# HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses

## TL;DR

This study shows that CD4+ T cells can drive HIV evolution by selecting for viral escape mutations, which could inform future vaccine strategies.

## Contribution

The study introduces a novel computational method to identify CD4+ T cell-driven HIV escape mutations using HLA-II associated polymorphisms.

## Key findings

- 29 HLA-II associated HIV sequence polymorphisms were identified as potential CD4+ T cell escape mutations.
- CD4+ T cell responses to escape epitopes were significantly lower compared to non-escape epitopes.
- Longitudinal data confirmed that CD4+ T cells drive viral escape mutations following acute HIV infection.

## Abstract

Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1) exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences and HLA-II allelic data, we identified 29 HLA-II associated HIV sequence polymorphisms or adaptations (HLA-AP) in an African cohort of chronically HIV-infected individuals. Epitopes encompassing the predicted adaptation (AE) or its non-adapted (NAE) version were evaluated for immunogenicity. Using a CD8-depleted IFN-γ ELISpot assay, we determined that the magnitude of CD4+ T cell responses to the predicted epitopes in controllers was higher compared to non-controllers (p<0.0001). However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001). CD4+ T cell responses in patients with acute HIV infection (AHI) demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus. Longitudinal data in AHI off antiretroviral therapy demonstrated sequence changes that were biologically confirmed to represent CD4+ escape mutations. These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.

In HIV, CD4+ T cells are best known as the primary targets of infection. Although emerging data has suggested a more active role in viral pathogenesis, the CD4+ T cell population remains relatively understudied. Using a novel computational approach, we predicted 29 different epitopes with mutations that potentially represent escape from CD4+ T cell responses. The predicted escaped epitopes were found to be less immunogenic than the wild type forms, suggesting that the identified escapes allow HIV to reduce its visibility to the immune system. Using longitudinal samples, we were able to show CD4+ T cells driving viral escape following acute infection. Overall, these findings significantly expand our knowledge of how CD4+ T cells can exert HIV control and influence HIV evolution, providing important implications to future vaccine development strategies.