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Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine
Nicole Frahm, … , Stephen C. De Rosa, M. Juliana McElrath
Nicole Frahm, … , Stephen C. De Rosa, M. Juliana McElrath
Published December 27, 2011
Citation Information: J Clin Invest. 2012;122(1):359-367. https://doi.org/10.1172/JCI60202.
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Research Article

Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine

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Abstract

Recombinant viruses hold promise as vectors for vaccines to prevent infectious diseases with significant global health impacts. One of their major limitations is that preexisting anti-vector neutralizing antibodies can reduce T cell responses to the insert antigens; however, the impact of vector-specific cellular immunity on subsequent insert-specific T cell responses has not been assessed in humans. Here, we have identified and compared adenovirus-specific and HIV-specific T cell responses in subjects participating in two HIV-1 vaccine trials using a vaccine vectored by adenovirus serotype 5 (Ad5). Higher frequencies of pre-immunization adenovirus-specific CD4+ T cells were associated with substantially decreased magnitude of HIV-specific CD4+ T cell responses and decreased breadth of HIV-specific CD8+ T cell responses in vaccine recipients, independent of type-specific preexisting Ad5-specific neutralizing antibody titers. Further, epitopes recognized by adenovirus-specific T cells were commonly conserved across many adenovirus serotypes, suggesting that cross-reactivity of preexisting adenovirus-specific T cells can extend to adenovirus vectors derived from rare serotypes. These findings provide what we believe to be a new understanding of how preexisting viral immunity may impact the efficacy of vaccines under current evaluation for prevention of HIV, tuberculosis, and malaria.

Authors

Nicole Frahm, Allan C. DeCamp, David P. Friedrich, Donald K. Carter, Olivier D. Defawe, James G. Kublin, Danilo R. Casimiro, Ann Duerr, Michael N. Robertson, Susan P. Buchbinder, Yunda Huang, Gregory A. Spies, Stephen C. De Rosa, M. Juliana McElrath

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Figure 2

Baseline Ad-specific CD4+ T cell responses are inversely associated with insert-specific T cell responses.

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Baseline Ad-specific CD4+ T cell responses are inversely associated with...
The magnitude of the baseline Ad-specific CD4+ T cell response (defined as %CD4+ T cells producing IFN-γ and/or IL-2 following stimulation with empty Ad5 vector) on the x axis is plotted against (A) the magnitude of the HIV-specific CD4+ T cell response at the memory time point or (B) the estimated probability of having HIV-specific CD8+ T cells recognizing 0, 1, 2, or 3 proteins at the peak time point on the y axes. (A) The solid line is the regression line of the predicted HIV-specific CD4+ T cell response at the memory time point given the magnitude of the baseline Ad-specific CD4+ T cell response. (B) Estimated probabilities are based on a proportional odds model (see Methods). The regression line in A and probability estimates in B have been adjusted for sex, number of vaccinations, and log10 Ad5 nAb titer distributions.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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