The Determination of HIV-1 RT Mutation Rate, Its Possible Allosteric Effects, and Its Implications on Drug Resistance

Abstract

The high mutation rate of the human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance, from the development of vaccines to therapeutic drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 resulted in a large range of 10^-5-10^-3 errors/bp/cycle due to the use of different types of investigation methods. In this review, we discuss the different assay methods, their findings on the mutation rates of HIV-1 and how the locations of mutations can be further analyzed for their allosteric effects to allow for new inhibitor designs. Given that HIV is one of the fastest mutating viruses, it serves as a good model for the comprehensive study of viral mutations that can give rise to a more horizontal understanding towards overall viral drug resistance as well as emerging viral diseases.

Keywords: HIV-1; allostery; drug resistance; mutation rate; retroviruses; reverse transcriptase.

Figure 1

Human immunodeficiency virus type 1 (HIV-1) Reverse Transcriptase structure complexed with DNA (pdb 1T05) [27]. The image was generated using PyMOL [28].

Figure 2

Underlying allosteric communications were found within HIV-1 proteins. (A) Allosteric signaling maps (single-point mutation screening) of HIV-1 Reverse Transcriptase, Integrase, Protease, and Gag. Structural presentation using RT (pdb 3T19), IN (reconstructed from pdb 1K6Y and 1EX4), PR (pdb 2PC0), and Gag model from Su et al. [87]; (B) Allosteric-free energies (ΔΔg_site) on specific catalytic or cleavage sites (magenta spheres) were estimated based on individual perturbations at single residues (x-axis) to demonstrate the resulting stabilizing (ΔΔg_site < 0) or destabilizing (ΔΔg_site > 0) effects. The possible mutations which may potentially destabilize the sites of interest, are highlighted in red spheres and red dash ovals.