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Observational Study
. 2019 Jun;35(6):557-566.
doi: 10.1089/AID.2018.0211. Epub 2019 Apr 30.

Phylogenetic Analyses Comparing HIV Sequences from Plasma at Virologic Failure to Cervix Versus Blood Sequences from Antecedent Antiretroviral Therapy Suppression

Marta E Bull  1   2 , Jennifer L McKernan  2 , Sheila Styrchak  2 , Kelli Kraft  2 , Jane Hitti  3 , Susan E Cohn  4 , Kenneth Tapia  5 , Wenjie Deng  6 , Sarah Holte  5   7 , James I Mullins  5   6   8   9 , Robert W Coombs  8   9 , Lisa M Frenkel  1   2   5   8
Affiliations
Observational Study

Phylogenetic Analyses Comparing HIV Sequences from Plasma at Virologic Failure to Cervix Versus Blood Sequences from Antecedent Antiretroviral Therapy Suppression

Marta E Bull et al. AIDS Res Hum Retroviruses. 2019 Jun.

Abstract

Identifying tissue sources of HIV that rebound following "failure" of antiretroviral therapy (ART) is critical to evaluating cure strategies. To assess the role of the uterine cervix and peripheral blood mononuclear cells (PBMC) as viral reservoirs, nearest-neighbor phylogenetic analyses compared genetic relatedness of tissue sequences during ART suppression to those detected in plasma at viral rebound. Blood and genital tract specimens from a natural history cohort of HIV-infected women were collected over 5 years. HIV DNA sequences extracted from PBMC and cervical biopsies during ART suppression and plasma RNA from rebound (defined as HIV RNA >3 log10 copies/mL) were derived by single-genome amplification. Phylogenetic and nearest-neighbor analyses of HIV env sequences and drug resistance in pol sequences were compared between tissues. Nine instances of plasma viral rebound (median HIV RNA 3.6 log10 c/mL; IQR: 3.1-3.8) were detected in 7 of 57 women. Nearest-neighbor analyses found rebound plasma sequences were closer to uterine cervical sequences in 4/9 (44%), closer to PBMC in 3/9 (33%), and ambiguous in 2/9 (22%) cases. Rebound plasma clades (n = 27) shared identical sequences in seven instances with the cervix versus two with PBMC. Novel drug resistance mutations were detected in 4/9 (44%) rebounds. The observed tendency for greater sharing of identical HIV variants and greater nearest-neighbor association between rebounding plasma and uterine cervical versus PBMC sequences suggests that the uterine cervix may be a relevant HIV reservoir. The cervix, a readily accessible tissue in women that can be repeatedly sampled, could help assess the HIV reservoir when evaluating cure strategies.

Keywords: HIV reservoirs; HIV-infected women; drug resistance; nearest-neighbor analysis; phylogenetics; viral rebound.

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Conflict of interest statement

No competing financial interests exist.

Figures

<b>FIG. 1.</b>
FIG. 1.
HIV env pairwise diversity and divergence plots. Maximum likelihood phylogenetic analyses of HIV C2–V5 env single-genome sequences from PBMC and cervical DNA when HIV was suppressed by ART and viral rebound. (A) Pairwise diversity plots from the cell-associated PBMC and cervical biopsies and in some cases from HIV RNA for each of the seven participants during suppressive ART and from HIV RNA at the time of viral rebound in the plasma and in some cases the genital tract (participants 1 and 6). (B) Divergence from the MRCA of infection from the seven women. For both (A, B), the x-axis represents the tissue that was sampled and the month during the study that participants were sampled. ART, antiretroviral therapy; MRCA, most recent common ancestor; PBMC, peripheral blood mononuclear cells.
<b>FIG. 1.</b>
FIG. 1.
HIV env pairwise diversity and divergence plots. Maximum likelihood phylogenetic analyses of HIV C2–V5 env single-genome sequences from PBMC and cervical DNA when HIV was suppressed by ART and viral rebound. (A) Pairwise diversity plots from the cell-associated PBMC and cervical biopsies and in some cases from HIV RNA for each of the seven participants during suppressive ART and from HIV RNA at the time of viral rebound in the plasma and in some cases the genital tract (participants 1 and 6). (B) Divergence from the MRCA of infection from the seven women. For both (A, B), the x-axis represents the tissue that was sampled and the month during the study that participants were sampled. ART, antiretroviral therapy; MRCA, most recent common ancestor; PBMC, peripheral blood mononuclear cells.
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