IMMUNOPATHOGENESIS OF HUMAN IMMUNODEFICIENCY SYNDROME(HIV) INFECTION[contd]

Dendritic Cells

Characterized by large, dendritic cytoplasmic extensions, dendritic cells normally engage in efficient presentation of antigens to T and B lymphocytes in lymph nodes. Epidermal dendritic cells (Langerhans cells), characterized by expression of CD1a and Birbeck granules, may be among the first cells to encounter HIV at mucosal surfaces and, in the course of transporting antigens encountered at epidermal sites, have the capability of transporting HIV to lymphoid tissue. Two populations of dendritic cells can be identified in blood: myeloid dendritic cells (characterized by expression of CD11c) and plasmacytoid dendritic cells (CD123+). Circulating numbers of these cells tend to be diminished in HIV infection.(83-86) Recent studies suggest that there are decreases in both number and function of circulating dendritic cells in HIV-infected persons and that the decreases are not normalized with suppression of HIV replication.(87) The ability of these cells to mature remains incompletely determined. Studies of these cells are hampered by their relative scarcity, as they generally account for <1% of circulating mononuclear cells. The plasmacytoid dendritic cell is a major producer of interferon-alfa and a small but growing body of literature suggests that preservation of these cells in advanced HIV infection is associated with fewer severe opportunistic complications.(88,89)

The follicular dendritic cell found in lymphoid tissue is also a key antigen-presenting cell that traps and maintains intact antigens on its cell surface. In untreated HIV infection, the surface of this cell is often loaded with virus and viral antigen. In the lymph node follicles, this cell provides key signals for the activation of B lymphocytes. The follicular dendritic cell is related to the other dendritic cells discussed above only in terms of its dendritic morphology; the origin of this cell is not well understood.

Natural Killer Cells

Natural killer cells are large granular lymphocytes with cytolytic capabilities. Lytic activity is greatest against tumor cells and virus-infected cells that have diminished expression of major histocompatibility complex (MHC) class I antigens. Because MHC class I expression is required for peptide presentation to T-cell receptors, natural killer cells comprise a cellular component of the innate host defense system with activity against cells that may escape adaptive host defenses because of failure of MHC class I expression. Lysis by natural killer cells also can be directed against cells recognized by host antibodies through binding of immunoglobulin to fragment constant receptors on the natural killer cell. Thus, natural killer cells contribute to both innate and adaptive immune host defenses. Early studies have demonstrated impairments in natural killer cell activity in persons with AIDS and HIV infection,(90,91) and functional impairments of these cells have been attributed to a failure of the postbinding lytic event.(92) Some of this impairment is correctible in vitro after overnight cultivation in medium or after addition of the helper-cell-derived cytokines IL-2 or interferon-gamma,(90,93) suggesting that "exhaustion" and/or failure of CD4 cell help may underlie this defect.

Gamma-Delta T Cells

These infrequent cells (comprising between 1% and 5% of the T-lymphocyte pool) are cells that may, as do natural killer cells, play roles in both innate and adaptive immune responses. The antigen-binding sites of T-cell receptors of these lymphocytes are comprised of gamma and delta heterodimers as contrasted with the alpha and beta chains of most T lymphocytes. These T cells can recognize microbial antigens directly without processing and presentation on host human leukocyte antigen (HLA) molecules. Although the genes encoding these receptor chains also undergo rearrangement, the diversity of these receptors is more restricted than that of T cells with alpha-beta chain receptors. The cytokinetic and cytolytic functions of cytokinetic are often perturbed, whereas proliferation responses are variably affected in HIV infection.(94-96)

Immune Activation and HIV Infection

It has long been recognized that infection with HIV is characterized not only by development of profound immunodeficiency but also by sustained and dramatic immune activation.(97,98) In fact, a growing body of evidence establishes immune activation as a critical underlying mediator of immune dysfunction and immune deficiency.(99-101) This state of immune activation is manifested both by enhanced expression of phenotypic activation markers on peripheral blood T cells and B cells and by increased plasma levels of inflammatory cytokines; moreover, lymphocytes obtained from HIV-infected persons are more often found in activated phases of the cell cycle.

