EVIDENCE FOR AN INFLUENCE OF APOPTOSIS IN DISEASE PROGRESSION IN LENTIVIRUS INFECTION
Primate models provide important insights into the essential features of HIV immunopathogenesis. Chimpanzees infected with HIV-1 have detectable virus in blood and lymph nodes, yet the majority remain asymptomatic, with stable CD4 T lymphocyte counts, and, therefore, resemble LTNPs.41,42 In infected chimpanzees, there is a lack of chronic lymphocyte activation;43 however, longitudinal follow-up demonstrates that some chimpanzees can develop a progressive decline in CD4 T lymphocyte numbers and, subsequently, opportunistic infections.44 Coincident with the delayed disease progression, infected chimpanzees develop higher HIV viral loads and greater expression of lymphocyte activation markers such as CD38 on CD8 T lymphocytes.45 An additional feature of slow or nonprogressive primate models of retroviral infection is the absence of macrophage infection.46-48 In contrast to most cases of chimpanzee infection, pathogenic simian immunodeficiency virus (SIV) infections in macaques are characterized by CD4 T lymphocyte depletion and generalized activation of lymphocytes and infection of macrophages.49
Apoptosis induction was compared in models of progressive and nonprogressive lentivirus disease.
Elevated CD4 T lymphocyte apoptosis is not a feature of HIV infection in chimpanzees that in most cases demonstrate maintenance of CD4 T lymphocyte numbers.50 Increased levels of CD4 T lymphocyte activation-induced apoptosis are observed in pathogenic models of SIV infection in macaques, however, and are associated with CD4 T cell depletion.51 In vivo apoptosis occurs in bystander uninfected T lymphocytes in pathogenic macaque models.52 In the first 2 weeks of infection with SIVmac, levels of apoptotic T lymphocytes are predictive of subsequent clinical course and allow for identification of RPs and SPs.53 Transient apoptosis in thymic progenitors is also demonstrable in juvenile macaques infected with SIV.54 In a further apathogenic primate model, SIVsm infection of sooty mangabeys results in high levels of viral replication, despite also being characterized by an absence of immunodeficiency.55 In this model, levels of spontaneous and activation-induced CD4 T lymphocyte apoptosis are unaltered compared with SIV uninfected controls, and limited SIV-specific CD8 T lymphocyte responses are observed. Although immunodeficiency does not occur, CD4 T lymphocyte numbers vary between animals and are inversely correlated with CD8 T lymphocyte activation markers. Altogether, these models suggest that the critical determinants of rate of disease progression are the level of immune activation and CD4 T lymphocyte apoptosis rather than the level of viral replication and lentivirus-specific CTL response.With primate models, associations between specific molecular pathways of apoptosis induction and patterns of disease progression were identified. The Fas/Fas ligand (FasL) pathway of apoptosis induction was suggested to contribute to CD4 T lymphocyte depletion in some studies but not in others.56 In a SIV/HIV hybrid virus (SHIV)-infected macaque model, Fas upregulation on T lymphocytes occurred at the same time as the initial burst of viral replication.57 The initial transient drop in CD4 T lymphocytes coinciding with this was associated with increased spontaneous apoptosis of both CD4 and CD8 T lymphocytes. A second phase of gradual CD4 T lymphocyte decline was associated with enhanced apoptosis in CD4 T lymphocytes, increased Fas expression on CD4 T lymphocytes, and increased FasL in activated CD8 T lymphocytes and B lymphocytes. However, in another macaque model, the transient development of lymphopenia 1 week after infection preceded apoptosis and was not believed to be related to apoptosis.58 In contrast, infection with a nonpathogenic Nef-deletion derivative of SIV induced lower levels of apoptosis during the more chronic phase of infection, suggesting that CD4 T lymphocyte apoptosis might be more important in the chronic phase of CD4 T lymphocyte depletion than in the initial transient dip that characterizes acute infection.
HIV-infected chimpanzees do not have enhanced levels of CD4 or CD8 T lymphocyte activation or apoptosis after T cell receptor (TCR) activation and are resistant to Fas-mediated apoptosis.43,59 In the SIV-macaque model of progressive disease, Nef binds to the TCR -chain and stimulates FasL upregulation and cell activation via immunoreceptor tyrosine activation motifs (ITAMs).60 Nef, which exerts its effect via the transcription factor NFAT, is sufficient for FasL upregulation in a highly pathogenic model that involves the infection of pigtailed macaques with SIVsmmPBj14.62 Infection with an SIV strain containing a four-amino-acid deletion in Nef fails to induce the enhanced FasL expression and results in a nonprogressive form of disease in which apoptosis is not obsrved.61 Importantly, these elegant studies suggest that Nef not only contributes to CD4 T lymphocyte depletion but may also provide a mechanism by which directly infected cells can kill virus-responsive CTLs via FasL, facilitating immune evasion.
HIV Tat also contributes to FasL upregulation, but chimpanzee CD4 T cells are resistant to Tat-induced oxidative stress and fail to downregulate manganese superoxide dismutase, unlike lymphocytes in models of progressive lentivirus infection.63 HIV Vpr is another viral factor that can influence disease progression and induces apoptosis via mitochondrial membrane permeabilization.64,65 Of interest, there exist marked virus and speciesspecific differences in the ability of Vpr to induce apoptosis.66 Chimpanzee cells are resistant to the apoptotic effects of Vpr, and SIVagm Vpr does not induce apoptosis in African green monkey cells. These studies emphasize that the ability of viral factors to influence disease progression correlates to their ability to induce apoptosis in primate models.