A stable latent reservoir for HIV-1 in resting CD4 + T-cells precludes cure 1– 3 . Curative strategies targeting the reservoir are being tested 4, 5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays (QVOAs) for cells releasing infectious virus following one round of T-cell activation 1 . However, QVOAs and newer assays for cells producing viral RNA after activation 6 may underestimate reservoir size because one round of activation does not induce all proviruses 7 . Many studies rely on simple PCR-based assays to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority proviruses are defective 7– 9 . We describe a novel approach that separately quantifies intact and defective proviruses and show that the dynamics of cells carrying intact and defective proviruses are different in vitro and in vivo, a finding with implications for targeting the intact proviruses that are a barrier to cure.
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