HIV-1 Coreceptor Usage and Variable Loop Contact Impact V3 Loop Broadly Neutralizing Antibody Susceptibility.

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• HIV-1 broadly neutralizing antibodies (bnAbs) are effective in lowering viral load but their efficacy can be reduced by pre-existing less neutralization-susceptible viral strains.
• Predicting neutralization sensitivity based solely on sequence analysis is challenging.

Purpose of the Study:

• To investigate the relationship between HIV-1 coreceptor usage (CCR5 vs. CXCR4) and neutralization sensitivity to bnAbs, particularly V3 loop-directed bnAbs.
• To explore the structural basis for differential neutralization sensitivity using homology modeling.
• To determine if coreceptor usage and predicted structural features correlate with clinical outcomes of bnAb therapy.

Main Methods:

• Phenotypic confirmation of CXCR4- and CCR5-utilizing HIV-1 strains.
• Homology modeling of viral envelope proteins to assess V1 and V3 loop accessibility and interactions.
• Correlation analysis of pretreatment viral characteristics (coreceptor usage, V1 loop interference) with clinical data (viral rebound, plasma viremia decrease) from bnAb treatment.

Main Results:

• CXCR4-utilizing HIV-1 strains were less sensitive to V3 loop bnAbs compared to CCR5-utilizing strains in some cases.
• Homology modeling indicated V3 loop protrusions in CXCR4-utilizing strains may hinder CCR5 interaction, and V1 loop orientation can interfere with V3 loop bnAb binding in certain strains.
• Higher likelihood of CXCR4 usage and greater predicted V1 loop interference were associated with faster viral rebound and a smaller reduction in plasma viremia, respectively, after V3 loop bnAb treatment.

Conclusions:

• Structural differences in the V1 and V3 loops, related to coreceptor usage, contribute to varied bnAb susceptibility.
• Receptor usage and homology model-derived insights can potentially improve algorithms for predicting the efficacy of V3 loop bnAb therapies for HIV-1.
• Understanding these viral determinants is crucial for optimizing antibody-based HIV treatment strategies.