Paulous S, Zennou V, Borman A, Clavel F; Australasian Society for HIV Medicine. Conference.

Annu Conf Australas Soc HIV Med. 1996 Nov 14-17; 8: 87 (abstract no.90).

Unite d'Oncologie Virale, Institut Pasteur, Paris, France.

The HIV protease (PR) is required for proteolytic cleavage of the viral gag and gag-pol polyproteins, leading to proper assembly and function of the virion structural and enzymatic components. Potent Inhibitors of the HIV-1 PR have been synthesized and have proven clinically to be highly valuable antiviral agents. However, in spite of the strong antiviral activity of these compounds, HIV PR mutants with decreased sensitivity to PR inhibitors can arise in course of the treatment. Resistance to PR inhibitors is a gradual process through which mutations at specific sites are selected and added sequentially, leading to a parallel increase in resistance. Interestingly, some individual mutations or combinations of mutations that emerge during selection in vivo or in vitro appear to reduce PR enzymatic activity and to decrease the replicative capacity of the virus. We have reproduced in vitro the course of gradual accumulation of Ritonavir resistance mutations in the protease and precisely evaluated the joint effect of such mutations on resistance and on virus replicative capacity. In patient isolates, we found that proteases from Ritonavir- and Saquinavir-resistant viruses are impaired in their function, leading to a significant reduction of virus infectivity when compared to the parental sensitive viruses. Resistance mutations which reduce PR function do not always revert upon propagation of the virus in drug-free conditions. In those cases, serial virus passage in the absence of drug led to the selection of secondary mutations identical to those emerging in the presence of the drug. Another important issue regarding resistance to PR inhibitors is cross-resistance between distinct compounds. We found that most Ritonavir-resistant viruses retain high initial sensitivity to Saquinavir. However, upon serial tissue culture passages in the presence of Saquinavir, we found that Ritonavir-resistance could either speed up or slow down the selection for Saquinavir resistance, when compared to parental Ritonavir-sensitive strains. In both cases, reversion of some of the characteristic Ritonavir resistance mutations was observed, together with emergence of some (but not all) mutations that are characteristic of Saquinavir resistance.

Publication Types:

• Meeting Abstracts

Keywords:

• AIDS Vaccines
• Acquired Immunodeficiency Syndrome
• Antiviral Agents
• Gene Products, gag
• Genes, gag
• Genes, pol
• HIV Infections
• HIV Protease
• HIV Seropositivity
• HIV-1
• Humans
• In Vitro
• Mutation
• Protease Inhibitors
• Ritonavir
• Saquinavir
• genetics

Other ID:

• 97153670

UI: 102221925

From Meeting Abstracts