HIV-1 plasma variants encoding truncated reverse transcriptase (RT) in a patient with high RT-specific CD8+ memory...

Area of Science:

• Virology
• Immunology
• Genetics

Background:

• Human immunodeficiency virus type 1 (HIV-1) replication is error-prone due to its reverse transcriptase lacking proofreading and APOBEC-driven hypermutation.
• These processes can generate replication-deficient viral variants with in-frame stop codons, particularly in the Gag and Pol genes.

Observation:

• HIV-1 variants with multiple stop codons in the reverse transcriptase (RT) gene were detected in a subject with ongoing viral replication despite antiretroviral therapy.
• Sequential analysis revealed an accumulation of HIV-1 variants with stop codons in the Pol gene, reaching 100% in plasma samples.
• A sustained HIV-1-specific memory CD8(+) T-cell response was observed, particularly to a peptide region within the RT containing stop codons.

Findings:

• The study identified a strong T-cell response directed against a specific peptide at the C-terminus of the RT region, encompassing detected stop codons.
• This suggests a role for peptide-specific T-cell responses in the positive selection of cells expressing truncated HIV-1 RT.
• The accumulation of replication-deficient viral variants in plasma correlates with this immune response.

Implications:

• The findings suggest that T-cell responses can drive the selection of pathogenic HIV-1 variants.
• Exploiting antigen-specific CD8(+) T-cell responses could potentially redirect the immune response to select for less pathogenic viral variants.
• This strategy might lead to the in vivo selection of HIV-1 variants with reduced or abolished pathogenicity.