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Principal Investigator: Mary N. Carrington
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2024
Award: $1,166,652
Funding agency: National Cancer Institute
Associations between HLA Class I alleles and HIV disease have long been known. Established associations in Blacks include protective associations for B5702, B5703, B5801, and B8101, and susceptible associations for B1801, B1802, B4501, and B5802. As such, an understanding of the impact of HLA polymorphism on response to HIV vaccination may inform vaccine design. We investigated HLA associations with HIV-directed immunogenicity in the phase 1/2a APPROACH vaccine trial, which tested vaccine regimens containing mosaic inserts in Ad26 and MVA vectors, with or without a trimeric gp140 protein. This trial studied many aspects of the cellular immune response by ELISpot (Gag, Pol, and Env combined). Participants in the APPROACH trial were Asian in Thailand (N=43), White in USA (N=82), and Black, in USA, East Africa, and South Africa (N=26, 107, and 39, respectively). A principal components analysis (PCA) was performed to reduce the degrees of freedom for the multiple HIV antigens tested in the ELISA and ELISpot analysis. For both assays, the first principal component (PC1) captured more than half of the variance of responses across combined Black vaccinees to the different proteins (ELISA assay) or peptide pools (ELISpot assay). The different immune responses to the various antigens all contributed positively, and approximately equally, to PC1 for both ELISpot and ELISA. These features of the PCA indicated that for both ELISA and ELISpot, responses to the various antigens are strongly positively correlated to one another, and that PC1 effectively captures the overall magnitude of the immune response to the HIV antigens presented. No HLA class I or II allele had a significant association with ELISA PC1. These data indicate a lack of significant HLA allelic association with overall responses to the various antigens tested. All antigen responses contributed positively to ELISpot PC1, whereas in the second principal component (PC2), responses to the various pools of antigens were either positive or negative. Thus, while PC1 captures variance in the overall response to all antigens combined, PC2 captures differential response to the distinct antigens. There were no significant associations of class II alleles with ELISpot PC2 and none for either class I or II alleles with ELISA PC2. Gag responses provided the strongest positive contribution to the ELISpot PC2, Pol was only weakly positive, and Env responses were negative contributors to ELISpot PC2. Previous data have indicated that CD8+ T cell responses to Gag render superior virologic control relative to those targeting Env, and therefore, analyses were concentrated on Gag and Env specifically. Considering that differential responses to Gag antigens compared to Env antigens might provide a biological basis for the ELISpot PC2 association with certain HLA alleles, we therefore defined a "Gag - Env" variable for ELISpot and intracellular staining (ICS) by subtracting the mean Env response from the mean Gag response and tested for HLA class I associations with this variable. Several significant associations were observed. Two HLA class I allelic associations, B45:01 and A0202, reached significance in combined Black participants after correction for multiple tests. There were no significant associations of "Gag - Env" with class I alleles in White participants after correction. ICS provides a means for measuring cellular responses to Env, Gag and Pol peptide pools by CD4+ and CD8+ T cells separately, in contrast to the ELISpot results, which do not distinguish the contribution by these two T cell subsets. There were no HLA associations with CD4 T cell ICS response, indicating that associations observed with the ELISpot data are likely driven by CD8 T cell responses. B5703 showed a significant association with a stronger CD8 T cell ICS "Gag - Env" response for Black participants. There was a tendency towards HLA class I associations for CD8 T cell ICS "Gag - Env" response in White participants, but these fell short of significance after correction. B5703 had a similarly strong association in combined Black participants for the CD8 T cell ICS Gag response considered separately after correction for multiple tests. Associations with CD8 T cell ICS Gag among White participants were significant for two alleles, C0501 and B4402, after correction. We also observed a significant correlation between the effects of HLA-B alleles on HIV viral load control (measured as mean HIV viral load over time) and the Gag - Env variable. Given the virologic control conferred by responses to Gag in natural history HIV infection, these data suggest that HLA alleles conferring protection after HIV infection may also support a more effective cellular response to HIV vaccination. The diversity of HLA class I alleles defines the repertoire of antigenic peptides that are presented on the cell surface. We previously developed a metric to quantitate the functional divergence of HLA class I alleles. HIV cohort analysis demonstrated a significant influence of HLA functional divergence on AIDS progression among HIV-infected individuals. In the context of cancer immunotherapy, the results are less consistent which requires further development of the metric. Cancer presents major differences from infectious diseases such as loss of heterozygosity and neoantigen formation. These factors are being considered in further improvement of the metric.
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