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.
Highlights
The HIV/AIDS pandemic continues to be a significant problem worldwide [1]
M50I was identified in our subtype C IN sequences and this polymorphism has been reported to reduce DTG susceptibility when found in combination with the mutation R263K in HIV-1 subtype B IN [51,52]
This is in contrast to the study by Brado et al that reported an impact of naturally occurring polymorphisms (NOPs) on the stability of the protein complex, suggesting they may contribute to an overall potency against integrase strand transfer inhibitors (INSTIs)
Summary
The HIV/AIDS pandemic continues to be a significant problem worldwide [1]. The viral integration process, which is the insertion of viral DNA into host genomic DNA, is an indispensable step of the retroviral life cycle and is catalyzed by the viral integrase (IN) enzyme [2]. Integration is achieved via two distinct sequential catalytic activities, 30 processing and strand transfer. Viruses 2020, 12, 936 viral DNA by excising a dinucleotide at the 30 end, exposing hydroxyl ends. IN catalyzes the introduction of the prepared DNA into genomic DNA by facilitating a nucleophilic attack upon genomic. DNA [3,4]. HIV-1 IN is a 32 kDa protein that functions as a tetramer or multimer [3,4]. A monomer consists of three distinct domains; the N-terminal domain (NTD)
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