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Session 97 Poster Abstracts
Impact of Virus Type/Subtype on Resistance Development
Monday, 1:30 - 3:30 pm
Poster Hall


691
Natural Resistance of HIV-2 to Zidovudine
P Reid, H MacInnes, M Cong, W Heneine, and J G Garcia-Lerma*
CDC, Atlanta, GA, USA

Background:  Zidovudine (AZT) is widely used to treat persons infected with HIV-1, and is also used to treat persons infected with HIV-2. Recent studies suggest differences in the responses to AZT treatment between HIV-1- and HIV-2-infected persons.

Methods:  We evaluated the antiviral activity of AZT in HIV-2 using standard methods including in vitro selection experiments, analysis of growth kinetics in the presence of AZT, and phenotypic testing (MT4/MTT assay). A total of 5 wild type HIV-2 viruses including 3 clinical isolates (GB122HU, CDC77618, and CDC310319) and 2 laboratory-adapted strains (ROD and CBL-20/H9) were used in the analysis. For comparison, 4 wild type HIV-1 strains (HXB2, CC/H9, IIIB/H9, and LAI) and 1 HIV-1 mutant carrying the 215S mutation (HXB2S215) were evaluated in parallel.

Results:  All 5 HIV-1 strains acquired AZT resistance mutations after 3 to 6 passages with AZT or an increase in the concentration of AZT of 4- to 32-fold. Among these viruses, the fastest selection of resistance was seen in HXB2S215, which acquired S215Y (1 nucleotide change only) at passage 3 after only 17 days in culture. In contrast, none of the 5 HIV-2 viruses that naturally have S215 acquired S215Y or any other RT mutation during 10 passages with AZT or an increase in the concentration of AZT of 1024-fold, indicating absence of selective pressure. In the presence of AZT+ddI, both AZT and ddI resistance mutations were seen in HIV-1, while only mutations that are known to be associated with ddI resistance (K65R and M184I) were seen in HIV-2. All HIV-2 viruses replicated efficiently in a high concentration of AZT (12.2 mg/mL; 2800-fold higher than the EC50 value of HIV-1), and had EC50 values for AZT that were about 200-fold higher than those of HIV-1. In contrast, HIV-2 and HIV-1 were equally inhibited by ddI, a finding consistent with the selection of K65R and M184I in HIV-2 during passages with AZT+ddI.

Conclusions:  Our results demonstrate that HIV-2 is resistant to AZT and do not support the use of AZT to treat HIV-2-infected persons. These findings underscore the importance of developing new drugs specific for HIV-2 and indicate that the antiviral activity of AZT may not be as broad as previously thought.

Keywords: zidovudine; HIV-2; drug resistance