IN HIV-1 INFECTION

Elevated CD8⁺ T Cell Apoptosis In Vivo

An increase in the number of apoptotic CD8⁺ T cells has been observed in lymph nodes from chronically infected HIV⁺ subjects, and has been related to the state of activation of the lymph nodes¹⁴⁹ and the reduction in Bcl-2 expression.¹⁵⁰ Importantly, in one study, apoptosis was found to mostly involve uninfected T cells.¹⁵¹ These results suggest that activation of CD8⁺ T cells during HIV-1 infection predisposes the CD8⁺ T cells to an indirect apoptotic effect in vivo.

In acute SIV infection, increased apoptosis of T cells in lymphoid tissue has been observed.¹²⁵’¹⁵²’¹⁵³ In one of these studies, much greater lymphocyte apoptosis was observed very early in infection with pathogenic virus compared with infection with nonpathogenic virus strain.¹⁵² In another study, a greater ratio of apoptotic to cycling (Ki-67⁺) lymphocytes in the T cell areas of lymph nodes was observed in macaques that went on to progress rapidly, compared with a lower ratio of apoptotic cells to cycling cells in the lymph nodes of macaques that subsequently progressed more slowly.¹²⁵ Unfor­tunately, no further phenotyping of the apoptotic cells was possible.

These results suggest that early apoptosis may influence later pathogenesis, particularly if antiviral CD8⁺ T lymphocytes inappropriately die. It is important to consider that HIV-1 infection is most active in lymphoid tissues, and CD8⁺ T cells undergoing programmed cell death in these tissues will be rapidly phagocytosed¹⁵⁴ and will not return to the circulation. Therefore, investigation of CD8⁺ T cell apoptosis in lymphoid tissues may be important, even though most studies have examined the propensity of peripheral blood CD8⁺ T cells to undergo apoptosis in ex vivo culture.

Increased Rate of Spontaneous Apoptosis Ex Vivo

Several early studies described abnormal levels of apoptosis in cultures of CD4⁺ and CD8⁺ T cells from HIV-1-infected individuals in vitro.¹¹⁶’¹⁵⁵-¹⁶¹ In particular, increased spontaneous cell death was associ­ated with decreased expression of Bcl-2,¹⁶²’¹⁶³ as previously reported for spontaneous apoptosis of CD8⁺ T cells during acute EBV infection.¹⁰ Furthermore, incubation of cells with IL-2¹⁶² or IL-15¹⁶⁴’¹⁶⁵ simultaneously increased intracellular Bcl-2 levels and led to reduced spontaneous apoptosis.

The phenotype of the cells undergoing apoptosis showed that they were highly activated ex vivo.¹⁶¹’¹⁶³’¹⁶⁶ Similarly, during acute HIV-1 infection, incubation with IL-2 or IL-15 increased Bcl-2 expression and reduced spontaneous apoptosis of highly activated CD8⁺ T cells.¹⁶⁷ Further­more, in this study, decreased Bcl-2 levels were associated with decreased expression of the IL-7 receptor, and both changes were observed in Ki-67⁺ CD8⁺ T cells.¹⁶⁷ A recent study directly addressed the question of whether antigen-specific CD8⁺ T lymphocytes undergo spontaneous apoptosis ex vivo.¹⁶⁸ It was found that Bcl-2 was decreased in antigen-specific CD8⁺ T cells, which was associated with relatively increased spontaneous apoptosis—this could be inhibited by incu­bation with IL-15, which also induced an increase in intracellular Bcl-2.

