title: HIV-1 shedding from the female genital tract is associated with increased Th1 cytokines/chemokines that maintain tissue homeostasis and proportions of CD8+FOXP3+ T cells.
abstract: BACKGROUND
  HIV-1 shedding from the female genital tract is associated with increased sexual and perinatal transmission and has been broadly evaluated in cross-sectional studies. However, few longitudinal studies have evaluated how the immune microenvironment effects shedding.
  
  
  METHODS
  Thirty-nine HIV-1-infected women had blood, cervicovaginal lavage, and biopsies of the uterine cervix taken quarterly for up to 5 years. Cytokines/chemokines were quantified by Luminex assay in cervicovaginal lavage, and cellular phenotypes were characterized using immunohistochemistry in cervical biopsies. Comparisons of cytokine/chemokine concentrations and the percent of tissue staining positive for T cells were compared using generalized estimating equations between non-shedding and shedding visits across all women and within a subgroup of women who intermittently shed HIV-1.
  
  
  RESULTS
  Genital HIV-1 shedding was more common when plasma HIV-1 was detected. Cytokines associated with cell growth (interleukin-7), Th1 cells/inflammation (interleukin-12p70), and fractalkine were significantly increased at shedding visits compared with non-shedding visits within intermittent shedders and across all subjects. Within intermittent shedders and across all subjects, FOXP3 T cells were significantly decreased at shedding visits. However, there were significant increases in CD8 cells and proportions of CD8FOXP3 T cells associated with HIV-1 shedding.
  
  
  CONCLUSIONS
  Within intermittent HIV-1 shedders, decreases in FOXP3 T cells at the shedding visit suggests that local HIV-1 replication leads to CD4 T-cell depletion, with increases in the proportion of CD8FOXP3 cells. HIV-1-infected cell loss may promote a cytokine milieu that maintains cellular homeostasis and increases immune suppressor cells in response to HIV-1 replication in the cervical tissues.
authors.affiliation: *Department of Pediatrics, University of Washington, Seattle, WA; †Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA; ‡Department of Global Health, University of Washington, Seattle, WA; §Department of Medicine, University of Rochester Medical Center, Rochester, NY; Departments of ‖Pathology; ¶Medicine, University of Washington, Seattle, WA; #Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA; **Department of Laboratory Medicine, University of Washington, Seattle, WA; ††Department of Obstetrics and Gynecology, University of Washington, Seattle, WA (J. Legard is now with the Global Alliance to Prevent Prematurity and Stillbirth Program, Seattle Children's Hospital, Seattle, WA; B. Sorensen is now with Gilead, Seattle, WA; S. E. Cohn is now with the Department of Medicine, Northwestern University, Chicago, IL).
authors.forename: Marta E
authors.initials: ME
authors.lastname: Bull
authors.forename: Jillian
authors.initials: J
authors.lastname: Legard
authors.forename: Kenneth
authors.initials: K
authors.lastname: Tapia
authors.forename: Bess
authors.initials: B
authors.lastname: Sorensen
authors.forename: Susan E
authors.initials: SE
authors.lastname: Cohn
authors.forename: Rochelle
authors.initials: R
authors.lastname: Garcia
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Holte
authors.forename: Robert W
authors.initials: RW
authors.lastname: Coombs
authors.forename: Jane E
authors.initials: JE
authors.lastname: Hitti
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000502:physiology* / Q000821:virology; D054428:Chemokine CX3CL1 / Q000502:physiology; D018925:Chemokines / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005836:Genitalia, Female / Q000821:virology*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D015851:Interleukin-7 / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000502:physiology; D018417:Th1 Cells / Q000502:physiology* / Q000821:virology; D019562:Viral Load / Q000502:physiology; D017201:Virus Shedding / Q000502:physiology*
chemical_list: D054428:Chemokine CX3CL1; D018925:Chemokines; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D015851:Interleukin-7