Abstract
BackgroundOur understanding of the peripheral human immunodeficiency virus type 1 (HIV-1) reservoir is strongly biased towards subtype B HIV-1 strains, with only limited information available from patients infected with non-B HIV-1 subtypes, which are the predominant viruses seen in low- and middle-income countries (LMIC) in Africa and Asia.ResultsIn this study, blood samples were obtained from well-suppressed ART-experienced HIV-1 patients monitored in Uganda (n = 62) or the U.S. (n = 50), with plasma HIV-1 loads < 50 copies/ml and CD4+ T-cell counts > 300 cells/ml. The peripheral HIV-1 reservoir, i.e., cell-associated HIV-1 RNA and proviral DNA, was characterized using our novel deep sequencing-based EDITS assay. Ugandan patients were slightly younger (median age 43 vs 49 years) and had slightly lower CD4+ counts (508 vs 772 cells/ml) than U.S. individuals. All Ugandan patients were infected with non-B HIV-1 subtypes (31% A1, 64% D, or 5% C), while all U.S. individuals were infected with subtype B viruses. Unexpectedly, we observed a significantly larger peripheral inducible HIV-1 reservoir in U.S. patients compared to Ugandan individuals (48 vs. 11 cell equivalents/million cells, p < 0.0001). This divergence in reservoir size was verified measuring proviral DNA (206 vs. 88 cell equivalents/million cells, p < 0.0001). However, the peripheral HIV-1 reservoir was more diverse in Ugandan than in U.S. individuals (8.6 vs. 4.7 p-distance, p < 0.0001).ConclusionsThe smaller, but more diverse, peripheral HIV-1 reservoir in Ugandan patients might be associated with viral (e.g., non-B subtype with higher cytopathicity) and/or host (e.g., higher incidence of co-infections or co-morbidities leading to less clonal expansion) factors. This highlights the need to understand reservoir dynamics in diverse populations as part of ongoing efforts to find a functional cure for HIV-1 infection in LMICs.
Highlights
Our understanding of the peripheral human immunodeficiency virus type 1 (HIV-1) reservoir is strongly biased towards subtype B HIV-1 strains, with only limited information available from patients infected with non-B HIV-1 subtypes, which are the predominant viruses seen in low- and middle-income countries (LMIC) in Africa and Asia
Development of an Envelope Detection by Induced Transcription-based Sequencing (EDITS) assay that accurately quantifies latently HIV‐1‐infected cells with B and non‐B subtypes Multiple assays have been developed to quantify the HIV-1 reservoir [15, 18, 19], most of them to be performed in North America, Europe, and Australia, where subtype B HIV-1 strains are predominant [41]
Since the main goal of this study was to evaluate the HIV-1 reservoir in Uganda, it was important to test the ability of the modified EDITS assay to measure inducible cell-associated spliced HIV-1 env mRNA in individuals infected with more worldwide prevalent non-B HIV-1 strains
Summary
Our understanding of the peripheral human immunodeficiency virus type 1 (HIV-1) reservoir is strongly biased towards subtype B HIV-1 strains, with only limited information available from patients infected with non-B HIV-1 subtypes, which are the predominant viruses seen in low- and middle-income countries (LMIC) in Africa and Asia. Joussef‐Piña et al Retrovirology (2022) 19:1 controls HIV-1 replication in plasma to below current detection levels, HIV-1 persists mostly in latentlyinfected effector and transitional memory C D4+ T cells, with minimal decay despite prolonged ART [5,6,7] This pool of latent proviruses is quickly established after infection, usually leading to a steady source of potentially replication-competent HIV-1 that persists indefinitely even in well suppressed cART-treated people living with HIV-1 (PLWH) [8]. In the absence of HIV-1 transcription and virus production, the host immune system is not able to recognize latently HIV-infected cells or target them for elimination [8, 10] To circumvent this problem, one avenue to eradicate the latent HIV-1 reservoir has been the “shock and kill” strategy, which involves activation of latent HIV-1 by latency reversal agents (LRA) in the presence of ART in conjunction with immunological approaches designed to purge the reactivated cells [11,12,13]. Numerous complementary approaches are being explored for a functional HIV-1 cure, such as stand-alone immunological enhancements, including broadly neutralizing antibodies, direct targeting of the genome with CRISPRs, and induction of permanent epigenetic silencing [17]
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