title: Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals.
abstract: Efficacy trials of adenovirus 5-vectored candidate HIV vaccines [recombinant Ad5 (rAd5)-HIV] were halted for futility due to lack of vaccine efficacy and unexpected excess HIV infections in the vaccine recipients. The potential immunologic basis for these observations is unclear. We comparatively evaluated the HIV susceptibility and phenotypes of human CD4 T cells specific to Ad5 and CMV, two viruses that have been used as HIV vaccine vectors. We show that Ad5-specific CD4 T cells, either induced by natural Ad5 exposure or expanded by rAd5 vaccination, are highly susceptible to HIV in vitro and are preferentially lost in HIV-infected individuals compared with CMV-specific CD4 T cells. Further investigation demonstrated that Ad5-specific CD4 T cells selectively display a proinflammatory Th17-like phenotype and express macrophage inflammatory protein 3α and α4β7 integrin, suggestive of gut mucosa homing potential of these cells. Analysis of HIV p24 and cytokine coexpression using flow cytometry revealed preferential infection of IL-17- and IL-2-producing, Ad5-specific CD4 T cells by HIV in vitro. Our data suggest a potential mechanism explaining the excess HIV infections in vaccine recipients after rAd5-HIV vaccination and highlight the importance of testing the HIV susceptibility of vaccine-generated, vector and insert-specific CD4 T cells in future HIV vaccine studies.
authors.affiliation: US Military HIV Research Program and Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817; hhu@hivresearch.org.
authors.forename: Haitao
authors.initials: H
authors.lastname: Hu
authors.affiliation: US Military HIV Research Program and Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eller
authors.affiliation: US Military HIV Research Program and Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817;
authors.forename: Shah
authors.initials: S
authors.lastname: Zafar
authors.affiliation: Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140;
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102;
authors.forename: Mengnan
authors.initials: M
authors.lastname: Gu
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102;
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910;
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Currier
authors.affiliation: Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20817;
authors.forename: Mary A
authors.initials: MA
authors.lastname: Marovich
authors.affiliation: Makerere University Walter Reed Project, Kampala, Uganda; and.
authors.forename: Hannah N
authors.initials: HN
authors.lastname: Kibuuka
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.affiliation: US Military HIV Research Program and Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817;
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.affiliation: US Military HIV Research Program and.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.affiliation: US Military HIV Research Program and.
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: US Military HIV Research Program and Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817;
authors.forename: Silvia
authors.initials: S
authors.lastname: Ratto-Kim
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000256:Adenoviridae / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology; D004198:Disease Susceptibility; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000473:pathology; D010641:Phenotype; D011995:Recombination, Genetic / Q000235:genetics; D013045:Species Specificity; D058504:Th17 Cells / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D020381:Interleukin-17; D007376:Interleukin-2
keywords: AIDS; antigen-specific CD4 T cells; viral vectors