Potential Associations of Mutations within the HIV-1 Env and Gag Genes Conferring Protease Inhibitor (PI) Drug Resistance

Abstract

An increasing number of patients in Africa are experiencing virological failure on a second-line antiretroviral protease inhibitor (PI)-containing regimen, even without resistance-associated mutations in the protease region, suggesting a potential role of other genes in PI resistance. Here, we investigated the prevalence of mutations associated with Lopinavir/Ritonavir (LPV/r) failure in the Envelope gene and the possible coevolution with mutations within the Gag-protease (gag-PR) region. Env and Gag-PR sequences generated from 24 HIV-1 subtype C infected patients failing an LPV/r inclusive treatment regimen and 344 subtype C drug-naïve isolates downloaded from the Los Alamos Database were analyzed. Fisher’s exact test was used to determine the differences in mutation frequency. Bayesian network probability was applied to determine the relationship between mutations occurring within the env and gag-PR regions and LPV/r treatment. Thirty-five mutations in the env region had significantly higher frequencies in LPV/r-treated patients. A combination of Env and Gag-PR mutations was associated with a potential pathway to LPV/r resistance. While Env mutations were not directly associated with LPV/r resistance, they may exert pressure through the Gag and minor PR mutation pathways. Further investigations using site-directed mutagenesis are needed to determine the impact of Env mutations alone and in combination with Gag-PR mutations on viral fitness and LPV/r efficacy.

HIV-1 envelope facilitates the development of protease inhibitor resistance through acquiring mutations associated with viral entry and immune escape

“…From the structural changes observed in Gag, the Q69K that was previously reported to coevolve with gp120 and minor protease mutations (Codoñer et al, 2017;Maphumulo and Gordon, 2021), showed a longer α-4/5 loop than the WT. This position has been reported to contribute to the structural flexibility of MA and the longer loop seen in the mutant suggests that it occupied more volume than the WT (Khan and Vihinen, 2007).…”

“…Env gp41 mutations associated with PI treatment failure that have been previously reported were found in the Ectodomain (I515L, S543A,T536M, A607T, D632E, and L641), Transmembrane (I688V), and cytoplasmic tail (CT) (L721I, P724S, I781T, T818, V832I, and I/ L836F) (Coetzer et al, 2017;Manasa et al, 2017;Castain et al, 2019;Perrier et al, 2019;Maphumulo and Gordon, 2021). The N-terminal HR and C-terminal HR regions are located in an antiparallel orientation and are linked by a loop region that plays a critical role in fusion (Bär and Alizon, 2004).…”

“…More recent research has confirmed the involvement of Gag and gp41 during PI failure ( Castain et al, 2019 ; Perrier et al, 2019 ; Hikichi et al, 2021 ). The possible co-evolution of the gag and env genes in the development of PI resistance has also been suggested, although very limited data is currently available ( Maphumulo and Gordon, 2021 ).…”

“…Researchers have reported mutations associated with PI treatment failure in both gp120 ( Maphumulo and Gordon, 2021 ) and gp41 of Env ( Coetzer et al, 2017 ; Manasa et al, 2017 ; Castain et al, 2019 ). Most reported gp120 mutations were located in the V1/V2 and V3 loop regions.…”

“…Using Bayesian Network probability, Maphumulo suggested that Env mutations found in higher frequencies in LPV failures were linked to Gag mutations found in MA/CA (Q69K, R76K, S111C/I, T239S, I256V) and were involved in the pathway to LPV resistance ( Maphumulo and Gordon, 2021 ). The MA domain and the CT tail of gp41 interact during incorporation of the Env glycoproteins into the budding virus ( Yu et al, 1992 ; Freed and Martin, 1995 ), therefore it is quite possible that mutations in these regions could co-evolve as a result of PI selection pressure.…”