Depletion of CD4⁺ T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques.
ABSTRACT CD4+ T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of CD4+ T cells as mediators of antiviral immune responses and targets for virus replication is still unclear. Here, we have generated data in SIV-infected rhesus macaques (RMs) that suggest that CD4+ T cells are essential in establishing control of virus replication during acute infection. To directly assess the role of CD4+ T cells during primary SIV infection, we in vivo depleted these cells from RMs prior to infecting the primates with a pathogenic strain of SIV. Compared with undepleted animals, CD4+ lymphocyte-depleted RMs showed a similar peak of viremia, but did not manifest any post-peak decline of virus replication despite CD8+ T cell- and B cell-mediated SIV-specific immune responses comparable to those observed in control animals. Interestingly, depleted animals displayed rapid disease progression, which was associated with increased virus replication in non-T cells as well as the emergence of CD4-independent SIV-envelopes. Our results suggest that the antiviral CD4+ T cell response may play an important role in limiting SIV replication, which has implications for the design of HIV vaccines.
SourceAvailable from: Vijayakumar Velu[Show abstract] [Hide abstract]
ABSTRACT: The inhibitory receptor programmed death-1 (PD-1) has been shown to regulate CD8 T cell function during chronic SIV infection; however, its role on CD4 T cells, specifically in the gut-associated lymphoid tissue, is less well understood. In this study, we show that a subset of CD4 T cells expresses high levels of PD-1 (PD-1(hi)) in the rectal mucosa, a preferential site of virus replication. The majority of these PD-1(hi) CD4 T cells expressed Bcl-6 and CXCR5, markers characteristic of T follicular helper cells in the lymph nodes. Following a pathogenic SIV infection, the frequency of PD-1(hi) cells (as a percentage of CD4 T cells) dramatically increased in the rectal mucosa; however, a significant fraction of them did not express CXCR5. Furthermore, only a small fraction of PD-1(hi) cells expressed CCR5, and despite this low level of viral coreceptor expression, a significant fraction of these cells were productively infected. Interestingly, vaccinated SIV controllers did not present with this aberrant PD-1(hi) CD4 T cell enrichment, and this lack of enrichment was associated with the presence of higher frequencies of SIV-specific granzyme B(+) CD8 T cells within the lymphoid tissue, suggesting a role for antiviral CD8 T cells in limiting aberrant expansion of PD-1(hi) CD4 T cells. These results highlight the importance of developing vaccines that enhance antiviral CD8 T cells at sites of preferential viral replication and support the need for developing therapeutic interventions that limit expansion of SIV(+)PD-1(hi) CD4 T cells at mucosal sites as a means to enhance viral control.The Journal of Immunology 09/2014; 193(9). DOI:10.4049/jimmunol.1401222 · 5.36 Impact Factor
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ABSTRACT: The mechanism of myeloid dendritic cell (mDC) mediated impaired T-cell function was investigated during HIV infection. HIV or gp120 were found to inhibit lipopolysaccharide induced mDC maturation and cause defects in allogeneic T-cell proliferation, IL-2 and IFNγ production and pSTAT1 expression. gp120 treated mDCs down-regulated autologous T-cell proliferation and IFNγ production against a peptide pool consisting of cytomegalovirus, Epstein-Barr virus and influenza (CEF). These T-cell defects were associated with a decrease in TH1 polarizing cytokine IL-12p70, and an increase in IL-23 production by gp120 treated mDCs. gp120 induced IL-23 upregulated suppressor of cytokine signaling 1 (SOCS1) protein in T cells which inhibited IFNγ production and killing of CEF pulsed monocytes. These effector functions were recovered by silencing SOCS1 in T cells. Furthermore, we observed IL-23 induced SOCS1 binding to the IFNγ transcription complex. These results identify SOCS1 as a novel target to improve the immune function in HIV-infected persons.The Journal of Infectious Diseases 09/2014; 211(5). DOI:10.1093/infdis/jiu523 · 5.78 Impact Factor
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ABSTRACT: In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes. In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells. CD4-depleted animals showed (i) set-point viral load two-logs higher than controls; (ii) macrophages constituting 80% of all SIV vRNA+ cells in lymph node and mucosal tissues; (iii) substantial expansion of pro-inflammatory monocytes; (iv) aberrant activation and infection of microglial cells; and (v) lifespan of productively infected cells significantly longer in comparison to controls, but markedly shorter than previously estimated for macrophages. The net effect of CD4+ T-cell depletion is an inability to control SIV replication and a shift in the tropism of infected cells to macrophages, microglia, and, potentially, other CD4-low cells which all appear to have a shortened in vivo lifespan. We believe these findings have important implications for HIV eradication studies.PLoS Pathogens 10/2014; 10(10):e1004467. DOI:10.1371/journal.ppat.1004467 · 8.14 Impact Factor