AEGiS-11IAC: Differential processing of HIV-1 GAG polyproteins by wild type and mutant HIV-1 proteases.

11th International AIDS Conference


Vancouver, British Columbia — July 7-12, 1996

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Differential processing of HIV-1 GAG polyproteins by wild type and mutant HIV-1 proteases.

Int Conf AIDS 1996 Jul 7-12; 11:6 (abstract no. We.A.152)
Tritch RJ, Corman JI, Erickson-Viitanen S; The DuPont Merck Pharmaceutical Co., Wilmington, DE, USA.

INTRODUCTION: The virally encoded protease of HIV is required for proper processing of the GAG polyprotein of the virus, to produce the four large (p17, Matrix, p24, Capsid, p7 Nucleocapsid, and p6) and two small (p2, p1) polypeptides that are essential for the mature virion architecture conferring infectivity. Both the fidelity and timing of the processing events appear crucial for the production of infectious particles. Several inhibitors of the viral protease have shown clinical efficacy in AIDS patients; however, long term exposure both in vivo and in vitro lead to the selection of variants with mutations within the protease gene that confer resistance to the inhibitor employed. For example, variants of HIV with mutations at position 82 and 84 of the viral protease show resistance to members of the cyclic urea class of HIV protease inhibitors.

RESULTS: We have examined the fidelity and timing of the processing of GAG polyprotein precursors by purified viral protease corresponding to wild type and 82F/84V mutant variants. Utilizing GAG p55 precursor proteins corresponding to the RF or BH10 isolates produced with an in vitro transcription/translation system we have found that cleavage by the mutant protease is about 10-fold slower than that catalyzed by wild type enzyme, and differs in a relatively earlier appearance of mature p24 from p41 intermediate. In addition, cleavage of GAG p15 to p7 and p6 by the mutant protease is also altered such that unique cleavages occur that are not observed with wild type enzyme.

CONCLUSIONS: Our data suggest that subtle alterations in the processing of the viral structural proteins may occur as a compensatory consequence of selection for mutant, and partially crippled variants of HIV protease.

Keywords: AEGIS, HIV Protease, Gene Products, gag, HIV-1, HIV Protease Inhibitors, HIV Infections, Anti-HIV Agents, Mutation, Virion, HIV, Capsid, Variation (Genetics), Endopeptidases, In Vitro, Human, genetics, ICA11KWDaegis,hivprotease,geneproducts,gag,hiv-1,hivproteaseinhibitors,hivinfections,anti-hivagents,mutation,virion,hiv,capsid,variation(genetics),endopeptidases,invitro,human,genetics,ica11

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WeA152

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