title: T cell chemo-vaccination effects after repeated mucosal SHIV exposures and oral pre-exposure prophylaxis.
abstract: Pre-exposure prophylaxis (PrEP) with anti-viral drugs is currently in clinical trials for the prevention of HIV infection. Induction of adaptive immune responses to virus exposures during anti-viral drug administration, i.e., a "chemo-vaccination" effect, could contribute to PrEP efficacy. To study possible chemo-vaccination, we monitored humoral and cellular immune responses in nine rhesus macaques undergoing up to 14 weekly, low-dose SHIV(SF162P3) rectal exposures. Six macaques concurrently received PrEP with intermittent, oral Truvada; three were no-PrEP controls. PrEP protected 4 macaques from infection. Two of the four showed evidence of chemo-vaccination, because they developed anti-SHIV CD4(+) and CD8(+) T cells; SHIV-specific antibodies were not detected. Control macaques showed no anti-SHIV immune responses before infection. Chemo-vaccination-induced T cell responses were robust (up to 3,940 SFU/10(6) PBMCs), predominantly central memory cells, short-lived (≤22 weeks), and appeared intermittently and with changing specificities. The two chemo-vaccinated macaques were virus-challenged again after 28 weeks of rest, after T cell responses had waned. One macaque was not protected from infection. The other macaque concurrently received additional PrEP. It remained uninfected and T cell responses were boosted during the additional virus exposures. In summary, we document and characterize PrEP-induced T cell chemo-vaccination. Although not protective after subsiding in one macaque, chemo-vaccination-induced T cells warrant more comprehensive analysis during peak responses for their ability to prevent or to control infections after additional exposures. Our findings highlight the importance of monitoring these responses in clinical PrEP trials and suggest that a combination of vaccines and PrEP potentially might enhance efficacy.
authors.affiliation: Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America. egk6@cdc.gov
authors.forename: Ellen N
authors.initials: EN
authors.lastname: Kersh
authors.forename: Debra R
authors.initials: DR
authors.lastname: Adams
authors.forename: Ae S
authors.initials: AS
authors.lastname: Youngpairoj
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Qi
authors.initials: Q
authors.lastname: Zheng
authors.forename: Mian-er
authors.initials: ME
authors.lastname: Cong
authors.forename: Wutyi
authors.initials: W
authors.lastname: Aung
authors.forename: James
authors.initials: J
authors.lastname: Mitchell
authors.forename: Ron
authors.initials: R
authors.lastname: Otten
authors.forename: R Michael
authors.initials: RM
authors.lastname: Hendry
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
authors.forename: Janet
authors.initials: J
authors.lastname: McNicholl
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: Garcia-Lerma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D000939:Epitopes / Q000276:immunology; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D008297:Male; D009092:Mucous Membrane / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000276:immunology*; D014611:Vaccination
chemical_list: D016207:Cytokines; D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D000939:Epitopes; D009943:Organophosphorus Compounds; D003841:Deoxycytidine