Abstract
Subtype F wild type HIV protease has been kinetically characterized using six commercial inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) commonly used for HIV/AIDS treatment, as well as inhibitor TL-3 and acetyl-pepstatin. We also obtained kinetic parameters for two multi-resistant proteases (one of subtype B and one of subtype F) harboring primary and secondary mutations selected by intensive treatment with ritonavir/nelfinavir. This newly obtained biochemical data shows that all six studied commercially available protease inhibitors are significantly less effective against subtype F HIV proteases than against HIV proteases of subtype B, as judged by increased Ki and biochemical fitness (vitality) values. Comparison with previously reported kinetic values for subtype A and C HIV proteases show that subtype F wild type proteases are significantly less susceptible to inhibition. These results demonstrate that the accumulation of natural polymorphisms in subtype F proteases yields catalytically more active enzymes with a large degree of cross-resistance, which thus results in strong virus viability.
Acknowledgements
We thank to FAPESP for grants 99/03387-4, 04/11890-8, 04/12201-1 and 06/00182-8 and to CNPq. Authors thank Dr. Jordan J. Tang (Oklahoma Medical Research Foundation, USA) for a kind gift of a plasmid of artificial HIV PR subtype B gene and Dr. Amilcar Tanuri (UFRJ, Brasil) for cDNAs of HIV Bmut, Fwt and Fmut.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.