475   Sensitivity of HIV-1 to the Fusion Inhibitors T-20 and T-649 Is Modulated by Coreceptor Specificity and Involves Distinct Regions of gp41.

C. A. Derdyn*¹, J. M. Decker², J. N. Sfakianos¹, W. A. O'Brien³, L. Ratner⁴, G. M. Shaw², and E. Hunter¹.
¹Univ. of Alabama at Birmingham;²Howard Hughes Med. Inst., Birmingham, AL;³Univ. of Texas Med. Branch, Galveston; and⁴Washington Univ. Sch. of Med., St. Louis, MO

Background:T-20 and T-649 are synthetic peptides that potently inhibit replication of HIV-1 by interfering with the transition of gp41 to a fusion-active state. We show here that sensitivity to both peptides is strongly influenced by coreceptor specificity defined by the V3 loop of gp120.

Methods and Results:When the sensitivity of 38 inhibitor-naïve primary isolates was analyzed, the mean IC₅₀s of T-20 and T-649 for CCR5-specific (R5) isolates were 0.5 log₁₀and 0.31 log₁₀higher, respectively, than the mean IC₅₀s for CXCR4-specific (X4) isolates. Using NL4.3-based envelope chimeras that contain combinations of envelope sequences derived from R5 or X4 viruses, we confirmed that determinants of coreceptor specificity contained within the V3 loop modulate sensitivity to both T-20 and T-649. The IC₅₀for all chimeric viruses containing R5 V3 sequences was 0.2 to 0.8 log₁₀higher than the parent X4 virus, depending on the specific V3 sequence present, and the pattern of decreased sensitivity for each set of R5 chimeras was identical for both inhibitors. Viruses containing GIV at positions 36 to 38 of gp41 were about 1.0 log₁₀more sensitive to T-20 than viruses containing a G-to-D substitution, and the effect of this substitution was specific to T-20. Investigation into an HL-to-RM substitution present at positions 53 to 54 of gp41 in JRFL-derived chimeric viruses showed that this site was not associated with the decreased sensitivity of these viruses to T-649.

Conclusion:The results presented here have important implications for the therapeutic uses of peptide inhibitors as well as for understanding of complex mechanisms of virus fusion and entry.