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106 A Post-CD4-Binding Step Involving the Central V3-Loop Region Is Common to Infection by X4 and R5 Strains of HIV-1
P. Nehete*1, M. Houssain1, N. Yahi2, J. Fantini2, and K. J. Sastry1
1The Univ. of Texas M. D. Anderson Cancer Ctr., Bastrop, USA and 2Inst. Mediterraneen de Recherche en Nutrition, Marseille, France
Background: The V3-loop region in HIV-1 gp120 of is critical for viral infection, particularly coreceptor interactions and cellular tropism. Using linear V3 peptides as reagents, we attempted to further elucidate early events in HIV-1 entry.
Methods: Synthetic peptides corresponding to the central 15(21 amino acids sequence of the V3 region in gp120 from X4 and R5 strains were tested for competitive inhibition of viral entry and interaction between cell-surface glycoshingolipids (GSL) and gp120 from diverse HIV-1 strains.
Results: Linear V3 peptides from both X4 and R5 strains of HIV-1 exhibited dose-dependent inhibition of infection by both types of HIV-1 isolates by competing with the virus for cellular binding and entry. Also, these linear HIV-inhibitory V3 peptides did not inhibit cellular binding of specific antibodies to either the primary receptor CD4 or the coreceptors CXCR-4 and CCR5. However, R15K, the V3 peptide from HIV-1 IIIB gp120, revealed specific binding to cell surface GSL like GM3, Gb3, and GalCer and exhibited competitive inhibition of interaction of gp120 from either X4 or X4R5 strains with purified GM3, Gb3, or GSL isolated from human PBMC microdomains.
Conclusions: These results suggest a critical V3-mediated event involving cell surface GSL binding, that is common for the entry of diverse HIV-1 strains and may be targeted for the development of novel HIV therapeutics. Our results together with the literature reports further support the hypothesis that host cell surface GSL function as membrane rafts that move the virion, bound to CD4 through gp120, on the target cell surface toward the appropriate coreceptor for binding and subsequent gp41-mediated fusion. In this scenario, it is possible to envision multiple interactions for distinct sequences and structural features of the V3-loop region in HIV-1 gp120 with different cell surface molecules like the membrane GSL and the chemokine receptors.
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