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CD4 depletion in SIV-infected macaques results in macrophage and microglia infection with rapid turnover of infected cells.

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.

SUBMITTER: Micci L

PROVIDER: S-EPMC4214815 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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CD4 depletion in SIV-infected macaques results in macrophage and microglia infection with rapid turnover of infected cells.

Micci Luca L Alvarez Xavier X Iriele Robin I RI Ortiz Alexandra M AM Ryan Emily S ES McGary Colleen S CS Deleage Claire C McAtee Brigitte B BB He Tianyu T Apetrei Cristian C Easley Kirk K Pahwa Savita S Collman Ronald G RG Derdeyn Cynthia A CA Davenport Miles P MP Estes Jacob D JD Silvestri Guido G Lackner Andrew A AA Paiardini Mirko M

PLoS pathogens 20141030 10

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 const ...[more]

PMID: 25356757

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Project description:Microglia and macrophages are essential for homeostatic maintenance and innate immune response in the brain. They are the first line of defense against infections such as HIV/SIV in the brain. However, they are susceptible to infection and function as viral reservoirs even under effective viral suppression. While current antiretroviral regimens successfully suppress viremia and improve quality of life and lifespan, neurologic complications persist and are in part attributed to activated microglia. We sought to test the hypothesis that brain microglia return to a more homeostatic-like state when viremia is suppressed by combination antiretroviral therapy. Using the SIV-rhesus macaque model, we combined single-cell RNA sequencing, bioinformatics, and pathway analysis to compare gene expression profiles of brain myeloid cells under 4 conditions: uninfected, SIV infected, SIV infected with cART suppression, and SIV encephalitis (SIVE). Our study reveals greater myeloid diversity and an elevated proinflammatory state are associated with untreated SIV infection compared with uninfected animals. The development of encephalitis and suppression of viremia both reduced myeloid diversity. However, they had converse effects on the activation state of microglia and inflammation. Notably, suggestive of a restoration of a homeostatic state in microglia, gene expression and activation of pathways related to inflammation and immune response in cART-suppressed monkeys were most similar to that in uninfected monkeys. Untreated SIV infection shared characteristics, especially in brain macrophages to SIVE, with SIVE showing dramatic inflammation. In support of our hypothesis, our study demonstrates that cART indeed restores this key component of the brain's homeostatic state. Summary: ScRNA-seq of rhesus monkey microglia reveals clusters of cells in activated states in the setting of SIV infection, which is primarily reversed by suppressing viremia with combination antiretroviral therapy.

Dataset Information

CD4 depletion in SIV-infected macaques results in macrophage and microglia infection with rapid turnover of infected cells.

Publications

CD4 depletion in SIV-infected macaques results in macrophage and microglia infection with rapid turnover of infected cells.

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