In HIV-infected subjects, T lymphocytes often express surface markers of immune activation such as HLA class II molecules and CD38, a membrane-bound adenosine 5'-diphosphate (ADP) ribosyl cyclase.(102,103) These markers of activation are elevated in direct proportion to the magnitude of HIV replication (104,105) and some studies have found that the extent of CD38 expression predicts ultimate HIV disease course more accurately than do plasma levels of HIV itself.(104,106) Although a simple explanation for this state of persistent immune activation would be a reflection of HIV-specific T-cell expansion, the frequency of phenotypically activated CD8+ T cells found in HIV-infected subjects is often greater than 80%,(101) substantially exceeding the proportion of cells that can be shown to recognize HIV peptides.(107)

Thus, a significant proportion of this activation may represent a response to other antigens, or may be an indirect (or bystander) effect of HIV replication. In HIV infection, T cells are also more extensively primed to enter the replication phases of the cell cycle. This propensity is evidenced by an increased frequency both of cells expressing the nuclear antigen Ki67 (101,108) and of cells exhibiting increased DNA content and 5-bromo-2'-deoxyuridine (BrdU) incorporation, a reflection of spontaneous progression to the synthesis phase of the cell cycle.(109,110)

Plasma levels of TNF-alpha, IL-1, and IL-6 are often elevated in later stages of HIV infection, and both TNF and IL-6 levels also are directly correlated with plasma HIV RNA levels.(111) Interestingly, in lymphoid tissue, the primary site of HIV replication, levels of TNF-alpha are not generally increased, although expression of IL-1, IL-2, IL-6, IL-12, and interferon-gamma may be elevated.(112)

With administration of antiretroviral therapies, these indices of immune activation tend to fall, indicating that HIV replication induces the state of high-level activation.(113-117) The plausible hypothesis that HIV-induced activation enhances the magnitude of HIV replication by increasing the numbers of cells susceptible to and supportive of productive viral replication remains unproven. In this regard, it should be noted that expression of CD38 may limit the susceptibility of cells to productive HIV replication.(118)

Animal studies support the relationship between immune activation and progressive cellular immune deficiency. A natural host of SIV, the sooty mangabey permits high-level SIV replication but manifests limited evidence of disease.(119) Strikingly, this lack of pathogenicity is accompanied by absence of the extensive immune activation and cellular proliferation that characterizes SIV infection of other primates such as the rhesus macaque, in which immune activation closely mimics the activation seen in HIV-infected humans.(120) Moreover, mangabeys seem to maintain thymic and bone marrow function and do not demonstrate so-called bystander lymphocyte apoptosis,(121) whereby uninfected cells in the vicinity of an infected cell are induced to undergo programmed cell death. Finally, in a preliminary human study, blocking immune activation by administration of the immune suppressant cyclosporine A concomitantly with initiation of combination antiretroviral therapies resulted in more sustained CD4+ T-cell restoration than had been seen with antiviral therapies alone.(122)

Immune Response to HIV

As noted above, infection with HIV is associated with a brisk immune response to HIV antigens. Although antibody levels are high, neutralizing antibody responses against HIV are not strong, and are followed in rapid sequence by the emergence of viruses resistant to the neutralizing activity of these antibodies.(25) Thus, although these antibodies possess sufficient activity to exert selection pressure, the target epitopes are in regions that can readily sustain mutational escape (123) or can be shielded by mutations altering the numerous glycosylation sites on the viral envelope.(25)

