CD8+ T-cells are a critical component of the cellular immune response and they play an important role in the control of viral infection. During HIV infection, CD8+ T-cells are able to recognize infected cells through an MHC-I dependent process and are able to lyse cells harboring viral infection by the secretion of perforin and granzymes. These cytotoxic T-lymphocytes (CTL) can also eliminate virally infected cells through the engagement of death-inducing ligands expressed by CD8+ T-cells with death receptors on the surface of the infected cell. In addition, CD8+ CTL secrete soluble factors such as beta-chemokines and the CD8+ antiviral factor (CAF) that suppress viral binding and transcription, respectively. In order for HIV to survive the pressures placed upon it by the immune system, the virus has adopted numerous strategies to evade the CD8+ T-cell response. The high mutation rate of HIV has allowed the virus to escape CD8+ T-cell recognition in addition to its ability to down-regulate surface MHC-I expression from infected cells. Also, by altering the pattern of cytokine production and engagement of cellular receptors, HIV disrupts proper CD8+ T-cell signaling. The resultant improper T-cell receptor (TcR) stimulation creates an anergic state in these cells. By affecting the function of CD4+ T-cells and antigen presenting cells that are required for proper CD8+ T-cell maturation, HIV is able to decrease the circulating pool of effector and memory CD8+ T-cells that are able to combat viral infection. The end result is the aberration of CD8+ T-cell function.

This study set out to determine whether T cell dysfunction associated with HTLV-I led to increased sensitivity of infected cells to apoptosis or, owing to their potential to develop ATL, if infected cells would become resistant to this process. To test this hypothesis we utilized the monoclonal antibody anti-APO-1, which has been demonstrated to induce apoptosis in human T cells. Human T cell lines expressing HTLV-I showed reduced susceptibility to anti-APO-1-induced apoptosis despite expression of high levels of cell surface APO-1. Cell-free supernatant of the Tax-expressing cell line C8166 and heat-inactivated supernatant of the HTLV-I-producing cell line MT2 transferred increased resistance to anti-APO-1 to susceptible Jurkat T cells. Susceptible T cells transfected with an HTLV-I Tax-expressing vector or treated with soluble Tax protein became less susceptible to anti-APO-1-induced cell death. Furthermore, primary human lymphocytes treated with soluble Tax were less susceptible to apoptosis induced by anti-APO-1. The protective effect of Tax in T cell lines and primary human lymphocytes was reversed by the addition of anti-Tax antibodies. Anti-APO-1-induced apoptosis was also found to be inhibited in Jurkat cells by the induction of protein kinase C (PKC) with 12-O-tetradecanoylphorbol-13-acetate (TPA). Resistance to apoptosis conferred by HTLV-I Tax and an active PKC pathway may be factors contributing to the survival of dysregulated HTLV-I-infected T cells prone to the development of adult T cell leukemia.

CD8+ T lymphocytes of HIV-1-infected individuals can efficiently suppress HIV-1 replication in CD4+ T lymphocytes. To elucidate the molecular events underlying this suppression, we have used the HIV-1 LTR directing the chloramphenicol acetyltransferase gene (CAT) in transient transfection assays using human Jurkat T cells. In addition to supernatants of patient CD8+ T lymphocytes (CD4+ > 350/microliters), supernatant of a T cell clone derived by Herpesvirus saimiri (HVS)-mediated transformation of CD8+ T lymphocytes of a patient demonstrating inhibition of virus replication were examined. Similar levels of inhibition of LTR-mediated gene expression in response to Tat or mitogenic activation with phorbol ester and calcium ionophore were observed by supernatants of both sources. The inhibitory effect of CD8+ T lymphocytes was not exclusive to lentiviral LTRs since transcription of both the HTLV-I LTR and RSV LTR in response to mitogen was effectively inhibited. In examination of the influence of CD8+ T cell-derived supernatant on NF kappa B-mediated activation, a dimer of the HIV-1 NF kappa B elements directing CAT was markedly inhibited by supernatants of both patient CD8+ lymphocytes and the HVS-derived CD8+ clone. Thus the inhibitory nature of CD8+ T lymphocytes appears not to be specific to lentiviral promoters and may mediate an inhibitory effect via the NF kappa B element.

CD8+ T lymphocytes of HIV-1-infected individuals can efficiently suppress HIV-1 replication in CD4+ T lymphocytes via soluble factors. We compared the effect of CD8+ T cell-derived supernatants on HIV-1 LTR-driven gene expression in T cells and monocytic cell lines. Our results demonstrate that CD8+ T cell supernatants that suppressed HIV-1 LTR-driven gene expression in Jurkat T cells significantly enhanced expression in Tat-activated U38 monocytic cells in the presence and absence of mitogenic stimulation. Examination of a panel of CD8+ T cell-derived supernatants form HIV-infected individuals demonstrated that the extent of enhancement of transcription in U38 cells was mirrored in most cases by a similar level of suppression of transcription in Jurkat T cells. In latently infected U1 cells treated with TNF-alpha, culture with CD8+ T cell supernatants markedly enhanced virus production. In addition, the percentage increase in the enhancement of HIV-1 LTR-driven CAT expression by CD8+ T cell supernatants correlated strongly (r = 0.911) with the level of p24 detected. The level of LTR-mediated gene expression in U38 cells was not influenced by rhMIP-1 alpha rhMIP-1 beta, or rhRANTES over a wide range of chemokine concentration. Treatment of CD8+ T cell supernatant with a combination of antibodies to these chemokines resulted in a further augmentation of LTR-mediated CAT expression in U38 cells. Taken together, these results demonstrate that CD8+ T cell suppressive factors may have opposite effects on HIV-1 LTR-driven gene expression and replication dependent on target cell type and further suggest that the beta-chemokines do not influence HIV-1 LTR-mediated gene expression in monocytic cells.