Structural Comparison of Diverse HIV-1 Subtypes using Molecular Modelling and Docking Analyses of Integrase Inhibitors

Abstract

The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.

Keywords: HIV-1; diversity; integrase; molecular docking; molecular modelling; naturally occurring polymorphisms.

Figure 1

Amino acid sequence alignment of integrase variants subtype B, subtype Cza, and CRF_02_AG, respectively. Red highlighted residues indicate polymorphism locations in comparison with the Subtype B template. Blue highlighted residues indicate the aspartate (D64), aspartate (D116) and glutamate (E152) DDE motif.

Figure 2

(a) A superimposition of all three integrase models showing high backbone identity and secondary structure conservation. (b) CRF02_AG integrase (IN) model colored according to secondary structure and in cartoon depiction. (c) Subtype B IN model colored according to secondary structure and in cartoon depiction. (d) Subtype C IN model colored according to secondary structure and in cartoon depiction. Encircled in red is the secondary structure difference observed between the template structure and the generated IN models. Light blue indicates the helices, purple indicates beta-sheets, and tint color indicates loops.

Figure 3

Linear relationship between the predicted binding constants calculated from the docking studies of integrase strand transfer inhibitors (INSTI) with HIV Ins and the experimental half-maximal effective concentration (EC50) values determined from the TZM-bl cells-based assay.