Pol-Driven Replicative Capacity Impacts Disease Progression in HIV-1 Subtype C Infection

Area of Science:

• Virology and Immunology
• HIV Pathogenesis
• Vaccine Development

Background:

• CD8+ T cell escape mutations in HIV-1 Gag reduce viral replication capacity (RC) and alter disease progression.
• Less is understood about immune-mediated attenuation in other HIV-1 proteins, such as RT-integrase.
• The functional impact of the conserved Pol protein on HIV disease progression requires further definition.

Purpose of the Study:

• To investigate the clinical relevance of reverse transcriptase (RT)-integrase-driven RC in HIV-1 subtype C infection.
• To explore evidence of immune-mediated attenuation in RT-integrase.
• To identify specific RT-integrase polymorphisms associated with reduced HIV-1 replication ability for potential vaccine targets.

Main Methods:

• Generated 487 recombinant HIV-1 subtype C viruses encoding RT-integrase from individuals with recent and chronic infections.
• Measured in vitro RC using a green fluorescent protein (GFP) reporter T cell assay.
• Analyzed correlations between RT-integrase RC, viral load, CD4+ T cell counts, and host HLA allele expression.

Main Results:

• RT-integrase-driven RC correlated significantly with viral load set point and CD4+ T cell decline in recent infection.
• Significant associations between RT-integrase RC, viral load, and CD4+ T cell count persisted in chronic infection.
• Host HLA alleles (e.g., HLA-B*81, HLA-B*07, HLA-A*30:09) were associated with lower RC, indicating immune-driven attenuation. Specific polymorphisms (V241I, I257V, P272K, E297K in RT; I201V in integrase) were linked to reduced RC.

Conclusions:

• RT-integrase-driven RC is clinically relevant and significantly impacts HIV disease progression.
• Evidence suggests immune-driven selection of mutations in RT-integrase can compromise viral replication capacity.
• Identified specific RT-integrase polymorphisms associated with reduced RC provide potential targets for rational HIV vaccine design.