Role of viral vectors in candidate HIV vaccine-induced immune responses

Over 30 years since the discovery of HIV, the development of a vaccine for the prevention of HIV/AIDS remains a global research priority. Several candidate vaccines have reached clinical efficacy trials in recent years; of these, only the RV144 trial, which utilized the recombinant canarypox vector ALVAC, demonstrated moderate, short-term efficacy, while multiple trials utilizing the recombinant human adenovirus vector Ad5 either demonstrated no efficacy or transiently increased the risk of HIV infection in vaccine recipients with pre-existing immunity to the Ad5 vector. The aim of this dissertation is to help fill the gap in our knowledge of host responses to vaccine vectors in HIV vaccination. Using PBMC collected from participants in the RV144 and HVTN204 clinical trials who received an ALVAC- or Ad5-vectored vaccine, respectively, we show that ALVAC-specific CD4 T cells are significantly less susceptible to HIV infection than Ad5-specific CD4 T cells, which could potentially contribute to the efficacy or non-efficacy of the vaccine regimens employing these two vectors. We also show that, compared to Ad5-specific CD4 T cells, ALVAC-specific CD4 T cells have lower surface expression of CCR5 and CXCR4, higher β-chemokine production, and a more Th1-slanted phenotype, all of which are associated with resistance to HIV infection. Unexpectedly, we also found that ALVAC, but not Ad5, induced a robust vector-specific CD8 T cell response which limited the proliferation of autologous vector-specific CD4 T cells and contributed to their reduced HIV susceptibility. We show that ALVAC-primed APCs are sufficient to induce reduced HIV susceptibility and CCR5 expression in autologous CD4 T cells. We also show that ALVAC- but not Ad5-primed APCs significantly upregulate the Th1-promoting cytokine IL-12, which has been previously reported to induce β-chemokine production and reduce surface expression of CCR5 on CD4 T cells. Finally, we show that ALVAC-primed APCs are themselves less susceptible to HIV infection than Ad5-primed APCs, as well as expressing higher levels of HIV restriction genes, particularly TRIM5 and tetherin. Taken together, our findings reveal a previously unappreciated role for vector-induced immune responses in HIV vaccination and provide new insights for rationale design of candidate HIV vaccines.