title: Compartmentalization of HIV-1 within the female genital tract is due to monotypic and low-diversity variants not distinct viral populations.
abstract: BACKGROUND
  Compartmentalization of HIV-1 between the genital tract and blood was noted in half of 57 women included in 12 studies primarily using cell-free virus. To further understand differences between genital tract and blood viruses of women with chronic HIV-1 infection cell-free and cell-associated virus populations were sequenced from these tissues, reasoning that integrated viral DNA includes variants archived from earlier in infection, and provides a greater array of genotypes for comparisons.
  
  
  RESULTS
  Multiple sequences from single-genome-amplification of HIV-1 RNA and DNA from the genital tract and blood of each woman were compared in a cross-sectional study. Maximum likelihood phylogenies were evaluated for evidence of compartmentalization using four statistical tests. Genital tract and blood HIV-1 appears compartmentalized in 7/13 women by >/=2 statistical analyses. These subjects' phylograms were characterized by low diversity genital-specific viral clades interspersed between clades containing both genital and blood sequences. Many of the genital-specific clades contained monotypic HIV-1 sequences. In 2/7 women, HIV-1 populations were significantly compartmentalized across all four statistical tests; both had low diversity genital tract-only clades. Collapsing monotypic variants into a single sequence diminished the prevalence and extent of compartmentalization. Viral sequences did not demonstrate tissue-specific signature amino acid residues, differential immune selection, or co-receptor usage.
  
  
  CONCLUSIONS
  In women with chronic HIV-1 infection multiple identical sequences suggest proliferation of HIV-1-infected cells, and low diversity tissue-specific phylogenetic clades are consistent with bursts of viral replication. These monotypic and tissue-specific viruses provide statistical support for compartmentalization of HIV-1 between the female genital tract and blood. However, the intermingling of these clades with clades comprised of both genital and blood sequences and the absence of tissue-specific genetic features suggests compartmentalization between blood and genital tract may be due to viral replication and proliferation of infected cells, and questions whether HIV-1 in the female genital tract is distinct from blood.
authors.affiliation: Seattle Children's Hospital Research Institute, Seattle, Washington, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Bull
authors.forename: Gerald
authors.initials: G
authors.lastname: Learn
authors.forename: Indira
authors.initials: I
authors.lastname: Genowati
authors.forename: Jennifer
authors.initials: J
authors.lastname: McKernan
authors.forename: Jane
authors.initials: J
authors.lastname: Hitti
authors.forename: David
authors.initials: D
authors.lastname: Lockhart
authors.forename: Kenneth
authors.initials: K
authors.lastname: Tapia
authors.forename: Sarah
authors.initials: S
authors.lastname: Holte
authors.forename: Joan
authors.initials: J
authors.lastname: Dragavon
authors.forename: Robert
authors.initials: R
authors.lastname: Coombs
authors.forename: James
authors.initials: J
authors.lastname: Mullins
authors.forename: Lisa
authors.initials: L
authors.lastname: Frenkel
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use; D002474:Cell-Free System; D003430:Cross-Sectional Studies; D004279:DNA, Viral / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005836:Genitalia, Female / Q000821:virology*; D005838:Genotype; D015658:HIV Infections / Q000097:blood* / Q000821:virology*; D015497:HIV-1 / Q000145:classification* / Q000378:metabolism*; D006801:Humans; D016013:Likelihood Functions; D010802:Phylogeny; D012367:RNA, Viral / Q000378:metabolism; D013045:Species Specificity
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D012367:RNA, Viral