Dis. 4:397C413 [PubMed] [Google Scholar] 3. transcriptional signature indicative of B lymphocyte activation. Validation experiments demonstrated that animals during this period experienced elevated levels of B cells coupled with higher expression of the proliferative marker Ki67, indicating that CD8+ depletion brought on a potent growth of B cell figures. Collectively, these data identify antiviral pathways perturbed by CD8+ T cell depletion that may contribute to noncytolytic control of SIV replication. INTRODUCTION The global spread of the human immunodeficiency computer virus (HIV) pandemic, currently affecting over 30 million individuals worldwide, emphasizes the urgency to develop a safe and effective vaccine. However, fundamental hurdles remain at the level of the basic biology of the conversation between HIV and the human immune system (1C3). Due to the current absence of immunogens that can elicit HIV-specific broadly neutralizing antibodies (4C6), numerous vaccine strategies have been proposed that are based on antiviral cellular immunity (7). Virus-specific T cell responses, in particular those mediated by CD8+ cytotoxic T lymphocytes (CTLs), confer protection against many viral infections by favoring both viral clearance and resistance to reinfection (8, 9). Classical studies suggested a role for CTL responses in the control of HIV by demonstrating that major histocompatibility complex (MHC)-restricted CD8+ cells from seropositive individuals were capable of lysing autologous cells loaded with HIV Balicatib antigen by vaccinia computer virus transduction (10, 11). Here, several lines of evidence have bolstered a model in which CD8+ lymphocytes mediate control of computer virus replication during both HIV contamination of humans and simian immunodeficiency computer virus (SIV) contamination of rhesus macaques (RMs). First, the postpeak decline of viremia in acute HIV infection is usually coincident with the growth of HIV-specific CD8+ T cells (12, 13). Second, during acute and chronic HIV/SIV contamination, immunologic pressure mediated by HIV/SIV-specific CD8+ T cells is usually manifested by viral escape mutations (14). Third, a clear association between certain MHC class I alleles and reduced disease progression during both HIV contamination of humans and SIV contamination of RMs has been exhibited (15, 16). Fourth, HIV-1-infected individuals with multifunctional Balicatib HIV-1-specific T cells progress less rapidly than those with Mouse monoclonal to Myostatin limited T cell functionality (17). Perhaps the most convincing evidence for a direct effect of CD8+ lymphocytes on suppressing HIV/SIV replication came from a series of elegant studies in which these cells were depleted in SIV-infected RMs. Initial work exhibited that antibody-mediated depletion of CD8+ lymphocytes is usually consistently associated with increased plasma viremia (18C20). Following these studies, similar experimental methods yielded the observations that depletion of CD8+ T cells directly led to (i) a loss of host control of live attenuated SIVnef Balicatib viruses (LAVs) (21), (ii) SIV recrudescence after initial control due to early antiretroviral therapy (ART) treatment (22), (iii) partial loss of challenge computer virus suppression in nef LAV-vaccinated RMs, and, importantly (23), (iv) poorer survival and increased CD4+ T cell loss during SIVmac contamination of RMs (24). These studies powerfully exhibited a causative, rather than correlative, relationship between CD8+ T cells and SIV Balicatib replication. While it has been broadly assumed that the primary mechanism by which CTLs exert this control is usually by the killing of infected target cells, this model has not been formally exhibited (25). Studies conducted by us as well as others have shown that depletion of CD8+ lymphocytes in SIV-infected RMs followed by ART treatment did not alter the life span of productively SIV-infected cells or impact viral decay kinetics compared to undepleted animals (26, 27). In addition, decay rates of wild-type and escape mutant.