[21] FITNESS ANALYSIS OF VIRUSES WITH UNIQUE T215D/C/S MUTATIONS FROM TREATMENT-NAIVE PERSONS: IMPLICATIONS ON PERSISTENCE IN VIVO AND MECHANISMS OF REVERSION OF T215Y

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] FITNESS ANALYSIS OF VIRUSES WITH UNIQUE T215D/C/S MUTATIONS FROM TREATMENT-NAÏVE PERSONS: IMPLICATIONS ON PERSISTENCE IN VIVO AND MECHANISMS OF REVERSION OF T215Y

[AUTHOR(S):] JG García-Lerma¹, S Nidtha¹, K Blumoff¹, H Weinstock² and W Heneine¹
¹ HIV and Retrovirology Branch, Centers for Disease Control and Prevention, Atlanta, Ga., USA; and ² Prevention Services Research Branch, Centers for Disease Control and Prevention, Atlanta, Ga., USA
Antivir Ther. 2001;6 Suppl 1:18

Viruses with unusual mutations at codon 215, such as 215D_(GAC), 215C_(TGC) and 215S_(TCC), are commonly seen in drug-naïve persons. They differ from 215Y_(TAC) by a single nucleotide change, and are thought to represent revertants of the zidovudine-selected T215Y mutation. To better understand the mechanisms of reversion of 215Y, and assess implications on persistence of these viruses in vivo, we evaluated both replication capacity and relative replicative fitness of recombinant viruses carrying reverse transcriptase (RT) sequences with these mutations. All RT sequences were derived from treatment-naïve persons and had the 215D, 215C or 215S mutations alone or in association with M41L and/or L210W (HIV-1_210W/215C, HIV-1_{41L/210W/215C}, HIV-1_210W/215D and HIV-1_41L/215D). All viruses carrying 215C, 215D or 215S replicated as efficiently as wild-type viruses (HIV-1_T215). Viral infectivity/total virion particles ratios were also similar, further supporting comparable replication capabilities. However, analysis of relative replicative fitness by a competitive HIV-1 replication assay showed differences in fitness among these viruses. Fitness of both HIV-1215C and HIV-1215D was higher than that of HIV-1215S in viruses that also had the 41L and/or 210W mutations. In contrast, fitness of HIV-1_215S was higher than that of HIV-1_215C or HIV-1_215D in viruses that lacked the 41L and/or 210W mutations. These findings might explain the frequent association of 215D/C but not 215S with 41L and/or 210W observed in vivo, and suggest that 215D and 215C may represent early reversion events of 215Y in viruses that carry additional zidovudine-resistance mutations. The observed fitness gain conferred by the 215S mutation in the absence of other zidovudineselected mutations suggests that 215S may represent a late reversion event from 215Y. Our findings suggest that reversion of 215Y may be a stepwise process in which several intermediates may be involved, and in which the RT background may favour specific intermediates. The observed efficient replication of all three intermediates suggests that they are stable mutations that may persist in drug-naïve persons.

PRESENTING AUTHOR: JG García-Lerma

Download Presentation

010604
21

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.