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

Publication Type:

Journal Article

Source:

AIDS (London, England), Volume 30, Issue 11, p.1703-1712 (2016)

Abstract:

OBJECTIVES: The ability of HIV-1 vaccine candidates; MRKAd5, VRC DNA/Ad5 and ALVAC/AIDSVAX to elicit CD8 T-cells with direct anti-viral function was assessed and compared with HIV-1 infected subjects. 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 subjects infected subsequently. Failure may be due in part to a lack of CD8 T-cells with effective anti-viral functions. METHODS: An in vitro viral inhibition assay (VIA) tested the ability of bi-specific antibody expanded CD8 T-cells from peripheral blood mononuclear cells (PBMC) to inhibit replication of a multi-clade panel of HIV-1 isolates in autologous CD4 T-cells. HIV-1 proteins recognized by CD8 T-cells were assessed by IFNγ ELISpot 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 naïve HIV-1 infected subjects naturally controlling viremia (plasma viral load (pVL) < 10000/mL). HIV-1 inhibitory CD8 T-cells were not elicited by the ALVAC/AIDSVAX regimen. CONCLUSIONS: 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 VIA can be used in vaccine design and to prioritise promising candidates with greater inhibition breadth for further clinical trials.