title: RT-SHIV subpopulation dynamics in infected macaques during anti-HIV therapy.
abstract: BACKGROUND
  To study the dynamics of wild-type and drug-resistant HIV-1 RT variants, we developed a methodology that follows the fates of individual genomes over time within the viral quasispecies. Single genome sequences were obtained from 3 pigtail macaques infected with a recombinant simian immunodeficiency virus containing the RT coding region from HIV-1 (RT-SHIV) and treated with short-course efavirenz monotherapy 13 weeks post-infection followed by daily combination antiretroviral therapy (ART) beginning at week 17. Bioinformatics tools were constructed to trace individual genomes from the beginning of infection to the end of the treatment.
  
  
  RESULTS
  A well characterized challenge RT-SHIV inoculum was used to infect three monkeys. The RT-SHIV inoculum had 9 variant subpopulations and the dominant subpopulation accounted for 80% of the total genomes. In two of the three monkeys, the inoculated wild-type virus was rapidly replaced by new wild type variants. By week 13, the original dominant subpopulation in the inoculum was replaced by new dominant subpopulations, followed by emergence of variants carrying known NNRTI resistance mutations. However, during ART, virus subpopulations containing resistance mutations did not outgrow the wide-type subpopulations until a minor subpopulation carrying linked drug resistance mutations (K103N/M184I) emerged. We observed that persistent viremia during ART is primarily made up of wild type subpopulations. We also found that subpopulations carrying the V75L mutation, not known to be associated with NNRTI resistance, emerged initially in week 13 in two macaques. Eventually, all subpopulations from these two macaques carried the V75L mutation.
  
  
  CONCLUSIONS
  This study quantitatively describes virus evolution and population dynamics patterns in an animal model. The fact that wild type subpopulations remained as dominant subpopulations during ART treatment suggests that the presence or absence of at least some known drug resistant mutations may not greatly affect virus replication capacity in vivo. Additionally, the emergence and prevalence of V75L indicates that this mutation may provide the virus a selective advantage, perhaps escaping the host immure system surveillance. Our new method to quantitatively analyze viral population dynamics enabled us to observe the relative competitiveness and adaption of different viral variants and provided a valuable tool for studying HIV subpopulation emergence, persistence, and decline during ART.
authors.affiliation: Advanced Biomedical Computing Center, SAIC Frederick, Inc, National Cancer Institute at Frederick, Frederick, MD, USA. shaow@mail.nih.gov
authors.forename: Wei
authors.initials: W
authors.lastname: Shao
authors.forename: Mary
authors.initials: M
authors.lastname: Kearney
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stephens
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Vineet N
authors.initials: VN
authors.lastname: KewalRamani
authors.forename: Zandrea
authors.initials: Z
authors.lastname: Ambrose
authors.forename: John M
authors.initials: JM
authors.lastname: Coffin
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Palmer
mesh_terms: D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D048588:Benzoxazines / Q000627:therapeutic use; D044822:Biodiversity; D016000:Cluster Analysis; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000235:genetics*; D008251:Macaca; D020125:Mutation, Missense; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000235:genetics; D011995:Recombination, Genetic; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D012367:RNA, Viral; C098320:efavirenz