Blood biomarkers of expressed and inducible HIV-1

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Objective:To define the relationships between molecular measures of viral persistence in blood (i.e., plasma viremia, cellular HIV-1 DNA, and mRNA) and expressed or inducible virus from resting CD4+ T cells of individuals on suppressive antiretroviral therapy.Design:We compared molecular measurements of HIV-1 in plasma and in uncultured peripheral blood mononuclear cells (PBMCs) to the levels of virions produced by either unstimulated or phorbol myristate acetate and ionomycin (PMA/iono)-stimulated PBMC or resting CD4+ T cells from 21 donors on suppressive antiretroviral therapy.Results:We found that unstimulated virion release from cultured resting CD4+ T cells was positively correlated with the levels of plasma viremia in vivo (Spearman rho = 0.67, P = 0.0017). We also found that levels of both cellular HIV-1 DNA and unspliced HIV-1 mRNA per million uncultured PBMC were positively correlated with the levels of inducible virion release from both PMA/iono-stimulated PBMC (total HIV-1 DNA: rho = 0.64, P = 0.0017; unspliced HIV-1 RNA: rho = 0.77, P < 0.001) and PMA/iono-stimulated resting CD4+ T cells (total HIV-1 DNA: rho = 0.75, P < 0.001; unspliced HIV-1 RNA: rho = 0.75, P < 0.001).Conclusion:These results show for the first time that there are strong associations between in-vivo measures of HIV-1 persistence and ex-vivo measures of spontaneous and inducible virus production from cultured PBMC and resting CD4+ T cells. Findings from this study provide insight into the biology of HIV-1 persistence and suggest methods to guide the evaluation of clinical strategies to reduce the size of the viral reservoir.

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