Abstract
Response to ritonavir-boosted-protease inhibitors (PI/r)-based regimen is associated with some Gag mutations among HIV-1 B-clade. There is limited data on Gag mutations and their covariation with mutations in protease among HIV-1 non-B-clades at PI/r-based treatment failure. Thus, we characterized Gag mutations present in isolates from HIV-1 infected individuals treated with a PI/r-regimen (n = 143) and compared them with those obtained from individuals not treated with PI/r (ART-naïve [n = 101] or reverse transcriptase inhibitors (RTI) treated [n = 118]). The most frequent HIV-1 subtypes were CRF02_AG (54.69%), A (13.53%), D (6.35%) and G (4.69%). Eighteen Gag mutations showed a significantly higher prevalence in PI/r-treated isolates compared to ART-naïve (p < 0.05): Group 1 (prevalence < 1% in drug-naïve): L449F, D480N, L483Q, Y484P, T487V; group 2 (prevalence 1–5% in drug-naïve): S462L, I479G, I479K, D480E; group 3 (prevalence ≥ 5% in drug-naïve): P453L, E460A, R464G, S465F, V467E, Q474P, I479R, E482G, T487A. Five Gag mutations (L449F, P453L, D480E, S465F, Y484P) positively correlated (Phi ≥ 0.2, p < 0.05) with protease-resistance mutations. At PI/r-failure, no significant difference was observed between patients with and without these associated Gag mutations in term of viremia or CD4 count. This analysis suggests that some Gag mutations show an increased frequency in patients failing PIs among HIV-1 non-B clades.
Highlights
Response to ritonavir-boosted-protease inhibitors (PI/r)-based regimen is associated with some Gag mutations among Human Immunodeficiency Virus (HIV)-1 B-clade
The protease has five cleavage sites on the Gag gene: the first cleavage separates the nucleocapsid protein (NC) from the capsid protein (CA) downstream of the 14 amino acid binding peptide called spacer peptide 1 (SP1); the capsid is subsequently separated from the matrix protein (MA), which remains associated with the virion m embrane13–15; this event is almost simultaneous to the release of the C-terminal p6 Gag protein, downstream of another linker peptide located between NC and p6, termed SP2; the two linker peptides SP1 and SP2 are trimmed from the CA and NC proteins, respectively13–15
Our study population consisted of 362 PLHIV, of whom 101 were antiretroviral therapy (ART)-naïve, 118 on a regimen containing only reverse transcriptase inhibitors (RTI) and 143 on a regimen containing a PI/r
Summary
Response to ritonavir-boosted-protease inhibitors (PI/r)-based regimen is associated with some Gag mutations among HIV-1 B-clade. In the current era of "Test and Treat" in resource-limited settings (RLS), there is a need to closely monitor and study determinants of poor therapeutic outcomes, so as to ensure a sustained long-term efficacy of available drug regimens. In the current era of "Test and Treat" in resource-limited settings (RLS), there is a need to closely monitor and study determinants of poor therapeutic outcomes, so as to ensure a sustained long-term efficacy of available drug regimens2 Such goals are of paramount importance; as viral suppression remains suboptimal (only 81.1% of adults on ART, below the expected 95% target for achieving the elimination goal by 2030). Mutations in Gag ere reported to be contribute substantially to PI/r resistance besides compensating for fitness loss11,12 These potential effects are essentially driven by the C-terminal region, with little contribution from MA, CA and S P111
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