Interestingly, a recent study showed an increase in the intracellular concentration of the proap- optotic molecules Bim and Bak in T cells from SIV⁺ macaques.¹⁶⁹ In previous studies, it was found that proapoptotic Bax was not significantly increased in circulating T cells from HIV-infected individuals.¹⁷⁰’¹⁷¹ The decrease in Bcl-2, combined with an increase in Bim and its association with spontaneous apoptosis,¹⁶⁹ is consistent with studies showing the nonredundant role of Bim in the decrease of effector CD8⁺ T cells after viral infection.⁴³ Disruption to mitochondrial membrane potential, where Bim and Bak have their effects,⁴⁹ was widely reported in PBMC during chronic HIV-1¹⁷²’¹⁷³ and SIV infection¹⁶⁹ and during acute HIV-1 infection.¹⁷⁴

Taken together, these results suggest that spontaneous apoptosis is primarily related to cytokine regulation of Bcl-2 family members and involves the intrinsic mitochondrial pathway, which is consistent with the cytokine control of antigen-specific effector and memory CD8⁺ T cell numbers observed in murine models.⁶² However, the observation that forced expression of Bcl-2 in trans­genic mice did not prevent apoptosis of effector CD8⁺ T cells^40,41 does not fit this hypothesis.

The continued spontaneous apoptosis after resolution of acute infection seems to reflect con­tinued activation of CD8⁺ T cells, which is characteristic of untreated HIV-1 infection but is not observed after acute EBV infection.¹²⁶ It is not clear whether the spontaneous apoptosis observed in vitro is an exact correlate of the apoptosis observed in lymph nodes, but it is clearly related to the increased activation of CD8⁺ T cells, which is, in turn, clearly associated with CD4⁺ T cell decline (see above).

Apoptosis in Nonpathogenic HIV-1 and SIV Infections and after HAART

The level of spontaneous apoptosis and mitochondrial dysfunction of CD4⁺ and CD8⁺ T cells is lower in HIV⁺ long-term nonprogressors than in subjects with rapidly progressive disease.^173,175 Similarly, spontaneous apoptosis of CD8⁺ T cells in nonpathogenic SIV infection in sooty mang­abeys or HIV-1 infection in chimpanzees is not significantly different compared with uninfected controls.¹¹⁶,¹¹⁷,¹⁵²,¹⁷⁶

Similarly, initiation of HAART leads to a reduction in the level of spontaneous apoptosis as well as CD95-induced apoptosis (see below).^177-179 These results are consistent with the observed decrease in activation of CD8⁺ T cells observed after antiretroviral therapy^86,87 and is associated with increases in Bcl-2 expression.¹⁷¹

Role of CD95/CD95L Interactions in Elevated Apoptosis of CD8⁺ T Cells

in HIV-1 Infection

Many studies have demonstrated an increased expression of CD95 on the surface of circulating CD8⁺ T cells during HIV-1 infection and have demonstrated that these cells are highly sensitive to treatment with anti-CD95 antibodies and readily undergo apoptosis, compared to cells from unin­fected controls.^180-183 However, memory CD8⁺ T cells in uninfected controls also express CD95 and, therefore, some additional change must account for the increased sensitivity during HIV-1 infection.

Several studies have suggested that, as with spontaneous apoptosis, increased sensitivity to CD95 ligation is related to decreased intracellular Bcl-2 and can be counteracted by incubation with IL-2¹⁸⁵ or IL-15.¹⁸⁶ IL-12 prevents Fas-mediated apoptosis of CD4⁺ T cells from HIV-infected persons,¹⁸¹ but IL-10 prevents Fas-mediated apoptosis of CD8⁺ T cells from HIV-infected persons and has no preventive effect on CD4 T cell death.¹⁸⁵ These observations are reminiscent of previous studies that show that IL-10 can rescue CD8⁺ T cells from apoptotic cell death.^187,188 Altogether, these results are consistent with the suggestion that the intrinsic and extrinsic pathways cooperate in terminating immune responses.⁴⁹

The signaling cascades activated by IL-2 and IL-15 differ from that used by IL-10. IL-2 and IL-15 receptors share a common γ-chain and use a common JAK3/STAT5 signaling pathway.¹⁸⁹ Moreover, the activation of STAT5 by IL-2 has been reported to be involved in T cell proliferation and activation-induced cell death (AICD), whereas the IL-2Rβ chain has been reported to be involved in the activation of the protein kinase Akt and Bcl-2 production.⁵⁵ The binding of IL-10 to its receptor complex activates the JAK1 and Tyk2 kinases and involves STAT3 and STAT1, similar to interferon receptors.^190-192

