An effective vaccine for AIDS may require development of novel vectors capable of eliciting long-lasting immune responses. Here we report the development and use of replication-competent and replication-defective strains of recombinant herpes simplex virus (HSV) that express envelope and Nef antigens of simian immunodeficiency virus (SIV). The HSV recombinants induced antienvelope antibody responses that persisted at relatively stable levels for months after the last administration. Two of seven rhesus monkeys vaccinated with recombinant HSV were solidly protected, and another showed a sustained reduction in viral load following rectal challenge with pathogenic SIVmac239 at 22 weeks following the last vaccine administration. HSV vectors thus show great promise for being able to elicit persistent immune responses and to provide durable protection against AIDS.
The frequency of cytomegalovirus (CMV)-specific CD4؉ T lymphocytes was determined in CMV-seropositive rhesus macaques with or without simian immunodeficiency virus (SIV) infection by using the sensitive assays of intracellular cytokine staining and gamma interferon ELISPOT. Both techniques yielded 3-to 1,000-foldhigher frequencies of CMV-specific CD4 ؉ T lymphocytes than traditional proliferative limiting dilution assays. The median frequency of CMV-specific CD4 ؉ T lymphocytes in 23 CMV-seropositive SIV-negative macaques was 0.63% (range, 0.16 to 5.8%). The majority of CMV-specific CD4 ؉ T lymphocytes were CD95 pos and CD27 lo but expressed variable levels of CD45RA. A significant reduction (P < 0.05) in the frequency of CMV-specific CD4 ؉ T lymphocytes was observed in pathogenic SIV-infected macaques but not in macaques infected with live attenuated strains of SIV. CMV-specific CD4 ؉ T lymphocytes were not detected in six of nine pathogenic SIV-infected rhesus macaques. CMV DNA was detected in the plasma of four of six of these macaques but in no animal with detectable CMV-specific CD4 ؉ T lymphocytes. In pathogenic SIV-infected macaques, loss of CMV-specific CD4 ؉ T lymphocytes was not predicted by the severity of CD4 ؉ T lymphocytopenia. Neither was it predicted by the pre-SIV infection frequencies of CD45RA neg or CCR5 pos CMV-specific CD4 ؉ T lymphocytes. However, the magnitude of activation, as evidenced by the intensity of CD40L expression on CMV-specific CD4 ؉ T lymphocytes pre-SIV infection, was three-to sevenfold greater in the two macaques that subsequently lost these cells after SIV infection than in the two macaques that retained CMV-specific CD4 ؉ T lymphocytes post-SIV infection. Future longitudinal studies with these techniques will facilitate the study of CMV pathogenesis in AIDS.
Although opportunistic infections like cytomegalovirus (CMV) are common sequelae of end-stage AIDS, the immune events leading to CMV reactivation in human immunodeficiency virus (HIV)-infected individuals are not well defined.
Although lymphocyte turnover in chronic human immunodeficiency virus and simian immunodeficiency virus (SIV) infection has been extensively studied, there is little information on turnover in acute infection. We carried out a prospective kinetic analysis of lymphocyte proliferation in 13 rhesus macaques inoculated with pathogenic SIV. A short-lived dramatic increase in circulating Ki-67؉ lymphocytes observed at 1 to 4 weeks was temporally related to the onset of SIV replication. A 5-to 10-fold increase in Ki-67 ؉ CD8 ؉ T lymphocytes and a 2-to 3-fold increase in Ki-67 ؉ T-lymphocyte proliferation was associated with cell expansion, paralleled the onset of SIV-specific cytotoxic T-lymphocyte activity, and had an oligoclonal component. Thus, divergent patterns of proliferation and activation are exhibited by CD4 ؉ and CD8 ؉
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