Decreased pre-existing ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the step trial independent of vaccination

Cheng Cheng, Ling Shu Wang, Jason G D Gall, Martha Nason, Richard M. Schwartz, M. Juliana McElrath, Steven C. DeRosa, John Hural, Lawrence Corey, Susan P. Buchbinder, Gary J. Nabel

Research output: Contribution to journalArticle

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. Methods and Findings: 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.

Original languageEnglish (US)
Article numbere33969
JournalPLoS One
Volume7
Issue number4
DOIs
StatePublished - Apr 4 2012
Externally publishedYes

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capsid
Capsid
Human immunodeficiency virus 1
Neutralizing Antibodies
neutralizing antibodies
HIV Infections
HIV-1
Vaccination
vaccination
seroprevalence
infection
Capsid Proteins
vaccines
coat proteins
volunteers
Fibers
Volunteers
Immunity
Vaccines
immunity

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Cheng, C., Wang, L. S., Gall, J. G. D., Nason, M., Schwartz, R. M., McElrath, M. J., ... Nabel, G. J. (2012). Decreased pre-existing ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the step trial independent of vaccination. PLoS One, 7(4), [e33969]. https://doi.org/10.1371/journal.pone.0033969

Decreased pre-existing ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the step trial independent of vaccination. / Cheng, Cheng; Wang, Ling Shu; Gall, Jason G D; Nason, Martha; Schwartz, Richard M.; McElrath, M. Juliana; DeRosa, Steven C.; Hural, John; Corey, Lawrence; Buchbinder, Susan P.; Nabel, Gary J.

In: PLoS One, Vol. 7, No. 4, e33969, 04.04.2012.

Research output: Contribution to journalArticle

Cheng, C, Wang, LS, Gall, JGD, Nason, M, Schwartz, RM, McElrath, MJ, DeRosa, SC, Hural, J, Corey, L, Buchbinder, SP & Nabel, GJ 2012, 'Decreased pre-existing ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the step trial independent of vaccination', PLoS One, vol. 7, no. 4, e33969. https://doi.org/10.1371/journal.pone.0033969
Cheng, Cheng ; Wang, Ling Shu ; Gall, Jason G D ; Nason, Martha ; Schwartz, Richard M. ; McElrath, M. Juliana ; DeRosa, Steven C. ; Hural, John ; Corey, Lawrence ; Buchbinder, Susan P. ; Nabel, Gary J. / Decreased pre-existing ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the step trial independent of vaccination. In: PLoS One. 2012 ; Vol. 7, No. 4.
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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. Methods and Findings: 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.",
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AU - Wang, Ling Shu

AU - Gall, Jason G D

AU - Nason, Martha

AU - Schwartz, Richard M.

AU - McElrath, M. Juliana

AU - DeRosa, Steven C.

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AB - 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. Methods and Findings: 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.

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