3rd International Workshop on HIV Drug Resistance 2-5 August 1994, Kauai, Hawaii, USA

IN VITRO SELECTION AND CHARACTERIZATION OF HIV-l VIRAL ISOLATES WITH REDUCED SENSITIVITY TO INHIBITORS OF HIV PROTEASE

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:8 (abstract no. 7)

J.A. Partaledis, K. Yamaguchi*, R. A. Byrn* and D.J. Livingston
Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA; *New England Deaconess Hospital, Boston, MA, USA

We have designed potent, nonpeptidal inhibitors of HIV-1 protease for clinical assessment in AIDS patients and HIV-infected individuals. As with other classes of anti-retroviral compounds, the development of resistance to these compounds in the clinic is a potential concern. Although viral resistance in vivo cannot be modeled precisely in vitro, we are attempting to identify HIV-1 protease variants that may arise in the clinic during therapy with protease inhibitors. Towards this end, we have performed an indepth study of HIV-1 resistance that develops in cell culture against several protease inhibitors of clinical interest.

CEMss cells were infected with HIV-1_IIIB and the virus produced was serially passaged in the presence of 2-fold increasing concentrations of VB-11,328. After extensive passaging, viral stocks were assessed for decreased sensitivity to the compound at various passages. The 90% inhibitory concentrations of the passaged viruses were 10 to 100-fold larger than the parental controls, a degree of resistance comparable to that reported for the protease inhibitor R03I-8959¹. The proviral DNA region encoding the VB-11,328-resistant HIV-1 protease was amplified from infected cell lysates by PCR and was sequenced directly. The amino acid substitutions identified within protease were L10F, M46I, I47V, I50V and I84V. The biochemical properties of these mutants are under investigation.

1. Craig, J.C., L. Whittaker, I.B. Duncan and N. A. Roberts, Antivir Chem Chemother 1993 4,335-339.

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1994-08-02
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