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J Virol. 2019 Dec 18. pii: JVI.01736-19. doi: 10.1128/JVI.01736-19. [Epub ahead of print]

CXCR4-using HIV strains predominate in naïve and central memory CD4+ T cells in people living with HIV on antiretroviral therapy: implications for how latency is established and maintained.

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The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.
School of Health and Biomedical Sciences, RMIT University, Bundoora, Australia.
Department of Infectious Diseases, Monash University and Alfred Hospital, Melbourne, Australia.
Department of Medicine, University of California, San Francisco, USA.
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia


HIV can persist in people living with HIV (PLWH) on antiretroviral therapy (ART) in multiple CD4+ T cell subsets, including naïve, central memory (CM) cells, transitional (TM) and effector memory (EM) cells. Since these cells express different levels of the viral co-receptors CXCR4 and CCR5 on their cell surface, we sought to determine whether the HIV envelope protein (Env) was genotypically and phenotypically different between CD4+ T cell subsets isolated from PLWH on suppressive ART (n=8). Single genome amplification for the HIV env gene was performed on genomic DNA extracts from different CD4+ T cell subsets. We detected CXCR4-using (X4) strains in five of the eight participants studied, and in these participants, the prevalence of X4 strains was higher in naïve CD4+ T-cells compared to the memory subsets. Conversely, R5 strains were mostly found in the transitional (TM) and effector memory (EM) populations. Identical sets of env sequences, consistent with clonal expansion of some infected cells, were more frequent in EM cells. These expanded identical sequences could also be detected in multiple CD4+ T cell subsets, suggesting that infected cells can undergo T-cell differentiation. These identical sequences largely encoded for intact and functional Env proteins. Our results are consistent with a model where X4 HIV strains infect and potentially establish latency in naïve and CM CD4+ T cells through direct infection, in addition to maintenance of the reservoir through differentiation and proliferation of infected cells.Importance In people living with HIV (PLWH) on suppressive ART, latent HIV can be found in a diverse range of CD4+ T cells including quiescent naïve and central memory cells that are typically difficult to infect in vitro It is currently unclear how latency is established in these cells in vivo We show that in CD4+ T-cells from PLWH on suppressive ART, the use of the coreceptor CXCR4 was prevalent amongst viruses amplified from naïve and central memory CD4+ T cells. Furthermore, we found that expanded numbers of identical viral sequences were most common in the effector memory population, and these identical sequences were also found in multiple different CD4+ T-cell subsets. Our results help to shed light on how a range of CD4+ T cell subsets come to harbor HIV DNA which is one of the major barriers to eradicating the virus from PLWH.


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