Publications (133) View all
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Article: Divergent kinetics of proliferating T cell subsets in SIV Infection: SIV eliminates the "first responder" CD4+ T cells in primary infection.
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ABSTRACT: Although increased lymphocyte turnover in chronic HIV and SIV infection has been reported in blood, there is little information on cell turnover in tissues, particularly in primary SIV infection. Here we examined levels of proliferating T cell subsets in mucosal and peripheral lymphoid tissues of adult macaques throughout SIV infection. To specifically label cells in S-phase division, all animals were inoculated with BrdU 24 hrs prior to sampling. In normal macaques, the highest levels of proliferating CD4+ and CD8+ T cells were in blood, and to a lesser extent, in spleen. Substantial percentages of proliferating cells were also found in intestinal tissues including jejunum, ileum and colon, but very few proliferating cells were detected in lymph nodes (axillary and mesenteric). Moreover, essentially all proliferating T cells in uninfected animals co-expressed CD95, and many co-expressed CCR5+ in tissues examined. Confocal microscopy also demonstrated proliferating cells were substantial viral target cells for SIV infection and viral replication. After acute SIV infection, percentages of proliferating CD4+ and CD8+ T cells were significantly higher in tissues of chronically infected macaques compared to controls. Surprisingly however, we found that proliferating CD4+ T cells were selectively decreased in very early infection (8-10 dpi). In contrast, levels of proliferating CD8+ T cells rapidly increased after SIV infection, peaked by 13-21 dpi, and remained significantly higher than controls thereafter. Taken together, these findings suggest SIV selectively infects and destroys dividing, non-specific CD4+ T cells in acute infection, resulting in homeostatic changes and perhaps continuing loss of replication capacity to respond to non-specific, and later, SIV-specific antigens.Journal of Virology 04/2013; · 5.40 Impact Factor -
Article: CD8 down-regulation and functional impairment of SIV-specific cytotoxic T lymphocytes in lymphoid and mucosal tissues during SIV infection.
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ABSTRACT: Functional impairment of virus-specific T cells is a hallmark of HIV/SIV infection, but the underlying mechanisms of this dysfunction are not well understood. To address this, we simultaneously analyzed the expression and intensity of CD8 and inhibitory PD-1 on CTL in blood and lymphoid tissues in SIV-infected rhesus macaques. The intensity (mean channel fluorescence) of CD8 expression was transiently down-regulated in early SIV infection (10-14 dpi), despite an increase in CD8(+) T cell proliferation. In chronic infection, CD8 expression was maintained at low levels on CD8(+) T cells in all tissues. Interestingly, Gag-specific CTLs were clearly divided into CD8high- and CD8low-expressing populations in SIV-infected macaques, and CD8low Gag-specific cells increased with disease progression, especially in lymphoid tissues when compared with peripheral blood or in Gag-vaccinated controls. Moreover, the CD8low CTL population secreted lower levels of cytokines upon SIV antigen stimulation and exhibited lower proliferative capacity during infection compared with the CD8high CTL population. Meanwhile, intensity of PD-1 expression on Gag-specific CTL in chronic infection was significantly higher than in acute SIV infection, although the frequencies of PD-1+ Gag-specific cells were similar in acute and chronic stages. In summary, down-regulation of CD8 expression and higher expression of PD-1 on SIV-specific CTLs could coordinately attenuate SIV-specific CTL responses and their ability to recognize virus-infected target cells, especially in lymphoid tissues, resulting in failure to contain viremia, and continued persistence and replication of HIV in lymphoid tissue reservoirs.Journal of leukocyte biology 03/2013; · 4.99 Impact Factor -
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