title: Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy.
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.
authors.affiliation: HIV-1 Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Kearney
authors.affiliation: HIV-1 Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Spindler
authors.affiliation: Advanced Biomedical Computing Center, SAIC, Frederick, Maryland, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Shao
authors.affiliation: HIV-1 Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Sloane
authors.initials: S
authors.lastname: Yu
authors.affiliation: HIV-1 Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Anderson
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH Bethesda, Maryland, United States of America.
authors.forename: Angeline
authors.initials: A
authors.lastname: O'Shea
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH Bethesda, Maryland, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rehm
authors.affiliation: HIV-1 Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Carry
authors.initials: C
authors.lastname: Poethke
authors.affiliation: HIV-1 Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kovacs
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University, Boston, Massachusetts, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Coffin
authors.affiliation: HIV-1 Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010802:Phylogeny; D012367:RNA, Viral / Q000032:analysis / Q000187:drug effects* / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D012367:RNA, Viral