Integrative Computational Approaches for Understanding Drug Resistance in HIV-1 Protease Subtype C

Abstract

Acquired immunodeficiency syndrome (AIDS) is a chronic disease condition caused by the human immunodeficiency virus (HIV). The widespread availability of highly active antiretroviral therapies has helped to control HIV. There are ten FDA-approved protease inhibitors (PIs) that are used as part of antiretroviral therapies in HIV treatment. Importantly, all these drugs are designed and developed against the protease (PR) from HIV subtype B. On the other hand, HIV-1 PR subtype C, which is the most dominant strain in countries including South Africa and India, has shown resistance to PIs due to its genetic diversity and varied mutations. The emergence of resistance is concerning because the virus continues to replicate despite treatment; hence, it is necessary to develop drugs specifically against subtype C. This review focuses on the origin, genetic diversity, and mutations associated with HIV-1 PR subtype C. Furthermore, computational studies performed on HIV-1 PR subtype C and mutations associated with its resistance to PIs are highlighted. Moreover, potential research gaps and future directions in the study of HIV-1 PR subtype C are discussed.

Keywords: AIDS; HIV protease; MD simulations; computational studies; insertion; mutation; structure activity relationship; subtype C.

Figure 1

Origin and timeline of HIV-1 subtype C.

Figure 2

3D structure of HIV PR subtype C [37] highlighting functionally important regions such as the flaps (residues 46–54; green), hinge (residues 35–42 and 57–61; yellow), cantilever (residues 62–75; red) and fulcrum (residues 10–23; blue). The binding site residues Asp25/Asp25′ are shown in ball-and-stick representation. The figure was generated using the structure of HIV PR subtype B (PDB code: 2AQU) [38] as the template.

Figure 3

(A) Sequence alignment between subtype B and subtype C showing the positions with naturally occurring polymorphisms (yellow). (B) The residues associated with naturally occurring polymorphisms in HIV-1 PR subtype C (S12, V15, I19, I36, K41, K69, M89 and L93) are represented as spheres. The colors yellow, orange, and green correspond to the functional regions of the hinge, fulcrum, and the base of the protease, respectively. The figure was generated using the structure of HIV PR subtype B (PDB code: 2AQU) [38] as the template.

Figure 4

Residues in HIV-1 PR subtype C that are prone to mutations (blue: away from the active site; red: active site).

Figure 5

The hydrogen bond interactions of HIV-1 PR subtype C with SQV (A) WT and (B) L38HL. The figure was adapted from Venkatachalam et al. [59].

Figure 6

Comparison of hinge regions (red circles and rectangles) showing lower (blue) and higher (red) fluctuations in (A) WT and (B) L38HL HIV-1 PR subtype C. The figure was adapted from Sankaran et al. [37].