Singh A, Collman RG; Conference on Retroviruses and Opportunistic Infections.

9th Conf Retrovir Oppor Infect Feb 24 28 2002 Wash State Conv Trade Cent Seattle Wash Conf Retrovir Oppor Infect 9th 2002 Seattle Wash. 2002 Feb 24-28; 9: abstract no. 183-M.

Univ. of Pennsylvania, Philadelphia

BACKGROUND: Dual-tropic R5X4 HIV-1 species bridge the transition from M-tropic R5 to T-tropic X4 variants by retaining the ability to use highly divergent N-terminal domain of CCR5 and acquiring the ability to use relatively conserved extracellular loops of CXCR4. Our recent studies have revealed the presence of distinct R5, R5X4, and X4 phenotypes within a high degree of genetic homologous quasispecies of HIV-1 89.6PI. Given the structurally complex interactions between HIV-1 and co-receptors, we sought to identify regions in CCR5 that play a role in membrane fusion mediated by swarms of functionally distinct variants within the HIV-1 89.6PI that may provide insight to understand the molecular basis of viral tropism. In addition we addressed whether genetically related variants of same phenotype also exhibited differences in their use of CCR5 co-receptor.METHODS: We utilized a panel of genetically related env quasi-species with distinct R5 and R5X4 phenotype generated from the original uncloned 89.6 viral swarm to evaluate their differential sensitivity for CCR5 fusion co-factor by utilizing CCR5 N-terminal domain deletion mutants and substitution mutants.RESULTS: We found that CCR5 N-terminal domain deletions differentiate between R5X4 and R5 quasi-species within the 89.6PI in CCR5 usage. R5X4 clones mediated env fusion was significantly more sensitive to deletions in N-terminal domain of CCR5 than R5 variants. The complexity of the interactions was also observed within multiple R5X4 variants cloned from 89.6PI for co-receptor CCR5. The fusion results with CCR5 substitution mutants suggest the significance of conformationally complex structure contributed by residues in N-terminal domain (Asp-11), II ECL (Lys-197) and III ECL (Asp-276) for R5X4 variants to utilize CCR5 as a fusion co-receptor.CONCLUSIONS: Multiple functionally important regions in CCR5 contribute to structurally complex structure mediating fusion with R5 and R5X4 HIV-1 quasi-species within 89.6PI. It is also suggestive that the receptor-virus interaction is not primarily determined by the sequence motifs, but involves conformationally distinct interactions between viral env and CCR5 fusion receptor. Thus, the relatively minor changes in HIV-1 env may alter the way it interacts with the fusion coreceptor that may further be important for viral species evolution.

Publication Types:

• Meeting Abstracts

Keywords:

• Base Sequence
• Genes, env
• HIV-1
• Membrane Fusion
• Phenotype
• Receptors, CCR5
• Receptors, CXCR4
• genetics

Other ID:

• GWAIDS0024673

UI: 102264297

From Meeting Abstracts