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Abstract
SENSITIVITY OF HIV-1 TO FUSION INHIBITORS IS MODULATED BY CORECEPTOR SPECIFICITY AND INVOLVES DISTINCT REGIONS OF GP41
DERDEYN C, DECKER J, SFAKIANDS J, D´BRIEN W, RATNER L, SHAW G, HUNTER E
T-20 is a synthetic peptide that corresponds to 36 amino acids within the C-terminal heptad repeat region (HR2) of HIV-1 gp41. T-20 has been shown to potently inhibit viral replication of HIV-1 both in vitro and in vivo and is currently being evaluated in a phase III clinical trial. T-649 is an inhibitory peptide that also corresponds to 36 amino acids within HR2 that overlap the T-20 sequence, shifting it toward the N terminus of gp41. Both inhibitors are thought to exert their antiviral activity by interfering with conformational changes that occur within gp41 to promote membrane fusion following gp120 interactions with CD4 and coreceptor molecules. We have shown previously that coreceptor specificity defined by the V3 loop of gp120 modulates sensitivity to T-20 and that a critical region within the N-terminal heptad repeat (HR1) of gp41 is the major determinant of sensitivity (Derdeyn et al., J. Virol 74(18) 2000). In this report, we show that (1) sensitivity to T-649 is also modulated by coreceptor specificity using chimeric viruses that contain sequences derived from CXCR4 and CCR5-specific envelopes and (2) regions within gp41 distinct from those associated with T-20 sensitivity govern the baseline sensitivity to T-649. Moreover, the pattern of sensitivity of CCR5-specific viruses with only minor differences in their V3 loop was consistent for both inhibitors, suggesting that the individual affinity for coreceptor may influence accessibility of these inhibitors to their target sequence. Studies to confirm the relationship between affinity for coreceptor and sensitivity to fusion inhibitors are underway. Finally, we analyzed the sensitivity of 55 primary, inhibitor-naïve HIV-1 isolates to both inhibitors and found that 0.3 log10 more T-20 (p<0.0001) and 0.2 log10 more T-649 (p=0.016) was required to inhibit CCR5-specific viruses compared to viruses that utilize CXCR4. The results presented here have important implications for understanding the role of coreceptor binding in triggering the complex conformational changes that occur in gp41 to promote fusion and entry and suggest that combination peptide therapy in vivo may delay the emergence of inhibitor-resistant viruses by targeting distinct regions of gp41.
The 1st. IAS Conference on HIV Pathogenesis and Treatment
Abstract no.
75
Suggested Citation
"DERDEYNC, et al.
SENSITIVITY OF HIV-1 TO FUSION INHIBITORS IS MODULATED BY CORECEPTOR SPECIFICITY AND INVOLVES DISTINCT REGIONS OF GP41.
Oral Presentation:
The 1st. IAS Conference on HIV Pathogenesis and Treatment
:
Abstract no.
75"
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