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Proviral Quasispecies Diversity Is Not Associated With Virologic Breakthrough or CD4⁺ T Cell Loss in HIV-1 Elite Controllers.

ABSTRACT: Elite controllers (EC) are able to control HIV-1 replication to extremely low levels (<50 HIV-1 RNA copies/mL) in the absence of antiretroviral therapy. However, some EC experience CD4⁺ T cell loss and/or lose their ability to control HIV-1 over the course of infection. High levels of HIV-1 env proviral diversity, activated T cells and proinflammatory cytokines were pointed out as relevant biomarkers for detection of EC at risk of virologic/immunologic progression. The aim of this study was to assess the importance of proviral diversity as a prognostic marker of virologic and/or immunologic progression in EC. To this end, we analyzed plasma viremia, total HIV DNA levels, T cells dynamics, and activation/inflammatory biomarkers in EC with low (EC_LD = 4) and high (EC_HD = 6) HIV-1 env diversity. None of EC_LD and EC_HD subjects displayed evidence of immunologic progression (decrease in absolute and percentage of CD4⁺ T cells) and only one EC_HD subject presented virologic progression (?2 consecutive viral loads measurements above the detection limit) 2-5 years after determination of proviral env diversity. Despite differences in proviral genetic diversity, the EC_LD and EC_HD subgroups displayed comparable levels of total cell-associated HIV DNA, activated CD8⁺ T (CD38⁺HLA-DR⁺) cells and plasmatic inflammatory biomarkers (IP-10, IL-18, RANTES, PDGF-AA, and CTACK). These results indicate that the genetic diversity of the HIV-1 proviral reservoir is not a surrogate marker of residual viral replication, immune activation or inflammation, nor an accurate biomarker for the prediction of virologic breakthrough or CD4⁺ T cells loss in EC.

SUBMITTER: de Azevedo SSD

PROVIDER: S-EPMC6454058 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Proviral Quasispecies Diversity Is Not Associated With Virologic Breakthrough or CD4+ T Cell Loss in HIV-1 Elite Controllers.

de Azevedo Suwellen S D SSD Côrtes Fernanda H FH Delatorre Edson E Ribeiro-Alves Marcelo M Hoagland Brenda B Grinsztejn Beatriz B Veloso Valdilea G VG Morgado Mariza G MG Bello Gonzalo G

Frontiers in microbiology 20190402

Elite controllers (EC) are able to control HIV-1 replication to extremely low levels (<50 HIV-1 RNA copies/mL) in the absence of antiretroviral therapy. However, some EC experience CD4+ T cell loss and/or lose their ability to control HIV-1 over the course of infection. High levels of HIV-1 env proviral diversity, activated T cells and proinflammatory cytokines were pointed out as relevant biomarkers for detection of EC at risk of virologic/immunologic progression. The aim of t ...[more]

PMID: 31001238

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Project description:BackgroundOngoing intra-host HIV-1 evolution has been shown in individuals that naturally suppress the viremia to low levels (HIV controllers) by the analysis of the RNA in plasma compartment. Detection of evolution at the DNA proviral compartment in HIV controllers, however, has been more challenging and the precise correlation between the systemic viral suppression level and rate of reservoir's reseeding in those individuals is not fully understood. In this sense, we examined the proviral DNA quasispecies by single genome amplification of the env gene in a cohort of 23 HIV controllers from Brazil, divided in three groups, according to the level of systemic viral suppression: (1) elite controllers with persistent undetectable viral load (PEC, n = 6); (2) elite controllers with occasional episodes of transient (51-400 copies/mL) viremia (EEC, n = 7); and (3) viremic controllers with persistent low-level (80-2000 copies/mL) viremia (VC, n = 10).ResultsThe HIV-1 diversity of the PBMC-associated proviral quasispecies in EC was significantly (P < 0.01) lower than in VC, but not significantly different between PEC and EEC groups. We detected a considerable variation in the average pairwise nucleotide distance and proportion of unique sequences in the HIV-1 proviral quasispecies of PEC and EEC. Some PEC and EEC displayed highly homogenous proviral populations with large clusters of identical sequences, while others exhibited relatively diverse proviral populations with a high proportion of unique sequences comparable to VC subjects. The long-term (10-15 years) follow-up of the HIV-1 proviral populations revealed a complete evolutionary stasis in one PEC and measurable divergence rates in one EEC [3.1 (1.2-5.6) × 10-3 substitutions/site/year and one VC [2.9 (0.7-5.1) × 10-3 substitutions/site/year].ConclusionsThere is no simple relationship between systemic viral suppression and intra-host proviral diversity or rate of reservoir's reseeding in chronically infected HIV controllers. Our results demonstrate that very divergent patterns of intra-host viral diversity and divergence could be detected in the setting of natural suppression of HIV-1 replication and that ongoing evolution and reseeding of the PBMC proviral reservoir occurs in some elite controllers.

Dataset Information

Proviral Quasispecies Diversity Is Not Associated With Virologic Breakthrough or CD4⁺ T Cell Loss in HIV-1 Elite Controllers.

Publications

Proviral Quasispecies Diversity Is Not Associated With Virologic Breakthrough or CD4<sup>+</sup> T Cell Loss in HIV-1 Elite Controllers.

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