title: Decreased pre-existing Ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the Step trial independent of vaccination.
abstract: BACKGROUND
  The Step trial raised the possibility that uncircumcised men with pre-existing Ad5 neutralizing antibodies carried an increased risk of HIV infection after vaccination. Thus, understanding Ad seropositivity in humans is important to the development of an AIDS vaccine. Here, we analyze the impact of different Ad5-specific neutralizing antibodies on immune function and clinical outcome.
  
  
  RESULTS
  Ad seropositivity in the Step trial volunteers was analyzed using chimeric rAd5/35 vectors to characterize their specificity for Ad5 fiber and non-fiber external (capsid) proteins. Immune responses and HIV seropositivity were correlated with the specificity of Ad5-neutralizing antibodies. Neutralizing antibodies induced by the vaccine in Ad5 seronegative subjects were directed preferentially to Ad5 capsid proteins, although some fiber-neutralizing antibodies could be detected. Pre-vaccination Ad5 serostatus did not affect the capsid-directed response after three vaccinations. In contrast, anti-fiber antibody titers were significantly higher in volunteers who were Ad5 seropositive prior to vaccination. Those Ad5 seropositive subjects who generated anti-capsid responses showed a marked reduction in vaccine-induced CD8 responses. Unexpectedly, anti-vector immunity differed qualitatively in Ad5 seropositive participants who became HIV-1 infected compared to uninfected case controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected subjects compared with uninfected case controls, while seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups.
  
  
  CONCLUSIONS
  Together, these findings suggest that the case subjects were less immunologically responsive prior to infection. Subjects infected during the Step trial had qualitative differences in immunity that increased their risk of HIV-1 infection independent of vaccination.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Insititutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Lingshu
authors.initials: L
authors.lastname: Wang
authors.forename: LingShu
authors.initials: L
authors.lastname: Wang
authors.forename: Jason G D
authors.initials: JG
authors.lastname: Gall
authors.forename: Martha
authors.initials: M
authors.lastname: Nason
authors.forename: Richard M
authors.initials: RM
authors.lastname: Schwartz
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: Steven C
authors.initials: SC
authors.lastname: DeRosa
authors.forename: John
authors.initials: J
authors.lastname: Hural
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: Susan P
authors.initials: SP
authors.lastname: Buchbinder
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000257:Adenoviridae Infections / Q000150:complications / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000209:etiology*; D006679:HIV Seropositivity / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D008297:Male; D012307:Risk Factors; D016036:Seroepidemiologic Studies; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D036022:Capsid Proteins