HIV vaccines induce CD8 <sup>+</sup> T cells with low antigen receptor sensitivity

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Abstract

Current HIV vaccines designed to stimulate CD8 ⁺ T cells have failed to induce immunologic control upon infection. The functions of vaccine-induced HIV-specific CD8 ⁺ T cells were investigated here in detail. Cytotoxic capacity was significantly lower than in HIV controllers and was not a consequence of low frequency or unaccumulated functional cytotoxic proteins. Low cytotoxic capacity was attributable to impaired degranulation in response to the low antigen levels present on HIV-infected targets. The vaccine-induced T cell receptor (TCR) repertoire was polyclonal and transduction of these TCRs conferred the same reduced functions. These results define a mechanism accounting for poor antiviral activity induced by these vaccines and suggest that an effective CD8 ⁺ T cell response may require a vaccination strategy that drives further TCR clonal selection.

Editor’s summary

Vaccine-generated CD8 ⁺ T cells could play an important role in containing HIV below detectable levels. In chronic infection, robust correlates of spontaneous immunologic control have been identified. Based upon preclinical work in SIV- or SHIV-challenged Rhesus macaques, CD8 ⁺ T cells induced by vaccines or passive transfer of antibodies during acute infection appear to fully suppress or even eradicate lentiviral infection. Despite these advances, the correlates of this activity are not fully understood. Migueles et al . report that low antigen levels present on HIV-infected targets caused impaired degranulation and low CD8 ⁺ T cell–mediated cytotoxicity. The TCR repertoire was polyclonal, and transduction of these TCRs conferred the same reduced functions. Thus, effective CD8 ⁺ T cell responses in HIV/AIDS vaccination may require a strategy that drives further TCR clonal selection. —Seth Thomas Scanlon

Abstract

HIV vaccine–induced cytotoxic T cells kill HIV-infected targets poorly due to low T cell receptor antigen sensitivity.

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Most cited references 53

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Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer.

Eric Tran, Simon Turcotte, Alena Gros … (2014)

Limited evidence exists that humans mount a mutation-specific T cell response to epithelial cancers. We used a whole-exomic-sequencing-based approach to demonstrate that tumor-infiltrating lymphocytes (TIL) from a patient with metastatic cholangiocarcinoma contained CD4+ T helper 1 (T(H)1) cells recognizing a mutation in erbb2 interacting protein (ERBB2IP) expressed by the cancer. After adoptive transfer of TIL containing about 25% mutation-specific polyfunctional T(H)1 cells, the patient achieved a decrease in target lesions with prolonged stabilization of disease. Upon disease progression, the patient was retreated with a >95% pure population of mutation-reactive T(H)1 cells and again experienced tumor regression. These results provide evidence that a CD4+ T cell response against a mutated antigen can be harnessed to mediate regression of a metastatic epithelial cancer.

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HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors.

Stephen Migueles, Alisha C Laborico, W Shupert … (2002)

It is unclear why immunological control of HIV replication is incomplete in most infected individuals. We examined here the CD8+ T cell response to HIV-infected CD4+ T cells in rare patients with immunological control of HIV. Although high frequencies of HIV-specific CD8+ T cells were present in nonprogressors and progressors, only those of nonprogressors maintained a high proliferative capacity. This proliferation was coupled to increases in perforin expression. These results indicated that nonprogressors were differentiated by increased proliferative capacity of HIV-specific CD8+ T cells linked to enhanced effector function. In addition, the relative absence of these functions in progressors may represent a mechanism by which HIV avoids immunological control.

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HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.

M. Juliana McElrath, Stephen De Rosa, Zoe Moodie … (2008)

In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-gamma ELISPOT and intracellular cytokine staining assays, using a case-cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2(lo)) CD4+ T cells expressing CCR5. We detected interferon-gamma-secreting HIV-specific T cells (range 163/10(6) to 686/10(6) peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon gamma or tumor necrosis factor alpha (TNFalpha), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0.4-1.0%) in 117 of 160 (73%) participants, expressing predominantly either interferon gamma alone or with TNFalpha. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2(lo)/CCR5+CD4+ T cells did not differ between cases and non-cases. Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.