title: HIV populations are large and accumulate high genetic diversity in a nonlinear fashion.
abstract: HIV infection is characterized by rapid and error-prone viral replication resulting in genetically diverse virus populations. The rate of accumulation of diversity and the mechanisms involved are under intense study to provide useful information to understand immune evasion and the development of drug resistance. To characterize the development of viral diversity after infection, we carried out an in-depth analysis of single genome sequences of HIV pro-pol to assess diversity and divergence and to estimate replicating population sizes in a group of treatment-naive HIV-infected individuals sampled at single (n = 22) or multiple, longitudinal (n = 11) time points. Analysis of single genome sequences revealed nonlinear accumulation of sequence diversity during the course of infection. Diversity accumulated in recently infected individuals at rates 30-fold higher than in patients with chronic infection. Accumulation of synonymous changes accounted for most of the diversity during chronic infection. Accumulation of diversity resulted in population shifts, but the rates of change were low relative to estimated replication cycle times, consistent with relatively large population sizes. Analysis of changes in allele frequencies revealed effective population sizes that are substantially higher than previous estimates of approximately 1,000 infectious particles/infected individual. Taken together, these observations indicate that HIV populations are large, diverse, and slow to change in chronic infection and that the emergence of new mutations, including drug resistance mutations, is governed by both selection forces and drift.
authors.affiliation: HIV Drug Resistance Program, NCI-Frederick, NIH, Frederick, Maryland, USA. fmalli@mail.nih.gov
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.forename: Mary
authors.initials: M
authors.lastname: Kearney
authors.forename: Sarah
authors.initials: S
authors.lastname: Palmer
authors.forename: Robert
authors.initials: R
authors.lastname: Stephens
authors.forename: JoAnn
authors.initials: J
authors.lastname: Mican
authors.forename: Michael A
authors.initials: MA
authors.lastname: Polis
authors.forename: Richard T
authors.initials: RT
authors.lastname: Davey
authors.forename: Joseph
authors.initials: J
authors.lastname: Kovacs
authors.forename: Wei
authors.initials: W
authors.lastname: Shao
authors.forename: Diane
authors.initials: D
authors.lastname: Rock-Kress
authors.forename: Julia A
authors.initials: JA
authors.lastname: Metcalf
authors.forename: Catherine
authors.initials: C
authors.lastname: Rehm
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Greer
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Lucey
authors.forename: Kristen
authors.initials: K
authors.lastname: Danley
authors.forename: Harvey
authors.initials: H
authors.lastname: Alter
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.forename: John M
authors.initials: JM
authors.lastname: Coffin
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D005260:Female; D014644:Genetic Variation; D006678:HIV / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D015658:HIV Infections / Q000821:virology*; D016333:HIV Protease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D055815:Young Adult; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D054302:pol Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease