CD8ɑ+ cells suppress SIV replication without the development of mutations within MHC class-I-restricted epitopes...

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Post-treatment control (PTC) is a rare phenomenon where individuals living with HIV (PLWH) maintain viral suppression after stopping antiretroviral therapy (ART).
• Mechanisms underlying PTC, especially concerning viral population dynamics during immune control, remain poorly understood, particularly in the absence of detectable viremia.

Purpose of the Study:

• To investigate how viral populations change during CD8+ T-cell-mediated PTC using a Mauritian cynomolgus macaque (MCM) model.
• To characterize viral lineages and T-cell epitopes to understand factors influencing durable, ART-free viral control.

Main Methods:

• Infection of MCMs with barcoded SIVmac239M, followed by ART, ART interruption, rechallenge, and CD8+ T-cell depletion.
• Deep sequencing of plasma virus barcodes to analyze viral lineage dynamics.
• Sequencing of CD8+ T-cell epitopes within plasma viruses to identify mutations.

Main Results:

• Early ART initiation limited viral diversity and delayed viral rebound after ART interruption.
• Viral lineages with high pre-ART viral loads dominated post-ART rebound populations.
• CD8+ T-cell depletion led to viral rebound, with mutations in T-cell epitopes observed only in viremic animals post-depletion.

Conclusions:

• Early ART initiation is associated with reduced viral diversity within cytotoxic T lymphocyte (CTL) epitopes and a longer time to viral rebound.
• Restricting the emergence of variant CTL epitopes is crucial for increasing the likelihood of PTC.
• The MCM model provides insights into mechanisms of durable ART-free viral control and highlights CD8-mediated immune control as a therapeutic target for HIV cure.