[17] SENSITIVITY OF HIV-1 TO FUSION INHIBITORS TARGETTED TO THE GP41 FIRST HEPTAD REPEAT INVOLVES DISTINCT REGIONS OF GP41 AND IS CONSISTENTLY MODULATED BY GP120 INTERACTIONS WITH CO-RECEPTOR

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] SENSITIVITY OF HIV-1 TO FUSION INHIBITORS TARGETTED TO THE GP41 FIRST HEPTAD REPEAT INVOLVES DISTINCT REGIONS OF GP41 AND IS CONSISTENTLY MODULATED BY GP120 INTERACTIONS WITH CO-RECEPTOR

[AUTHOR(S):] CA Derderyn¹, JM Decker¹, JN Sfakianos¹, Z Zhang¹, WA O’Brien², L Ratner³, GM Shaw¹ and E Hunter¹
¹ University of Alabama at Birmingham, Birmingham, Ala., USA; ² University of Texas Medical Branch, Galveston, Tex., USA; and ³ Washington University School of Medicine, St Louis, Mo., USA
Antivir Ther. 2001;6 Suppl 1:12

OBJECTIVES: Fusion inhibitors offer great promise as a new class of antiretroviral drugs. Virological determinants of sensitivity to these drugs will help to guide their clinical use.

METHODS: Sensitivity to two fusion inhibitors, T-20 and T-649 (Trimeris, Durham, N.C., USA) was determined in JC53-BL (Tranzyme, Birmingham, Ala., USA) which are indicator cells derived from HeLa cells that express high levels of CD4 and the HIV-1 co-receptors CCR5 and CXCR4. Infections were performed and maintained in the absence of inhibitor or in the presence of increasing amounts of inhibitor in quadruplicate wells, and mean inhibitory concentration 50% (IC₅₀) was calculated for each virus using all replicates for each virus. Wilcoxon rank-sum tests were applied to determine significance between viruses for both the inhibitors. Construction of chimeric viruses using R5 and X4 viruses were previously described.

RESULTS: Co-receptor specificity defined by the V3 loop of gp120 modulates sensitivity to T-20, as well as a critical region in end-terminal gp41, as previously shown. We now show that: (1) regions within gp41 distinct from those associated with T-20 sensitivity govern the baseline sensitivity to T-649; and (2) T-649 sensitivity of chimeric viruses is also modulated by coreceptor specificity. The pattern of sensitivity of CCR5-specific chimeras with only minor differences in V3 were consistent for both inhibitors. Although these peptide inhibitors contain overlapping sequences, mutations in distinct regions of gp41 confer resistance, suggesting potential benefits of combination therapy.

CONCLUSIONS: Virus affinity for co-receptor may influence accessibility of fusion inhibitors to their target sequence. These results implicate gp120-coreceptor interactions in driving the complex conformational changes that occur in gp41 to promote fusion and entry.

PRESENTING AUTHOR: CA Derderyn

Download Presentation

010604
17

Copyright © 2001 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.