the development of viral escape mutations that are driven by role in HIV pathogenesis is complex, as their function is of
immune selection pressure and evade the immunological response. most importance during acute infection but their contribution
In addition to their cytotoxicity, CD8 T cells secrete chemokines, to immune activation may be deleterious in the chronic stage.
such as RANTES and MIP-1β, which inhibit viral entry via CCR5, Studies including individuals who were exposed to HIV but did
and IFN-γ, which activates immune cells and increases HLA not develop infection have suggested that an increased innate
expression (Chapter 10). Although severely reduced in number, immune response generated in the mucosal microenvironment
IFN-γ–secreting HIV-specific CD4 T cells are present in individu- may explain the failure to develop a specific anti-HIV response. 17
als with HIV infection. The role of adaptive cellular immunity
in protection against natural infection is currently challenged, NK Cells in HIV Infection
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since about 40–60% of noninfected but exposed individuals do NK cells are dramatically altered in HIV infection. A small subset
not present with detectable anti-HIV responses. of NK cells has been found to express both CD4 and CCR5 or
CXCR4. These NK cells can be infected by HIV and may serve
Mechanisms of T-Cell Depletion as one of the sites of latent infection or can be activated and
Three major mechanisms of T-cell depletion have been reported: contribute to the state of immune chronic activation. CCR5 and
direct lytic infection, apoptosis, and autophagy. Direct lytic inhibitory receptor expression are higher on NK cells in patients
infection is the result of massive activation of the immune system with HIV infection than in HIV-seronegative subjects. In contrast,
with production of inflammatory cytokines, as in the GALT (see there is reduced expression of surface receptors on NK cells that
Cytokines in HIV infection). induce cytotoxic activity, such as NK-cell protein 30 (NKp30),
NKp44, and NKp46. Antibody-dependent cellular cytotoxicity
Apoptosis (ADCC) is reduced in patients with HIV infection, as well as the
Increased apoptosis of T cells in HIV infection was described NK-cell responsiveness to IL-2. The expression of HLA-C–specific
early in the history of the epidemic. Several explanations have inhibitory NK-cell receptors has been found to be increased in
been offered: (i) HIV-induced apoptosis of infected cells (viral patients with HIV. Interestingly, studies of Vietnamese patients
cytopathic effect); (ii) bystander effect from HIV-infected neighbor who were exposed to HIV through IDU but were seronegative
cells releasing viral proteins; (iii) death of HIV-specific effectors showed that the NK cells of these patients not only secreted greater
following their migration to infected sites; (iv) perturbation of quantities of chemokines compared with those of the controls
proapoptotic signaling molecules on immune cells secondary but they also had greater direct cytotoxicity. Genetic studies have
to the chronic immune activation; and (v) destruction of HIV- suggested that inheritance of particular killer inhibitor receptor
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infected cells by immune effectors. (KIR) alleles with their HLA ligands delays disease progression.
Late HIV infection is associated with the dominance of a The two subsets of DCs, myeloid and plasmacytoid, play an
syncytia-inducing form of the virus. Syncytia formation (cluster- additional role in HIV infection by stimulating innate immune
ing of CD4 T cells and membrane fusion) occurs through the responses, such as the type 1 IFNs, against HIV via plasmacytoid
interaction of HIV Env and CD4/CXCR4 on neighboring cells. DCs. DCs may have opposing roles, with myeloid DCs acting as
These cells are more prone to undergoing apoptosis through a reservoirs and favoring HIV dissemination and plasmacytoid DCs
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Fas-dependent pathway. Most of the HIV proteins have been inhibiting HIV replication by cytokine secretion. In fact, low levels
implicated at one time or another in HIV-induced apoptosis. of plasmacytoid DCs correlate with high viral loads, low CD4
T-cell counts, opportunistic infections, and disease progression.
Autophagy
Autophagy is a process by which cytoplasm and organelles Cytokines in HIV Infection
are sequestered and directed toward lysosomal pathways and The dysregulation of the immune system produced by HIV infection
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histone deacetylase. This process has been implicated in both includes significant perturbation in the balance of Th1 and Th2
the prevention and induction of apoptosis, reflecting common cytokine levels. The Th1 cytokines IL-2, TNF-α, IFN-γ, and IL-12
regulatory factors shared by both (e.g., tumor necrosis factor decrease during HIV infection, whereas the Th2 cytokines, IL-10,
[TNF]–related apoptosis inducing ligand [TRAIL], FADD, DAPk, and IL-4 increase or remain normal; levels of proinflammatory
ceramide, and Bcl-2). HIV Env has been shown to be a stimulus cytokines, such as IL-1, IL-6, and IL-8, also increase. Viral replication
for autophagy in uninfected CD4 T cells via its interaction with in HIV-infected T cells and monocytes is induced by IL-2, IL-7,
CXCR4. Inhibition of the autophagic pathway prevents Env- and IL-15, as well as by the proinflammatory cytokines. These
induced cell death in uninfected cells in vitro, demonstrating cytokines appear to induce viral replication by activating the host
that this mechanism contributes to the loss of uninfected cells. cell, a requirement for HIV productive replication. Some cytokines,
such as IL-10, decrease HIV production, likely by inhibiting the
Anti-HIV Humoral Immunity synthesis of the activating cytokines and by decreasing the expres-
After establishment of HIV infection, neutralizing antibodies sion of CCR5 and other chemokine receptors. In addition, the HIV
are produced; however, the virus quickly mutates to avoid them, long terminal repeat (LTR) promoter contains sequences that bind
such that the host continues to respond to evolving viral mutants. cellular factors that are activated as a response to cytokine binding,
The fact that antibodies can be effective in protecting hosts from such as nuclear factor (NF)-κB and AP1. IFN-α and IFN-β have
HIV infection has been demonstrated in macaques and in a activity against HIV, although their role of these cytokines in vivo is
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humanized mouse model of HIV infection. not well established and may have only an adjuvant effect. Their