Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals

Haitao Hu, Michael A. Eller, Shah Zafar, Yu Zhou, Mengnan Gu, Zhi Wei, Jeffrey R. Currier, Mary A. Marovich, Hannah N. Kibuuka, Robert T. Bailer, Richard A. Koup, Merlin L. Robb, Nelson L. Michael, Jerome H. Kim, Silvia Ratto-Kim

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)13439-13444
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number37
DOIs
StatePublished - Sep 16 2014
Externally publishedYes

Fingerprint

AIDS Vaccines
HIV
T-Lymphocytes
Infection
Vaccines
HIV Infections
Vaccination
HIV Core Protein p24
Medical Futility
Phenotype
Macrophage Inflammatory Proteins
Interleukin-17
Adenoviridae
Integrins
Interleukin-2
Flow Cytometry
Mucous Membrane
Cytokines
Viruses
In Vitro Techniques

Keywords

  • AIDS
  • Antigen-specific CD4 T cells
  • Viral vectors

ASJC Scopus subject areas

  • General

Cite this

Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals. / Hu, Haitao; Eller, Michael A.; Zafar, Shah; Zhou, Yu; Gu, Mengnan; Wei, Zhi; Currier, Jeffrey R.; Marovich, Mary A.; Kibuuka, Hannah N.; Bailer, Robert T.; Koup, Richard A.; Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.; Ratto-Kim, Silvia.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 37, 16.09.2014, p. 13439-13444.

Research output: Contribution to journalArticle

Hu, H, Eller, MA, Zafar, S, Zhou, Y, Gu, M, Wei, Z, Currier, JR, Marovich, MA, Kibuuka, HN, Bailer, RT, Koup, RA, Robb, ML, Michael, NL, Kim, JH & Ratto-Kim, S 2014, 'Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 37, pp. 13439-13444. https://doi.org/10.1073/pnas.1400446111
Hu, Haitao ; Eller, Michael A. ; Zafar, Shah ; Zhou, Yu ; Gu, Mengnan ; Wei, Zhi ; Currier, Jeffrey R. ; Marovich, Mary A. ; Kibuuka, Hannah N. ; Bailer, Robert T. ; Koup, Richard A. ; Robb, Merlin L. ; Michael, Nelson L. ; Kim, Jerome H. ; Ratto-Kim, Silvia. / Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 37. pp. 13439-13444.
@article{616ce48ccb854bd8891c242fc8c9d8ab,
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.",
keywords = "AIDS, Antigen-specific CD4 T cells, Viral vectors",
author = "Haitao Hu and Eller, {Michael A.} and Shah Zafar and Yu Zhou and Mengnan Gu and Zhi Wei and Currier, {Jeffrey R.} and Marovich, {Mary A.} and Kibuuka, {Hannah N.} and Bailer, {Robert T.} and Koup, {Richard A.} and Robb, {Merlin L.} and Michael, {Nelson L.} and Kim, {Jerome H.} and Silvia Ratto-Kim",
year = "2014",
month = "9",
day = "16",
doi = "10.1073/pnas.1400446111",
language = "English (US)",
volume = "111",
pages = "13439--13444",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "37",

}

TY - JOUR

T1 - Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals

AU - Hu, Haitao

AU - Eller, Michael A.

AU - Zafar, Shah

AU - Zhou, Yu

AU - Gu, Mengnan

AU - Wei, Zhi

AU - Currier, Jeffrey R.

AU - Marovich, Mary A.

AU - Kibuuka, Hannah N.

AU - Bailer, Robert T.

AU - Koup, Richard A.

AU - Robb, Merlin L.

AU - Michael, Nelson L.

AU - Kim, Jerome H.

AU - Ratto-Kim, Silvia

PY - 2014/9/16

Y1 - 2014/9/16

N2 - 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.

AB - 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.

KW - AIDS

KW - Antigen-specific CD4 T cells

KW - Viral vectors

UR - http://www.scopus.com/inward/record.url?scp=84907190281&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907190281&partnerID=8YFLogxK

U2 - 10.1073/pnas.1400446111

DO - 10.1073/pnas.1400446111

M3 - Article

VL - 111

SP - 13439

EP - 13444

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 37

ER -