Biomimetic reconstitution of viral fusion reveals insights into coreceptor binding and infectivity, distinguishing HIV-1 and HIV-2 subtypes
Presentation Type
Abstract
Faculty Advisor
Il Hyung Lee
Access Type
Event
Start Date
25-4-2025 12:00 PM
End Date
25-4-2025 1:00 PM
Description
Despite a shared simian origin, HIV-1 and HIV-2 differ in virulence and epidemiology, yet the molecular basis remains unclear. HIV infection begins with high-affinity binding between gp120 and CD4+ T cells, initiating coreceptor binding with CCR5 or CXCR4. Differences in infectivity have been linked to reduced diversity in the HIV-2 envelope, which shares 35% amino acid similarity with HIV-1 groups and is least homologous among retroviral genes. Both gp120 proteins share structural features, including a conserved variable loop 3 (v3), though HIV-2 exhibits limited v3 exposure during CCR5 interaction compared to HIV-1. We hypothesize a pattern residue in HIV-2 v3 may affect CCR5 binding, contributing to reduced infectivity and offering a rationale for virulence differences. Sequence data from the Los Alamos HIV database was used, focusing on HIV-1 group M and HIV-2 groups A and B. Local alignments highlighted v3 residue variations, and computational alanine scanning mutagenesis identified residues critical for stable interactions. Consensus data reveal v3 residue differences possibly driving sub-optimal gp120-CCR5 interaction in HIV-2. Our results support previously identified v3 hotspots and suggest physicochemical differences in HIV-2 gp120 may hinder viral entry and replication. To test translational validity, we are using assay peptides from representative HIV-1 and HIV-2 V3 sequences to bind CCR5 on supported lipid bilayers, allowing quantitative binding affinity analysis. These findings offer insights into HIV-2’s lower infectivity by identifying specific V3 residues influencing gp120-CCR5 binding and lay groundwork for exploring infectivity and drug design differences between HIV-1 and HIV-2.
Biomimetic reconstitution of viral fusion reveals insights into coreceptor binding and infectivity, distinguishing HIV-1 and HIV-2 subtypes
Despite a shared simian origin, HIV-1 and HIV-2 differ in virulence and epidemiology, yet the molecular basis remains unclear. HIV infection begins with high-affinity binding between gp120 and CD4+ T cells, initiating coreceptor binding with CCR5 or CXCR4. Differences in infectivity have been linked to reduced diversity in the HIV-2 envelope, which shares 35% amino acid similarity with HIV-1 groups and is least homologous among retroviral genes. Both gp120 proteins share structural features, including a conserved variable loop 3 (v3), though HIV-2 exhibits limited v3 exposure during CCR5 interaction compared to HIV-1. We hypothesize a pattern residue in HIV-2 v3 may affect CCR5 binding, contributing to reduced infectivity and offering a rationale for virulence differences. Sequence data from the Los Alamos HIV database was used, focusing on HIV-1 group M and HIV-2 groups A and B. Local alignments highlighted v3 residue variations, and computational alanine scanning mutagenesis identified residues critical for stable interactions. Consensus data reveal v3 residue differences possibly driving sub-optimal gp120-CCR5 interaction in HIV-2. Our results support previously identified v3 hotspots and suggest physicochemical differences in HIV-2 gp120 may hinder viral entry and replication. To test translational validity, we are using assay peptides from representative HIV-1 and HIV-2 V3 sequences to bind CCR5 on supported lipid bilayers, allowing quantitative binding affinity analysis. These findings offer insights into HIV-2’s lower infectivity by identifying specific V3 residues influencing gp120-CCR5 binding and lay groundwork for exploring infectivity and drug design differences between HIV-1 and HIV-2.
Comments
Poster presentation at the 2025 Student Research Symposium.