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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 3? and ?4?7 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.

SUBMITTER: Hu H

PROVIDER: S-EPMC4169982 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Hu Haitao H Eller Michael A MA Zafar Shah S Zhou Yu Y Gu Mengnan M Wei Zhi Z Currier Jeffrey R JR Marovich Mary A MA Kibuuka Hannah N HN Bailer Robert T RT Koup Richard A RA Robb Merlin L ML Michael Nelson L NL Kim Jerome H JH Ratto-Kim Silvia S

Proceedings of the National Academy of Sciences of the United States of America 20140902 37

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 induce ...[more]

PMID: 25197078

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Project description:Thrombospondin-related adhesive protein (TRAP) is essential for sporozoite motility and the invasion of mosquitoes' salivary gland and vertebrate's hepatocyte and is, thus, considered a promising pre-erythrocytic vaccine candidate. Despite the existence of a few reports on naturally acquired immune response against Plasmodium vivax TRAP (PvTRAP), it has never been explored so far in the Amazon region, so results are conflicting. Here, we characterized the (IgG and IgG subclass) antibody reactivity against recombinant PvTRAP in a cross-sectional study of 299 individuals exposed to malaria infection in three municipalities (Cruzeiro do Sul, Mâncio Lima and Guajará) from the Acre state of the Brazilian Amazon. In addition, the full PvTRAP sequence was screened for B-cell epitopes using in silico and in vitro approaches. Firstly, we confirmed that PvTRAP is naturally immunogenic in the cohort population since 49% of the individuals were IgG-responders to it. The observed immune responses were mainly driven by cytophilic IgG1 over all other sublcasses and the IgG levels that was corelated with age and time of residence in the studied area (p < 0.05). Interestingly, only the levels of specific anti-TRAP IgG3 seemed to be associated with protection, as IgG3 responders presented a significantly higher time elapse since the last malaria episode than those recorded for IgG3 non-responders. Regarding the B-cell epitope mapping, among the 148 responders to PvTRAP, four predicted epitopes were confirmed by recognition of antibodies (PvTRAPR197-H227; PvTRAPE237-T258; PvTRAPP344-G374; and PvTRAPE439-K454). Nevertheless, the frequency of responders against these peptides were low and did not show a clear correlation with the antibody response against the corresponding antigen. Moreover, none of the linear confirmed epitopes were located in the binding regions of PvTRAP in respect to the host cell ligand. Collectively, our data confirm the PvTRAP immunogenicity among Amazon inhabitants, while suggesting that the main important B-cell epitopes are not linear.

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Dataset Information

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

Publications

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

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