Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy

PLoS Pathog. 2014 Mar 20;10(3):e1004010. doi: 10.1371/journal.ppat.1004010. eCollection 2014 Mar.

Abstract

A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1-15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / therapeutic use
  • Anti-Retroviral Agents / therapeutic use*
  • Evolution, Molecular*
  • Female
  • Genetic Variation / drug effects
  • HIV Infections / drug therapy
  • HIV Infections / genetics
  • HIV Infections / virology*
  • HIV-1 / genetics*
  • Humans
  • Male
  • Middle Aged
  • Phylogeny
  • RNA, Viral / analysis
  • RNA, Viral / drug effects*
  • RNA, Viral / genetics
  • Virus Replication / drug effects
  • Virus Replication / genetics

Substances

  • Anti-HIV Agents
  • Anti-Retroviral Agents
  • RNA, Viral

Grant support

Funding for this research was provided with Federal funds from the National Cancer Institute, NIH. JMC was a Research Professor of the American Cancer Society, with support from the FM Kirby Foundation. Supported in part (JWM) by funding from the National Cancer Institute (SAIC contract 25XS119). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.