Following initial infection with HIV, the rapid emergence of cytolytic T-cell responses, largely CD8+ T-cell responses, is associated temporally with a decrease in plasma levels of HIV.(21) CD8+ T cells may help control HIV replication in several ways. First, binding of these cells to viral peptides presented by HLAs on the surface of infected cells can trigger a cytolytic response resulting in the destruction of the target cell that is producing virus. This function is largely mediated through the liberation of perforin, which generates a hole in the target cell through which granzymes can enter and destroy the cell before it can produce large numbers of progeny virions. Although most cytolytic activity against viral targets is mediated through this route, CD8+ T cells expressing Fas ligand also can bind to Fas (CD95) on the surface of target cells, thereby inducing apoptotic cell death. Finally, CD8+ T cells can liberate a number of soluble factors with antiviral activity. These include interferon-gamma, which can, via a complex cascade of receptor-mediated binding and activation, render nearby cells relatively resistant to productive viral infection. CD8+ T cells also are sources of the beta chemokines MIP-1a (macrophage inflammatory protein-1 alpha), MIP-1b (macrophage inflammatory protein-1 beta), and RANTES (regulated on activation, normal T expressed and secreted), which bind to CCR5 and, by promoting internalization of this critical HIV coreceptor, decrease the ability of HIV to gain entry into otherwise susceptible cells.(124) A number of other antiviral factors also can be expressed by CD8+ T cells and these may include an incompletely described "cell antiviral factor" (CAF) (125) that blocks HIV replication largely via inhibition of viral transcriptional activation.(126) The precise definition of CAF is not available although CAF activity does appear to be distinguishable from chemokine-mediated (127,128) or defensin-mediated (129) suppression of HIV. CD8-mediated suppression of HIV may be related to disease outcome since this cellular response is augmented by supernatants prepared from cells from long-term nonprogressors (persons with stable CD4 cell counts and sustained low levels of HIV replication in the absence of antiretroviral treatment).(130-133) It is difficult to determine whether these factors and activities actually cause a better disease outcome or whether they are merely reflections of better preservation of host defenses.

Whereas it is clear from both human and animal models that CD8+ T cells are important in control of retroviral replication, it is not entirely clear what, if any, kind of CD8+ T-cell response can confer sustained control of HIV replication. Nor is it clear whether or not the magnitude or the breadth of CD8+ T-cell target recognition reliably predicts disease course.(134,135)

Despite relatively high frequencies of HIV-specific CD8+ T cells in HIV-infected individuals,(134,136-138) sustained suppression of viral replication is rarely achieved. The emergence of viral escape mutations that render virus-infected cells undetectable by host cytotoxic T-lymphocyte assay may help to explain this observation.(139,140) Moreover, there is some evidence that HIV-specific CD8+ T cells may be dysfunctional, as indicated by reduced lytic activity,(141,142) poor proliferation function in vitro,(58) and decreased expression of key signaling molecules (143) that mediate TCR activation. Whether this is a consequence of sustained exposure to high levels of viral antigen or is related to the lack of CD4 help or direct exposure to toxic viral products and the effects of chronic inflammation remains to be determined.

Importantly, CD4+ T-cell responses to HIV antigens are dysregulated in HIV infection, to an extent that exceeds the impairment of responses to other microbial antigens.(103,144,145) Although interferon-gamma expression is readily induced in response to HIV antigens even in advanced disease,(146) CD4 T-cell proliferation is rarely detected in untreated infection except among long-term nonprogressors.(147) CD4+ T-cell proliferation responses to HIV antigens sometimes can be preserved or restored in HIV-infected persons who are treated shortly after acquisition of infection (148) and in a proportion of chronically infected persons in whom viral replication is suppressed by antiretroviral therapies.(149,150) Importantly, restoration of these responses is less common in persons who begin suppressive antiretroviral therapy with moderately advanced or advanced infection.(103,151)

Thus, CD4+ T-cell responses to HIV antigens appear to be selectively impaired during high-level viremia and may be restored when HIV replication is brought under control by therapy.(149,152) Although HIV-reactive CD4+ T cells are preferentially susceptible to HIV infection,(153) it is not likely that this phenomenon is sufficient to explain the impaired proliferation responses seen during uncontrolled HIV replication. For example, the persistence of HIV-specific interferon-gamma responses even in persons with advanced disease (146) suggests that the ability of HIV-specific CD4 cells to expand may be selectively impaired while other HIV-specific immune functions (such as interferon production) may be preserved. Conceivably, HIV-reactive cells potentially capable of proliferation are selectively targeted and destroyed, or their replication capacity is impaired in the setting of viral activity. Sustained and relatively selective infection of HIV-reactive CD4+ cells may underlie the failure to restore CD4+ T-cell proliferation responses when persons with advanced disease initiate treatment with antiretroviral therapy.

Pathogenesis of Immune Deficiency in HIV Infection

The characteristic depletion of CD4+ T lymphocytes in HIV disease appears to result from factors other than the direct cytopathic effect of HIV itself. Cellular destruction, diminished cellular production, and cellular sequestration all appear to contribute to decreases in numbers of circulating CD4+ T cells.