Upgrading the HIV vaccine paradigm: accounting for host-pathogen diversity through geotargeting-based vaccine design

Effective HIV vaccine development, with satisfactory levels of response and coverage, remains an elusive goal in immunology. In this context, considerations of host-pathogen interactions from a geotargeting perspective could enhance disease control efforts. Current HIV vaccine strategies increasingly seek to address viral diversity, but the combined effects of regional viral variation and host HLA diversity on antigen processing and presentation remain insufficiently considered. Here, we evaluated whether integrating these host-pathogen variables could support geographically informed prioritization of HIV vaccine targets.

Using NetMHCpan 4.1, NetChop 3.1, and the IEDB antigen-processing prediction tool, we evaluated antigen-processing and presentation steps for HIV epitopes associated with viral control. We recovered Human Leukocyte Antigen (HLA) alleles associated with HIV control and their frequencies, and the protein sequences for the most common HIV subtypes in different African countries. We created maps linking both sets of information for each specific region. We then predicted the impact of mutations associated with different HIV strain sequences on proteasome processing score, TAP transportation and HLA binding affinity for the alleles in each host population.

The generated maps provide a landscape of the impact of genetic diversity on T cell responses for each examined epitope target. TW10 epitope variants in the main HIV subtypes showed consistent HLA binding, proteasome cleavage and processing rankings across the continent. Conversely, TI8 variants carrying I8T or I8R substitutions lost predicted HLA-B*51:01 binding and showed marked deterioration in the combined processing ranking, from 10th for the reference epitope to positions as low as 97th among the analyzed variants.

The adoption of uniform immunotherapy strategies based solely on reference HIV epitopes may be an inefficient approach. Certain epitopes may be suitable vaccine targets for specific locations, when matching a prevalent HIV strain with a host population with high prevalence of HLA alleles that can effectively display the vaccine's epitopes. However, HLA matching is not enough if the HIV strains in the region have upstream or downstream mutations that prevent the proper processing and presentation of the targeted viral epitope. Based on this complex host-pathogen interplay, we propose a geotargeting approach to vaccine design, considering customized targets for specific geographical locations and host populations. By incorporating regional viral and HLA diversity into target selection, this strategy may increase the likelihood of developing more effective HIV vaccines, although the resulting predictions will require experimental validation.