Phylogenetic approach to recover integration dates of latent HIV sequences within-host

Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):E8958-E8967. doi: 10.1073/pnas.1802028115. Epub 2018 Sep 5.


Given that HIV evolution and latent reservoir establishment occur continually within-host, and that latently infected cells can persist long-term, the HIV reservoir should comprise a genetically heterogeneous archive recapitulating within-host HIV evolution. However, this has yet to be conclusively demonstrated, in part due to the challenges of reconstructing within-host reservoir establishment dynamics over long timescales. We developed a phylogenetic framework to reconstruct the integration dates of individual latent HIV lineages. The framework first involves inference and rooting of a maximum-likelihood phylogeny relating plasma HIV RNA sequences serially sampled before the initiation of suppressive antiretroviral therapy, along with putative latent sequences sampled thereafter. A linear model relating root-to-tip distances of plasma HIV RNA sequences to their sampling dates is used to convert root-to-tip distances of putative latent lineages to their establishment (integration) dates. Reconstruction of the ages of putative latent sequences sampled from chronically HIV-infected individuals up to 10 y following initiation of suppressive therapy revealed a genetically heterogeneous reservoir that recapitulated HIV's within-host evolutionary history. Reservoir sequences were interspersed throughout multiple within-host lineages, with the oldest dating to >20 y before sampling; historic genetic bottleneck events were also recorded therein. Notably, plasma HIV RNA sequences isolated from a viremia blip in an individual receiving otherwise suppressive therapy were highly genetically diverse and spanned a 20-y age range, suggestive of spontaneous in vivo HIV reactivation from a large latently infected cell pool. Our framework for reservoir dating provides a potentially powerful addition to the HIV persistence research toolkit.

Keywords: HIV; evolution; latency; phylogenetics; reservoir.

Publication types

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

MeSH terms

  • Datasets as Topic
  • HIV Infections / blood
  • HIV Infections / genetics*
  • HIV Infections / virology
  • HIV-1 / genetics*
  • HIV-1 / isolation & purification
  • Host-Pathogen Interactions / genetics*
  • Humans
  • Models, Genetic
  • Phylogeny*
  • Proviruses / genetics
  • Proviruses / isolation & purification
  • RNA, Viral / genetics
  • RNA, Viral / isolation & purification
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA
  • Time Factors
  • Viremia / blood
  • Viremia / genetics
  • Viremia / virology
  • Virus Integration / genetics
  • Virus Latency / genetics*


  • RNA, Viral

Associated data

  • GENBANK/MG822917
  • GENBANK/MG823179