The impact of antiretroviral therapy duration on the HIV-1 infection of T-cells within anatomic sites

Understanding the impact of antiretroviral therapy (ART) duration on HIV-infected cells is critical for developing successful curative strategies. To address this issue, we conducted a cross-sectional/inter-participant genetic characterization of HIV-1 RNA from pre- and on-therapy plasma and HIV-1 DNA from CD4+ T-cell subsets derived from peripheral blood (PB), lymph node (LN) and gut tissues of 26 participants after 3-17.8 years of ART. Our studies revealed in four acute/early participants who had paired PB and LN samples a substantial reduction in the proportion of HIV-infected cells per year on therapy within the LN. Extrapolation to all 12 acute/early participants estimated a much smaller reduction in the proportion of HIV-1 infected cells within LN per year on therapy that was similar to the participants treated during chronic infection. LN-derived effector memory T-cells (TEM) contained HIV-1 DNA that was genetically identical to viral sequences derived from pre- and on-therapy plasma samples. The proportion of identical HIV-1 DNA sequences increased within PB-derived TEM cells. However, the infection frequency of TEM cells in PB was stable, indicating cellular proliferation that compensates for T-cell loss over time contributes to HIV-1 persistence. This study suggests that ART reduces HIV-infected T-cells, and that clonal expansion of HIV-infected cells maintains viral persistence. Importantly, LN-derived TEM cells are capable of encoding infectious HIV-1, and should be targeted by future curative strategies.Importance HIV-1 persists as an integrated genome in CD4+ memory T-cells during effective therapy, and cessation of current treatments results in resumption of viral replication. To date, the impact of antiretroviral therapy duration on the HIV-infected CD4+ T-cells and the mechanisms of viral persistence in different anatomic sites is not clearly elucidated. In the current study, we found treatment duration was associated with a reduction of HIV-infected T-cells. Our genetic analyses revealed that CD4+ effector memory T-cells (TEM) derived from the lymph node appear to contain provirus which is genetically identical to plasma-derived virions. Moreover, we found that cellular proliferation counterbalances the decay of HIV-infected cells throughout therapy. The contribution of cellular proliferation to viral persistence is particularly significant in TEM cells. Our study emphasizes the importance of HIV-1 intervention and provides new insights into the location of memory T-cells infected with HIV-1 DNA which is capable of contributing to viremia. Copyright © 2019 Lee et al.

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