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

Marta E. Bull*, Jennifer L. Mckernan, Sheila Styrchak, Kelli Kraft, Jane Hitti, Susan E. Cohn, Kenneth Tapia, Wenjie Deng, Sarah Holte, James I. Mullins, Robert W. Coombs, Lisa M. Frenkel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)557-566
Number of pages10
JournalAIDS research and human retroviruses
Volume35
Issue number6
DOIs
StatePublished - Jun 2019

Keywords

  • HIV reservoirs
  • HIV-infected women
  • drug resistance
  • nearest-neighbor analysis
  • phylogenetics
  • viral rebound

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases

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