16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

THE HIV-1 ENVELOPE GENE DETERMINES VIRAL FITNESS IN BOTH DRUG SENSITIVE AND RESISTANT ISOLATES

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThLB0306

I. Nankya¹, A. Abraha¹, E. Fraundorf¹, A. Marozsan¹, Y. Gao¹, B. Johnston², D. Katzenstein², E. Arts^1
1Case Western Reserve University, (1) Division of Infectious Diseases, School of Medicine, Cleveland, United States, ²Stanford University, (2) Division of Infectious Diseases and Geographical Medicine, Stanford, United States

BACKGROUND: HIV-1 subtype C is the most predominant the global epidemic. Unlike other group M subtypes, subtype C is predominantly CCR5 (R5); the CXCR4 (X4) phenotype is rare even in late disease. We have demonstrated that like the subtype C NSI/R5, the subtype C SI/R5 HIV-1 isolates are less fit than other group M isolates. In addition, we showed that the efficiency of host cell entry controls fitness and this has been mapped to the envelope gene.

METHODS: Eight SI/X4 isolates were propagated by PBMC co-cultivation, then used in pair-wise competition experiments with SI/X4 isolates of subtypes A, B, C, D, CRF01 (E), and group O. Coincidentally, half of these isolates harbored drug resistant mutations; so we determined the role of the envelope gene in controlling fitness in the presence of RT-Protease mutations. The RT-Protease from each of these isolates was cloned into pNL4-3 and was used to determine fitness. In addition, the env gene from a drug resistant and a drug sensitive isolate were cloned into pNL4-3. These env chimeric viruses were used in pair-wise competitions with the other subtype C SI isolates, SI/X4 reference isolates, pNL4-3, and drug resistant reference isolates in both PBMCs and MT-2 cells.

RESULTS: In all competitions against other SI/X4, subtype C SI/X4 isolates were significantly less fit. Using the RT-Protease, the drug resistant isolates had low fitness while the sensitive isolates had high fitness. Using the envelope to determine fitness, the chimeric viruses exhibited fitness values that were comparable to their parental isolates. Surprisingly, the drug resistant isolate that exhibited low RT-Protease fitness, had a high total relative fitness value when both the whole virus and env chimera were used in competitions.

CONCLUSIONS: These findings further confirm that even in the presence of drug resistant mutations, the envelope gene plays a major role in fitness.

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2006-08-13
ThLB0306

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