Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression.

Area of Science:

• Immunology
• Virology
• Infectious Diseases

Background:

• Antiretroviral therapy (ART) controls HIV-1 replication but does not eliminate the latent viral reservoir.
• Understanding the viral reservoir's characteristics and immune evasion strategies is crucial for HIV-1 cure research.
• The interplay between HIV-1 genetic diversity, infection duration, and host humoral immunity requires further investigation.

Purpose of the Study:

• To investigate the role of autologous and heterologous antibodies in clearing the HIV-1 viral reservoir.
• To characterize antibody responses and viral reservoir sensitivity to broadly neutralizing antibodies (bNAbs) in individuals with varying infection durations and viral diversity.

Main Methods:

• Collected plasma from 8 HIV-1-positive males on ART with varied infection durations.
• Amplified and sequenced HIV-1 env genes from reservoir-derived outgrowth viruses to assess genetic diversity.
• Analyzed plasma IgG for binding and neutralizing antibody titers against HIV-1 proteins, global panels, and autologous viruses; assessed autologous virus sensitivity to bNAbs.

Main Results:

• Greater HIV-1 env genetic diversity correlated with higher neutralizing antibody titers against global panels and increased resistance to certain bNAbs.
• Despite robust autologous antibody titers, potent neutralization of autologous viruses was not observed; 3 of 8 participants had viruses resistant to autologous IgG.
• Viruses resistant to autologous neutralization remained sensitive to bNAbs, particularly CD4bs and MPER bNAbs, irrespective of ART duration or viral diversity.

Conclusions:

• The inducible HIV-1 reservoir harbors viruses that have evolved to escape autologous antibody responses.
• Autologous antibodies are generally ineffective at neutralizing viruses within the latent reservoir.
• Individuals with limited env gene diversity, often those starting ART early, may be more susceptible to bNAb-mediated clearance of the viral reservoir.