Abstract
BackgroundAlthough biochemical analysis of HIV-1 integrase enzyme suggested the use of integrase inhibitors (INIs) against HIV-1C, different viral subtypes may favor different mutational pathways potentially leading to varying levels of drug resistance. Thus, the aim of this study was to search for the occurrence and natural evolution of integrase polymorphisms and/or resistance mutations in HIV-1C Ethiopian clinical isolates prior to the introduction of INIs.MethodsPlasma samples from chronically infected drug naïve patients (N = 45), of whom the PR and RT sequence was determined previously, were used to generate population based sequences of HIV-1 integrase. HIV-1 subtype was determined using the REGA HIV-1 subtyping tool. Resistance mutations were interpreted according to the Stanford HIV drug resistance database (http://hivdb.stanford.edu) and the updated International Antiviral Society (IAS)-USA mutation lists. Moreover, rates of polymorphisms in the current isolates were compared with South African and global HIV-1C isolates.ResultsAll subjects were infected with HIV-1C concordant to the protease (PR) and reverse transcriptase (RT) regions. Neither major resistance-associated IN mutations (T66I/A/K, E92Q/G, T97A, Y143HCR, S147G, Q148H/R/K, and N155H) nor silent mutations known to change the genetic barrier were observed. Moreover, the DDE-catalytic motif (D64G/D116G/E152 K) and signature HHCC zinc-binding motifs at codon 12, 16, 40 and 43 were found to be highly conserved. However, compared to other South African subtype C isolates, the rate of polymorphism was variable at various positions.ConclusionAlthough the sample size is small, the findings suggest that this drug class could be effective in Ethiopia and other southern African countries where HIV-1C is predominantly circulating. The data will contribute to define the importance of integrase polymorphism and to improve resistance interpretation algorithms in HIV-1C isolates.
Highlights
Biochemical analysis of HIV-1 integrase enzyme suggested the use of integrase inhibitors (INIs) against HIV-1C, different viral subtypes may favor different mutational pathways potentially leading to varying levels of drug resistance
The aim of this study was to search for the occurrence and natural evolution of integrase polymorphisms and/or integrase inhibitors (INIs) resistance mutations in HIV-1C clinical isolates of ART naïve Ethiopian patients prior to the introduction of INIs of whom the PR and reverse transcriptase (RT) sequence was determined previously [19]
A subtype C-specific polymorphism associated with nucleoside reverse transcriptase inhibitors (NRTIs) (V118I) was detected in one patient
Summary
Biochemical analysis of HIV-1 integrase enzyme suggested the use of integrase inhibitors (INIs) against HIV-1C, different viral subtypes may favor different mutational pathways potentially leading to varying levels of drug resistance. HIV-1 IN is a 288 amino acid (aa) protein encoded by the 5′ end of the pol gene that folds in a multimeric form into 3 functional domains: the N-terminal domain (NTD: Mulu et al J Transl Med (2015) 13:377 proviral DNA for integration During this process, IN recognizes conserved sequences in the long terminal repeats promoting the removal of GT dinucleotide from the 3ʹ end, resulting in new 3′ hydroxyl ends [2]. The final step is strand transfer in which target DNA is cleaved and viral DNA is joined to the 5′ phosphate ends in the host chromosome which is most likely completed by the host DNA repair machinery [2] These enable HIV-1 to establish a permanent genetic reservoir that can initiate new virus’s production and to replicate through cellular mitosis [4, 5]
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