Trivalent Adenovirus Type 5 HIV Recombinant Vaccine Primes for Modest Cytotoxic Capacity That Is Greatest in Humans with Protective HLA Class I Alleles

Abstract

If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP. We observed readily detectable HIV-specific CD8+ T-cell recall cytotoxic responses in vaccinees at a median of 331 days following the last immunization. The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays. Although the recall cytotoxic capacity of the CD8+ T-cells of the vaccinee group was significantly less than that of LTNP and overlapped with that of progressors, we observed significantly higher cytotoxic responses in vaccine recipients carrying the HLA class I alleles B*27, B*57 or B*58, which have been associated with immune control over HIV replication in chronic infection. These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses.

Immunotherapy Against HPV16/18 Generates Potent T H 1 and Cytotoxic Cellular Immune Responses

“…As a possible dose effect was also observed in the IFN-γ ELISpot assay, a regression analysis was performed to determine whether the magnitude of IFN-γ ELISpot correlated with the magnitude of killing measured. As reported by other groups (46, 53), there was no significant correlation between IFN-γ and killing magnitudes ( P = 0.2315; fig. S3A).…”

Comprehensive analysis of unique cases with extraordinary control over HIV replication

“…by guest www.bloodjournal.org From patients and HIV-uninfected recipients of a replication incompetent adenovirus serotype 5/HIV vaccine, which suggested the series of events starting with proliferation and culminating in cytotoxicity are preferentially preserved in persons with protective HLA alleles. 3,17,18,46,50 Despite an exhaustive evaluation, we cannot definitively conclude what mechanisms are responsible for the unique phenotype of the cases and, for that matter, whether the same ones are operating in all 4 or to the same extent. Some possibilities include aborted infection occurring after acquisition of attenuated viruses, robust immune responses, or both.…”

“…These 2 measurements of killing were strongly correlated when all patients were analyzed ( Figure 6F), as shown previously. 3,17,46 In summary, the HIV-specific CD8 ϩ T-cell killing responses of the cases as a group were disproportionately high for the extremely low HIV RNA levels but were relatively low compared with those of typical LTNPs/ECs.…”

HLA and Pharmacogenetics of Drug Hypersensitivity

“…Additional significant SNPs were also identified in BAT1 (rs2734583) and HCP5 (rs3099844). BAT1 has a role in the regulation of TNF-a and has been associated with rheumatoid arthritis [109,110], while HCP5 is in strong LD with HLA-B*5701 has been linked to HIV progression and ABC HSR [111][112][113][114]. It is intriguing that in GWAS of both NVP-and allopurinol-induced adverse skin reactions the same susceptibility genes have been identified in unrelated populations and that they are also associated with other inflammatory-based skin disorders [91, 106,108].…”