ABSTRACT
BACKGROUND: The Integrase (IN) strand transfer inhibitor (INSTI), Dolutegravir (DTG), has been given the green light to form part of first-line combination antiretroviral therapy (cART) by the World Health Organization (WHO). DTG containing regimens have shown a high genetic barrier against HIV-1 isolates carrying specific resistance mutations when compared with other class of regimens. METHODS: We evaluated the HIV-1 CRF02_AG IN gene sequences from Cameroon for the presence of resistance-associated mutations (RAMs) against INSTIs and naturally occurring polymorphisms (NOPs), using study sequences (n = 20) and (n = 287) sequences data derived from HIV Los Alamos National Laboratory database. The possible impact of NOPs on protein structure caused by HIV-1 CRF02_AG variations was addressed within the context of a 3D model of the HIV-1 IN complex and interaction analysis was performed using PyMol to validate DTG binding to the Wild type and seven mutant structures. RESULTS: We observed 12.8% (37/287) sequences to contain RAMs, with only 1.0% (3/287) of the sequences having major INSTI RAMs: T66A, Q148H, R263K and N155H. Of these,11.8% (34/287) of the sequences contained five different IN accessory mutations; namely Q95K, T97A, G149A, E157Q and D232N. NOPs occurred at a frequency of 66% on the central core domain (CCD) position, 44% on the C-terminal domain (CTD) position and 35% of the N-terminal domain (NTD) position. The interaction analysis revealed that DTG bound to DNA, 2MG ions and DDE motif residues for T66A, T97A, Q148H, N155H and R263K comparable to the WT structure. Except for accessory mutant structure E157Q, only one MG contact was made with DTG, while DTG had no MG ion contacts and no DDE motif residue contacts for structure D232N. CONCLUSIONS: Our analysis indicated that all RAM's that resulted in a change in the number of interactions with encompassing residues does not affect DTG binding, while accessory mutations E157Q and D232N could affect DTG binding leading to possible DTG resistance. However, further experimental validation is required to validate the in silico findings of our study.
Subject(s)
Drug Resistance, Viral/genetics , HIV Infections/drug therapy , HIV Integrase Inhibitors/therapeutic use , HIV Integrase/genetics , HIV-1/enzymology , Heterocyclic Compounds, 3-Ring/therapeutic use , Models, Molecular , Mutation , Oxazines/therapeutic use , Piperazines/therapeutic use , Pyridones/therapeutic use , Cameroon/epidemiology , HIV Infections/epidemiology , HIV Infections/virology , HIV Integrase/chemistry , HIV Integrase Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Oxazines/chemistry , Phylogeny , Piperazines/chemistry , Polymorphism, Genetic , Pyridones/chemistryABSTRACT
HIV-1 integrase (IN) is a primary target for combination antiretroviral therapy. Only a limited number of studies report on the emergence of resistance-associated mutations (RAMs) in Cameroon. We observed that 1.4% of sequence from treatment-naive patients had IN strand transfer inhibitor (INSTI) RAMs. These mutations confer resistance to raltegravir and elvitegravir. We also observed that 10.1% of the sequences have INSTI accessory RAMs. HIV-1 CRF02_AG was the predominant subtype (44.7%) in this study analyses. The occurrence of INSTI RAMs among the sequences at baseline needs to be monitored carefully.
Subject(s)
HIV Infections , HIV Integrase Inhibitors , HIV Integrase , HIV-1 , Cameroon/epidemiology , Drug Resistance, Viral/genetics , Genotype , HIV Infections/drug therapy , HIV Integrase/genetics , HIV Integrase Inhibitors/pharmacology , HIV Integrase Inhibitors/therapeutic use , HIV-1/genetics , Humans , Mutation , Raltegravir Potassium/therapeutic useABSTRACT
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.
