Adenovirus-based HIV-1 vaccine candidates tested in efficacy trials elicit CD8+ T cells with limited breadth of HIV-1 inhibition

Objectives: The ability of HIV-1 vaccine candidates MRKAd5, VRC DNA/Ad5 and ALVAC/AIDSVAX to elicit CD8(+) T cells with direct antiviral function was assessed and compared with HIV-1-infected volunteers. Design: Adenovirus serotype 5 (Ad5)-based regimens MRKAd5 and VRC DNA/Ad5, designed to elicit HIV-1-specific T cells, are immunogenic but failed to prevent infection or impact on viral loads in volunteers infected subsequently. Failure may be due in part to a lack of CD8(+) T cells with effective antiviral functions. Methods: An in-vitro viral inhibition assay tested the ability of bispecific antibody expanded CD8(+) T cells from peripheral blood mononuclear cells to inhibit replication of a multiclade panel of HIV-1 isolates in autologous CD4(+) T cells. HIV-1 proteins recognized by CD8(+) T cells were assessed by IFNg enzyme-linked immunospot assay. Results: Ad5-based regimens elicited CD8(+) T cells that inhibited replication of HIV-1 IIIB isolate with more limited inhibition of other isolates. IIIB isolate Gag and Pol genes have high sequence identities (>96%) to vector HIV-1 gene inserts, and these were the predominant HIV-1 proteins recognized by CD8(+) T cells. Virus inhibition breadth was greater in antiretroviral naive HIV-1-infected volunteers naturally controlling viremia (plasma viral load <10 000/ml). HIV-1-inhibitory CD8(+) T cells were not elicited by the ALVAC/AIDSVAX regimen. Conclusion: The Ad5-based regimens, although immunogenic, elicited CD8(+) T cells with limited HIV-1-inhibition breadth. Effective T-cell-based vaccines should presumably elicit broader HIV-1-inhibition profiles. The viral inhibition assay can be used in vaccine design and to prioritize promising candidates with greater inhibition breadth for further clinical trials. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.