Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1

Benlahrech, Adel; Harris, Julian D.; Meiser, Andrea; Papagatsias, Timos; Hornig, Julia; Hayes, Peter; Lieber, André; Athanasopoulos, Takis; Bachy, Véronique; Csomor, Eszter; Daniels, Rod S.; Fisher, Kerry; Gotch, Frances; Seymour, Leonard W.; Logan, Karen; Barbagallo, R; Klavinskis, Linda; Dickson, George; Patterson, Steven

doi:10.1073/pnas.0907898106

Cited by 132 publications

(112 citation statements)

References 30 publications

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“…Furthermore, Ad5 seropositive male vaccine recipients in the Step study showed an increased rate of HIV-1 acquisition, making the influence of Ad5 nAbs on vaccine responses an area of intense research (3,4,7,8,(40)(41)(42). Although additional factors likely played a role in acquisition (43)(44)(45), the effect of Ad5 nAbs was significant and has been supported in the nonhuman primate SIV challenge model.…”

Section: Discussionmentioning

confidence: 78%

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 ⁺ T-cell responses but is attenuated by preexisting Ad5 immunity

Zak

Andersen‐Nissen²,

Peterson³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

144

126

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To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8 + T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity.

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Section: Discussionmentioning

confidence: 78%

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 ⁺ T-cell responses but is attenuated by preexisting Ad5 immunity

Zak

Andersen‐Nissen²,

Peterson³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

144

126

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“…Despite induction of vaccine-specific CD4 T cells, excess HIV infections were not observed after gp120/alum vaccination (14) or canarypox primed, gp120 boost vaccination (15). An earlier study using Ad5 vectorpulsed dendritic cells to stimulate autologous T cells reported that in vitro Ad5 activated CD4 T cells are susceptible to HIV infection, which was defined on the basis of comparison with nonactivated resting CD4 T cells in the culture (16). This raised a concern that any CD4 T cells activated in vitro could be preferentially infected by HIV.…”

Section: Discussionmentioning

confidence: 99%

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

Eller

Zafar

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Efforts to develop an efficacious HIV vaccine have been unsuccessful to date. Efficacy trials have reported that recombinant Ad5 (rAd5)-HIV vaccines were not efficacious and unexpectedly associated with excess HIV infection in vaccine recipients. Understanding the underlying mechanisms is urgent and will further HIV vaccine design. By comparing human CD4 T cells specific to Ad5 and CMV, we report that natural exposure- or vaccine-induced Ad5-specific CD4 T cells are highly susceptible to HIV compared with CMV-specific CD4 T cells and selectively manifest a Th17-like proinflammatory phenotype. Our findings suggest a potential mechanism for rAd5-associated excess HIV infections in vaccine recipients and highlight that testing HIV susceptibility of vaccine-generated CD4 T cells may have utility before vaccine evaluation in human trials.

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“…Adenovirus vector was a common virus vector in gene therapy (Benlahrech et al, 2009;Jiang, 2009). It had many advantages, such as strong infection ability, high titer, efficient multicopy, no insertional mutagenesis, no genetic toxicity, etc.…”

Section: Discussionmentioning

confidence: 99%

Preparation of Microspheres Encapsulating a Recombinant TIMP-1 Adenovirus and their Inhibition of Proliferation of Hepatocellular Carcinoma Cells

Dong¹,

Yao²,

Liu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1

Cited by 132 publications

References 30 publications

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 ⁺ T-cell responses but is attenuated by preexisting Ad5 immunity

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 ⁺ T-cell responses but is attenuated by preexisting Ad5 immunity

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

Preparation of Microspheres Encapsulating a Recombinant TIMP-1 Adenovirus and their Inhibition of Proliferation of Hepatocellular Carcinoma Cells

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Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1

Cited by 132 publications

References 30 publications

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 + T-cell responses but is attenuated by preexisting Ad5 immunity

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 + T-cell responses but is attenuated by preexisting Ad5 immunity

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

Preparation of Microspheres Encapsulating a Recombinant TIMP-1 Adenovirus and their Inhibition of Proliferation of Hepatocellular Carcinoma Cells

Contact Info

Product

Resources

About

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 ⁺ T-cell responses but is attenuated by preexisting Ad5 immunity

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 ⁺ T-cell responses but is attenuated by preexisting Ad5 immunity