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.
Highlights
The interaction between HIV and CD4+ T-cells is complex, and may result in contrasting effects with respect to virus replication
We have previously shown that experimental depletion of CD4+ Tcells prior to SIV infection in rhesus macaques results in higher viremia and the emergence of CD4-independent SIV-envelopes
Our new data indicate that depletion of CD4+ T-cells prior to SIV infection results in activation of monocyte and massive infection of tissue-resident macrophages, which appear to be the predominant population of productively infected cells
Summary
The interaction between HIV and CD4+ T-cells is complex, and may result in contrasting effects with respect to virus replication. CD4+ T-cells are key targets for infection and sustain virus replication [5,6]. To better understand the relationship between CD4+ T-cell availability and HIV replication, we recently conducted a CD4+ T-cell depletion study in rhesus macaques (RMs) prior to SIV infection [7]. This previous study showed that antibody-mediated depletion of CD4+ T-cells was associated with increased virus replication and rapid disease progression [7]. The absence of antibodies targeting conserved CD4-inducible epitopes has been proposed as one of the mechanisms allowing CD4-independent SIV to emerge in CD4-depleted RMs [8]. In that study one RM with the least effective CD4+ T-cell depletion showed the lowest viremia
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