# CD4+ T cell recognition of HIV-1 alternate reading frame proteins

## TL;DR

This study shows that HIV-1 alternate reading frame proteins can trigger CD4+ T cell responses, suggesting they may help in reversing HIV latency and could be targets for immune treatments.

## Contribution

The study identifies CD4+ T cell recognition of HIV-1 ARFPs and their potential role in latency reversal.

## Key findings

- CD4+ T cell responses to Gag ARFPs were detected in 7 out of 13 chronic progressors.
- ARFP peptides predicted to bind MHC-II were found to be immunogenic.
- HIV RNA was detected in culture supernatants after CD4+ T cell stimulation in 3 out of 6 chronic progressors.

## Abstract

HIV-1 alternative reading frame proteins (ARFPs) have been shown to elicit CD8+ T cell responses, but less is known about the recognition of these proteins by CD4+ T cells. In this study, we analyzed responses of CD8-depleted peripheral blood mononuclear cells from chronic progressors (CPs) on suppressive antiretroviral therapy to ARFP peptide pools derived from HIV Gag, polymerase (Pol), and envelope (Env) proteins. Memory CD4+ T cell responses were detected to Gag ARFP peptide pools in 7 out of 13 CPs and to Env ARFP peptide pools in 2 out of 13 CPs. Individual peptide stimulation identified immunogenic peptides that were predicted to bind to major histocompatibility complex class II (MHC-II) proteins. HIV RNA was detected in culture supernatants from 3 of 6 CPs following stimulation of CD4+ T cells with ARFP peptide pools. These findings demonstrate that ARFP-derived peptides elicit antigen-specific CD4+ T cell responses and may contribute to latency reversal. Our data expand the known HIV immunopeptidome and suggest that ARFPs may serve as potential targets for immune-based interventions.