The concerns raised from adenovirus 5 (Ad5)-based HIV vaccine clinical trials, where excess HIV infections were observed in some vaccine recipients, have highlighted the importance of understanding host responses to vaccine vectors and the HIV susceptibility of vector-specific CD4 T cells in HIV vaccination. Our recent study reported that human Ad5-specific CD4 T cells induced by Ad5 vaccination (RV156A trial) are susceptible to HIV. Here we further investigated the HIV susceptibility of vector-specific CD4 T cells induced by ALVAC, a canarypox viral vector tested in the Thai trial RV144, as compared to Ad5 vector-specific CD4 T cells in the HVTN204 trial. We showed that while Ad5 vector-specific CD4 T cells were readily susceptible to HIV, ALVAC-specific CD4 T cells in RV144 PBMC were substantially less susceptible to both R5 and X4 HIV in vitro. The lower HIV susceptibility of ALVAC-specific CD4 T cells was associated with the reduced surface expression of HIV entry co-receptors CCR5 and CXCR4 on these cells. Phenotypic analyses identified that ALVAC-specific CD4 T cells displayed a strong Th1 phenotype, producing higher levels of IFN-γ and CCL4 (MIP-1β) but little IL-17. Of interest, ALVAC and Ad5 vectors induced distinct profiles of vector-specific CD8 vs. CD4 T-cell proliferative responses in PBMC, with ALVAC preferentially inducing CD8 T-cell proliferation, while Ad5 vector induced CD4 T-cell proliferation. Depletion of ALVAC-, but not Ad5-, induced CD8 T cells in PBMC led to a modest increase in HIV infection of vector-specific CD4 T cells, suggesting a role of ALVAC-specific CD8 T cells in protecting ALVAC-specific CD4 T cells from HIV. Taken together, our data provide strong evidence for distinct HIV susceptibility of CD4 T cells induced by different vaccine vectors and highlight the importance of better evaluating anti-vector responses in HIV vaccination.

基于腺病毒5（Ad5）的HIV疫苗临床试验引起的关注（在某些疫苗接受者中观察到过量的HIV感染）凸显了理解宿主对疫苗载体的反应以及载体中CD4 T细胞对HIV敏感性的重要性。艾滋病毒疫苗接种。我们最近的研究报告说，通过Ad5疫苗接种诱导的人Ad5特异性CD4 T细胞（RV156A试验）易感染HIV。在这里，我们进一步研究了由ALVAC诱导的载体特异性CD4 T细胞对HIV的敏感性，ALVAC是在泰国试验RV144中测试的金丝雀痘病毒载体，与HVTN204试验中Ad5载体特异性CD4 T细胞相比。我们发现，虽然Ad5载体特异性CD4 T细胞很容易感染HIV，但RV144 PBMC中的ALVAC特异性CD4 T细胞对R5和X4 HIV的敏感性都大大降低体外。ALVAC特异性CD4 T细胞的较低HIV易感性与这些细胞上HIV进入共受体CCR5和CXCR4的表面表达降低有关。表型分析表明，ALVAC特异的CD4 T细胞表现出较强的Th1表型，产生更高水平的IFN-γ和CCL4（MIP-1β），而产生的IL-17却很少。令人感兴趣的是，ALVAC和Ad5载体在PBMC中诱导了载体特异性CD8与CD4 T细胞增殖反应的不同特征，其中ALVAC优先诱导CD8 T细胞增殖，而Ad5载体诱导CD4 T细胞增殖。PBMC中ALVAC而非Ad5-诱导的CD8 T细胞的耗竭导致HIV感染载体特异性CD4 T细胞的感染程度适度增加，表明ALVAC特异性CD8 T细胞在保护ALVAC特异性CD4 T细胞中的作用来自艾滋病毒。在一起