Diversity of Mexican HIV-1 Protease Sequences.

Abstract

Protease is one of three enzymes encoded within HIV's pol gene and a retroviral aspartyl-protease which unlike other aspartyl-proteases form a 22kDa homodimer to exert its activity. Protease is responsible for the cleavage of viral Gag-Pol polypeptide into mature viral proteins and a target of current anti-retroviral therapy (ART). Saquinavir was the first FDA-approved protease inhibitor. This image maps Shannon entropy levels of variable sites as derived from the study of 777 Mexican protease nucleotide sequences. Shannon entropy was calculated employing amino acid equivalents representing increases in entropy with regards to HXB2 reference. Entropy levels were arbitrarily classified as high (> 0.6), mid (between 0.6 and 0.2) and low (below 0.2). Protease sites having high and mid entropy levels were mapped into an X-ray diffraction crystal of HIV-1 protease dimer coupled to the anti-retroviral drug saquinavir. All sites exhibiting high and mid entropy affected the surface of the protein and were confined to an area located between the elbow and the 60's loop. High levels of entropy were observed in residues surrounding the 10's loop, the elbow region, the 60's loop and in the first half of the C-terminal domain. Protease sequence diversity is mostly a consequence of ART-driven selection for mutations that lower affinity for a drug, enabling viral replication in spite of continued ART use. Genetic variation continues to represent a major challenge for HIV prevention and treatment.