Natural polymorphisms of HIV-1 subtype-C integrase coding region in a large group of ARV-naïve infected individuals

Abstract

Integrase (IN) is an enzyme produced by human immunodeficiency virus (HIV)-1 that enables its genetic material to be integrated into the DNA of the infected cell. Still now, few data are available with detailed analysis of the natural IN polymorphisms of HIV-1 subtype-C in datasets retrieved from antiretroviral-naïve patients; this study focuses on these polymorphisms. The analysis included 335 HIV-1 subtype-C IN sequences (one per patient). Multi-alignment of IN sequences was performed, and for the definition of a polymorphism, only amino acid changes with prevalence ≥3% among treatment-naïve patients were considered. Seventy IN amino acid positions were fully conserved. Differently, forty-six IN amino acid polymorphic positions were observed, 12 within the N-terminal domain and 13 within the C-terminal domain. In the DDE-catalytic motif, only one mutation per site (D64G/D116G/E152K) was found, while a low variability (<1%) was observed for IN positions interacting with LEDGF/p75. A major drug resistance mutation for raltegravir (RAL) and elvitegravir (EVG), Q148H, was retrieved from one patient and another RAL primary resistance mutation, Y143H, was also retrieved from another patient. The results from the IN sequences analyzed underlined that some unexpected baseline substitutions affecting the susceptibility to RAL/EVG could be detected in drug-naïve individuals, and, therefore, it should be genotyped before the consideration of HIV-1 IN inhibitors (INIs). The impact of these mutations on the baseline drug susceptibility of HIV-1 subtype-C to INIs may need to be addressed prior to the introduction of these drugs in some Asiatic and African countries.