Research ArticleHIV

Different human resting memory CD4+ T cell subsets show similar low inducibility of latent HIV-1 proviruses

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Science Translational Medicine  29 Jan 2020:
Vol. 12, Issue 528, eaax6795
DOI: 10.1126/scitranslmed.aax6795

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Breaching the latent HIV reservoir

The main barrier to curing HIV-1 infection is a latent reservoir of the virus in resting CD4+ T cells, which allows the virus to persist in a form that is not detected by the immune system or affected by antiretroviral drugs. One cure strategy involves inducing viral gene expression so that latently infected T cells can be eliminated. It has been suggested that latent HIV-1 might be enriched in specific subpopulations of CD4+ T cells, which would allow more specific targeting of latency-reversing drugs. In a new study, Kwon et al. now report that surprisingly there was no preferential enrichment or differences in viral gene expression inducibility among naïve CD4+ T cells and three different subsets of memory CD4+ T cells from 10 HIV-infected individuals on antiretroviral therapy. This finding complicates targeted cure strategies based on CD4+ T cell subsets.

Abstract

The latent reservoir of HIV-1 in resting CD4+ T cells is a major barrier to cure. It is unclear whether the latent reservoir resides principally in particular subsets of CD4+ T cells, a finding that would have implications for understanding its stability and developing curative therapies. Recent work has shown that proliferation of HIV-1–infected CD4+ T cells is a major factor in the generation and persistence of the latent reservoir and that latently infected T cells that have clonally expanded in vivo can proliferate in vitro without producing virions. In certain CD4+ memory T cell subsets, the provirus may be in a deeper state of latency, allowing the cell to proliferate without producing viral proteins, thus permitting escape from immune clearance. To evaluate this possibility, we used a multiple stimulation viral outgrowth assay to culture resting naïve, central memory (TCM), transitional memory (TTM), and effector memory (TEM) CD4+ T cells from 10 HIV-1–infected individuals on antiretroviral therapy. On average, only 1.7% of intact proviruses across all T cell subsets were induced to transcribe viral genes and release replication-competent virus after stimulation of the cells. We found no consistent enrichment of intact or inducible proviruses in any T cell subset. Furthermore, we observed notable plasticity among the canonical memory T cell subsets after activation in vitro and saw substantial person-to-person variability in the inducibility of infectious virus release. This finding complicates the vision for a targeted approach for HIV-1 cure based on T cell memory subsets.

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