Variability in HIV-1 Integrase Gene and 3′-Polypurine Tract Sequences in Cameroon Clinical Isolates, and Implications for Integrase Inhibitors Efficacy

Abstract

Integrase strand-transfer inhibitors (INSTIs) are now included in preferred first-line antiretroviral therapy (ART) for HIV-infected adults. Studies of Western clade-B HIV-1 show increased resistance to INSTIs following mutations in integrase and nef 3′polypurine tract (3′-PPT). With anticipated shifts in Africa (where 25.6-million HIV-infected people resides) to INSTIs-based ART, it is critical to monitor patients in African countries for resistance-associated mutations (RAMs) affecting INSTIs efficacy. We analyzed HIV-1 integrase and 3′-PPT sequences in 345 clinical samples from INSTIs-naïve HIV-infected Cameroonians for polymorphisms and RAMs that affect INSTIs. Phylogeny showed high genetic diversity, with the predominance of HIV-1 CRF02_AG. Major INSTIs RAMs T66A and N155K were found in two (0.6%) samples. Integrase polymorphic and accessory RAMs found included T97A, E157Q, A128T, M50I, S119R, L74M, L74I, S230N, and E138D (0.3′23.5% of samples). Ten (3.2%) samples had both I72V+L74M, L74M+T97A, or I72V+T97A mutations; thirty-one (9.8%) had 3′-PPT mutations. The low frequency of major INSTIs RAMs shows that INSTIs-based ART can be successfully used in Cameroon. Several samples had ≥1 INSTIs accessory RAMs known to reduce INSTIs efficacy; thus, INSTIs-based ART would require genetic surveillance. The 3′-PPT mutations could also affect INSTIs. For patients failing INSTIs-based ART with no INSTIs RAMs, monitoring 3′-PPT sequences could reveal treatment failure etiology.

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

“…The 9 amino acid substitutions (V31I [22,35,54], T112V [35,39,54], I113V [26], T125A [24,26,35,54], G134N [35,39,54], K136Q [39,54], D167E [22,35,54], T218I [22,54], and L234I [22,35,54]) were described as polymorphic mutations in non-B clades, none of which were ascribed to INSTI resistance.…”

Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations

“…We performed a search on the HIV Los Alamos National Laboratory database (LANL) database for additional ( n = 287) INSTI treatment Naïve patients’ sequences ( https://www.hiv.lanl.gov/components/sequence/ HIVsearch.com ), completed on 01 February 2020. All Cameroonian HIV-1 subtype CRF02_AG IN sequences for treatment naïve patients, were included in our search criteria [ 14 ]. We selected one sequence per patient and every problematic sequence were excluded from further analyses.…”

“…The United States of America (USA) Food and Drug Administration (FDA) has approved four HIV-1 INSTIs, including raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG) and bictegravir (BIC) [ 13 ]. However, the high cost of INSTIs, has resulted in restricted access to this class of drugs in resource-limited countries [ 14 ]. Despite the cost, the World Health Organization (WHO) has given the green light to include DTG to an alternative 1st-line regimen [ 14 , 15 ].…”

“…However, the high cost of INSTIs, has resulted in restricted access to this class of drugs in resource-limited countries [ 14 ]. Despite the cost, the World Health Organization (WHO) has given the green light to include DTG to an alternative 1st-line regimen [ 14 , 15 ]. The strand transfer reaction catalyzed by HIV-1-expressed IN enzyme is blocked by the activity of INSTIs which bind to the catalytic site in the catalytic core domain (CCD) of the IN protein [ 16 , 17 ].…”

“…The goals of this study was to analyse the Cameroonian CRF02_AG IN gene sequences obtained from the Los Alamos National Laboratory ( http://www.hiv.lanl.gov/ ) HIV-1 database to assess the occurrence of mutations and natural occurring polymorphisms (NOPs). NOPs are categorized under secondary mutations which on their own play a limited role in resistance [ 14 ]. However, their pre-existence might favour a more rapid evolution towards resistance when additional mutations are selected under therapy [ 21 ].…”