HIV-1 Integrase Diversity and Resistance-Associated Mutations and Polymorphisms Among Integrase Strand Transfer Inhibitor-Naive HIV-1 Patients from Cameroon

Lakoh

et al. 2021

Genes

Human immunodeficiency virus (HIV) drug resistance (HIVDR) is widespread in sub-Saharan Africa. Children and pregnant women are particularly vulnerable, and laboratory testing capacity remains limited. We, therefore, used a cross-sectional design and convenience sampling to characterize HIV subtypes and resistance-associated mutations (RAMs) in these groups in Sierra Leone. In total, 96 children (age 2–9 years, 100% ART-experienced), 47 adolescents (age 10–18 years, 100% ART-experienced), and 54 pregnant women (>18 years, 72% ART-experienced) were enrolled. Median treatment durations were 36, 84, and 3 months, respectively, while the sequencing success rates were 45%, 70%, and 59%, respectively, among children, adolescents, and pregnant women. Overall, the predominant HIV-1 subtype was CRF02_AG (87.9%, 95/108), with minority variants constituting 12%. Among children and adolescents, the most common RAMs were M184V (76.6%, n = 49/64), K103N (45.3%, n = 29/64), Y181C/V/I (28.1%, n = 18/64), T215F/Y (25.0%, n = 16/64), and V108I (18.8%, n = 12/64). Among pregnant women, the most frequent RAMs were K103N (20.6%, n = 7/34), M184V (11.8%, n = 4/34), Y181C/V/I (5.9%, n = 2/34), P225H (8.8%, n = 3/34), and K219N/E/Q/R (5.9%, n = 2/34). Protease and integrase inhibitor-RAMs were relatively few or absent. Based on the genotype susceptibility score distributions, 73%, 88%, and 14% of children, adolescents, and pregnant women, respectively, were not susceptible to all three drug components of the WHO preferred first-line regimens per 2018 guidelines. These findings suggest that routine HIVDR surveillance and access to better ART choices may improve treatment outcomes in Sierra Leone.

Section: Discussionsupporting

confidence: 93%

Characterizing HIV-1 Genetic Subtypes and Drug Resistance Mutations among Children, Adolescents and Pregnant Women in Sierra Leone

Lakoh

et al. 2021

Genes

“…In 11 positions (14,20,74,119,124,126,134,218,234,255, and 283), A6 sequences were significantly different (p < 0.05) from the A1 clade, which can be used as a sub-subtype-specific marker to distinguish them.…”

Section: Prevalence Of Naturally Occurring Integrase Polymorphismsmentioning

confidence: 98%

“…HIV-1 integrase has three independent domains: The N-terminal domain, the catalytic core domain, and the C-terminal domain. Each region comprises motifs essential for the proper functioning of the enzyme, e.g., the conserved zinc finger motif (H12-H16-C40-C43) in the N-terminal domain, the active site (D64-D116-E153) in the catalytic core domain, and the minimal nonspecific DNA-binding region ranging from I220 to D270 in the C-terminal domain [9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs

Kirichenko

Lapovok

Baryshev

et al. 2020

Viruses

The increasing use of the integrase strand transfer inhibitor (INSTI) class for the treatment of HIV-infection has pointed to the importance of analyzing the features of HIV-1 subtypes for an improved understanding of viral genetic variability in the occurrence of drug resistance (DR). In this study, we have described the prevalence of INSTI DR in a Russian cohort and the genetic features of HIV-1 integrase sub-subtype A6. We included 408 HIV infected patients who were not exposed to INSTI. Drug resistance mutations (DRMs) were detected among 1.3% of ART-naïve patients and among 2.7% of INSTI-naïve patients. The prevalence of 12 polymorphic mutations was significantly different between sub-subtypes A6 and A1. Analysis of the genetic barriers determined two positions in which subtype A (A1 and A6) showed a higher genetic barrier (G140C and V151I) compared with subtype B, and one position in which subtypes A1 and B displayed a higher genetic barrier (L74M and L74I) than sub-subtype A6. Additionally, we confirmed that the L74I mutation was selected at the early stage of the epidemic and subsequently spread as a founder effect in Russia. Our data have added to the overall understanding of the genetic features of sub-subtype A6 in the context of drug resistance.

“…We selected one sequence per patient, and all problematic sequences were excluded from further analyses. The consensus sequence representing CRF02_AG was generated using the CRF02_AG study sequences ( n = 37) as previously reported [ 25 ], accession number: MN816445-MN816488, while the consensus sequence for subtype C was derived from cohort sequences ( n = 91,) as previously reported [ 26 ]. Nucleotide sequences were verified for stop codons, insertion, and deletions using an online quality control program on the HIVLANL database ( ).…”

Section: Methodsmentioning

confidence: 99%

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

Isaacs

Mikasi

Obasa

et al. 2020

Viruses

Self Cite

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.