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Antimicrobial Agents and Chemotherapy, September 2007, p. 3075-3080, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00146-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro Selection and Characterization of Human Immunodeficiency Virus Type 2 with Decreased Susceptibility to Lopinavir{triangledown}

Sherie Masse,1* Xiaozhi Lu,2 Tatyana Dekhtyar,1 Liangjun Lu,1 Gennadiy Koev,1 Feng Gao,2 Hongmei Mo,1 Dale Kempf,1 Barry Bernstein,1 George J. Hanna,1 and Akhteruzzaman Molla1

Antiviral Research, Global Pharmaceutical Research and Development, Abbott Park, Illinois,1 Duke University Medical Center, Durham, North Carolina2

Received 31 January 2007/ Returned for modification 15 March 2007/ Accepted 7 June 2007

Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2MS and HIV-2CBL-23) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2CDC310319. Passage of HIV-2MS with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2ROD molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.

* Corresponding author. Mailing address: Antiviral Research, Global Pharmaceutical Research and Development, AP52N-1 Rm. 1133, 200 Abbott Park Road, Abbott Park, IL 60064. Phone: (847) 938-9250. Fax: (847) 938-6603. E-mail: Sherie.masse{at}abbott.com

{triangledown} Published ahead of print on 18 June 2007.

Antimicrobial Agents and Chemotherapy, September 2007, p. 3075-3080, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00146-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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