Serum levels of soluble CD95L are elevated in HIV-1 infection compared to uninfected con- trols,¹⁹³ but it is not known if this translates into increased apoptosis of CD95⁺ CD8⁺ T cells in vivo.¹⁹⁴ Soluble CD95L is less able to induce apoptosis than the membrane-bound form,¹⁹⁵ and this may simply reflect increased expression of CD95L in HIV-1 and SIV infection.^169,196 HIV- and SIV-infected cells reportedly have increased expression of CD95L,^169,197-199 and this may be impor­tant in protecting infected cells from lysis by CD95⁺ CD8⁺ CTL.

Role of TNF/TNFR Interactions and TRAIL in Apoptosis

of CD8⁺ T Lymphocytes in HIV-1 Infection

In HIV-infected individuals, it has been found that the addition of TNF-α does not enhance spontaneous cell death.¹⁸⁵ A recent report described increased apoptosis of CD8⁺ T cells from HIV⁺ subjects mediated by antibodies to TNFR1 and TNFR2.²⁰1 Decreased levels of intracellular Bcl-2 and increased levels of activated caspases were also associated with this activity.

Some reports also suggest a role for TRAIL,^202-204 although this has not been observed in all studies.²⁰⁵

The level of TNF-α in serum is characteristically increased in HIV-1 infection²⁰⁶ and is implicated in viral replication.²⁰⁷ Furthermore, decreasing CD4⁺ T cell counts are most closely correlated with plasma TNFR2 levels, which are correlated with CD8⁺ T cell activation.²⁰⁸ Therefore, TNF-α seems to play a central part in HIV-1 pathogenesis, although treatment with inhibitors of TNF-α activity did not show any effect on plasma HIV RNA,²⁰⁹ and an effect on apoptosis was not reported in this study.

Role of AICD in Apoptosis of CD8⁺ T Lymphocytes in HIV-1 Infection

The original studies of apoptosis in HIV-1 infection demonstrated increased AICD,^116,156,160 possibly resulting from upregulation of CD95L expression.⁵⁹ Whereas CD95 ligation-mediated CD8 T cell death can be prevented by pretreatment with synthetic peptide inhibitors caspases, AICD mediated by TCR stimulation was not found to be prevented by an antagonistic Fas mAb or by a pan caspase inhibitor, zVAD-fmk,^185,210 suggesting that TCR-mediated CD8 T cell death occurs through Fas- and caspase-independent pathways.

It was recently found that stimulation through the TCR leads to increased expression of proapoptotic Bim,²¹¹ which may be responsible for the ensuing apoptosis.⁴⁹ Therefore, it seems that AICD may be regulated by exogenous cytokines and the intrinsic mitochondrial pathway, consistent with a role for Bcl-2 in regulation of AICD in murine models.⁴¹

Role of HIV-1 Proteins in Elevated Apoptosis of CD8⁺ T Cells

in HIV-1 Infection

The envelope glycoprotein complex (Env) seems to be one of the dominant apoptosis-inducing molecules encoded by the HIV-1 genome. Incubation of resting PBMCs from healthy donors with HIV, even in the presence of an inhibitor of the viral replication, has been sufficient to prime both CD4⁺ and CD8⁺ T cells to die by apoptosis in response to Fas ligation.^212-214 Therefore, as most of the HIV particles produced are noninfectious, the simple fixation or penetration of viruses, without integration, may be sufficient to prime T cells for Fas-mediated apoptosis in quiescent T cells. Furthermore, virions also contain host membrane proteins with immunomodulatory activity.²¹⁵ However, it has been reported that increased Fas sensitivity of CD8⁺ T cells from HIV-infected individuals and SIV-infected macaques did not correlate with plasma viral load.¹⁶⁹,²¹⁶

