title: Repeated Vaginal SHIV Challenges in Macaques Receiving Oral or Topical Preexposure Prophylaxis Induce Virus-Specific T-Cell Responses.
abstract: BACKGROUND
  Preexposure prophylaxis (PrEP) for HIV prevention is a novel biomedical prevention method. We have previously modeled PrEP during rectal SHIV exposures in macaques and identified that Simian/Human Immunodeficiency Virus chimera (SHIV)-specific T-cell responses were induced in the presence of antiretroviral drugs, an observation previously termed T-cell chemo-vaccination. This report expands those initial findings by examining a larger group of macaques that were given oral or topical PrEP during repeated vaginal virus exposure.
  
  
  METHODS
  Thirty-six female pigtail macaques received up to 20 repeat low-dose vaginal inoculations with wild-type (WT) SHIVSF162P3 (n = 24) or a clonal derivative with the tenofovir (TFV) K65R drug-resistant mutation (n = 12). PrEP consisted of oral Truvada (n = 6, WT), TFV vaginal gel (n = 6, K65R), or TFV intravaginal ring (n = 6, WT). The remaining animals were PrEP-inexperienced controls (n = 12, WT; n = 6, K65R). SHIV-specific T cells were identified and characterized using interferon γ Enzyme-Linked ImmunoSpot (ELISPOT) and multiparameter flow cytometry.
  
  
  RESULTS
  Of 9 animals that were on PrEP and remained uninfected during WT SHIV vaginal challenges, 8 (88.9%) developed virus-specific T-cell responses. T cells were in CD4 and CD8 compartments, reached up to 4900 interferon γ-producing cells per million peripheral blood mononuclear cells, and primarily pol directed. In contrast, the replication-impaired K65R virus did not induce detectable T-cell responses, likely reflecting the need for adequate replication.
  
  
  CONCLUSIONS
  Virus-specific T-cell responses occur frequently in oral or topical PrEP-protected pigtail macaques after vaginal exposure to WT SHIV virus. The contribution of such immune responses to protection from infection during and after PrEP warrants further investigation.
authors.affiliation: Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, NCHHSTP, Laboratory Branch, Atlanta, GA.
authors.forename: Theodros S
authors.initials: TS
authors.lastname: Tsegaye
authors.forename: Katherine
authors.initials: K
authors.lastname: Butler
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Jessica
authors.initials: J
authors.lastname: Radzio
authors.forename: Priya
authors.initials: P
authors.lastname: Srinivasan
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.forename: Rachael D
authors.initials: RD
authors.lastname: Aubert
authors.forename: Debra L
authors.initials: DL
authors.lastname: Hanson
authors.forename: Charles
authors.initials: C
authors.lastname: Dobard
authors.forename: Jose Gerardo
authors.initials: JG
authors.lastname: Garcia-Lerma
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
authors.forename: Janet M
authors.initials: JM
authors.lastname: McNicholl
authors.forename: Ellen N
authors.initials: EN
authors.lastname: Kersh
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives*; D004338:Drug Combinations; D024882:Drug Resistance, Viral; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D008254:Macaca nemestrina; D009943:Organophosphorus Compounds; D065129:Pre-Exposure Prophylaxis; D016865:Reassortant Viruses / Q000187:drug effects; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D009943:Organophosphorus Compounds; D003841:Deoxycytidine