HIV Env binding to CXCR4 has been reported to induce apoptosis of uninfected CD8⁺ T cells in vitro,²¹⁷ and infected macrophages have been reported to be capable of inducing CD8⁺ T cell apoptosis through a pathway involving TNF/TNFR.²¹⁸ However, the binding to a co-receptor by Env glycoproteins from clinical isolates is rarely CD4 independent.²¹⁹ Also, most HIV quasispecies, espe­cially during the early phases of infection, use CCR5 as co-receptor.¹⁰⁴,²²⁰ Therefore, a significant direct effect of Env on CD8⁺ T cells in vivo, particularly during acute infection, may not be plausible. It must be remembered, though, that a feature of activated effector CD8⁺ T cells during primary HIV-1 infection is upregulation of CCR5, and these are the cells that undergo spontaneous apoptosis in vitro.¹⁶⁷

FIGURE 14.1 Proposed model for elevated apoptosis of CD8+ T lymphocytes in HIV-1 infection. Apoptosis is regulated by the balance between the anti-apoptotic effect of γ-chain cytokines and co-stimulation of up­regulation of antiapoptotic Bcl-2 family members versus the pro-apoptotic effect of antigen-driven up-regu­lation of Bim and Myc and down-regulation of Bcl-2. Chronic antigenic stimulation also down-regulates the IL-7R and up-regulates CD95, CD95L, TNFR1, and TNF-α. Processes that increased during HIV-1 infection (HIV-1 Ag, CD95L, TNF-α, Bim, Myc, CD95, and TNFR) are shown in the upper right quadrant of the figure, whereas processes are shown in left half of the figure.

Other HIV-Related Mechanisms

Most reported effects of HIV-1 proteins on apoptosis apply to infected cells, and CD8⁺ T cells do not seem to be significantly infected in vivo,²²¹ presumably due to lack of CD4 expression. However, there may be upregulation of CD4 after activation of CD8⁺ T cells in vitro²²²; in vivo, it was shown that CD8⁺ T cells, which also express CD4, are infected early in the course of infection.²²³

Exogenous Tat reportedly increases apoptosis of bystander cells^224,225 but at relatively high concentrations.²²⁴ However, at such concentrations, Tat also was reported to have antiapoptotic effects.²²⁶ Therefore, the overall effect of Tat remains to be defined (Figure 14.1).

summary

Survival of CD8⁺ T cells under the normal conditions of homeostasis is primarily regulated by the effect of common γ-chain cytokines on expression of Bcl-2 family members, especially Bcl-2 itself. Antigenic activation in HIV-1 infection seems to upregulate Bim and decrease both IL-7R and Bcl-2, leading to a state in which CD8⁺ T cells are particularly sensitive to proapoptotic signals. A feature of chronic HIV-1 infection is an increase in plasma levels of soluble forms of CD95, CD95L, TNF- α, TNFR2, and IFN-γ, all of which may also be involved in feedback control of immune responses.

The resulting increased rate of apoptosis is directly related to increased turnover of activated, proliferating cells, which is also seen in other viral infections at acute stages but usually resolves as the virus is cleared. HIV antigen-driven chronic activation and proliferation occurs in an environment of greatly reduced CD4⁺ T cell help, as well as decreased dendritic cell numbers and function. Because longevity of memory CD8⁺ T cells is determined during the activation phase, HIV-specific CD8⁺ T cells may be programmed to contain lower amounts of antiapoptotic Bcl-2 family members and proceed rapidly toward senescence and apoptosis. Loss of effector CD8⁺ T cells with antiviral activity probably contributes significantly to disease progression.

ACKNOWLEDGMENTS

JC holds a Canada Research Chair in Medical Genomics. This research is supported by the San Diego Center for AIDS Research and the Veterans Medical Research Foundation.

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