ABSTRACT
The HIV-1 gp41 has been identified as an important target for the immune response, for the development of antiviral and vaccine strategies, and for epidemiologic studies. This study describes the HIV-1 env gp41 region mutations, associated with enfuvirtide (ENF) resistance, in proviral DNA from PBMCs in antiretroviral treatment-naive individuals from Pune, India. Twenty-one antiretroviral drug-naive chronically HIV-1-infected individuals were enrolled. The study sequences belonged to subtype C (n = 17), subtype A1 (n = 2), and CRF_AE (n = 2). In subtype B-infected individuals, the various HR1 region substitutions in env gp41 that have been associated with ENF resistance include A30V, L33S/T/V, L34M, G36D/E/S/V, I37T/K/V, V38A/M/E/G, Q39R, Q40H, N42T/D, N43D/K/S, L44M, L45M, R46M, L54M, and Q56K/R as well as N126K and S138A in the HR2 region. The study sequences did not reveal any ENF resistance-associated mutations at env gp41 amino acid positions: 36 to 45. The presence of L54M and Q56K in combination is associated with 5-fold reduced sensitivity to inhibition by ENF. The mutation L54M was seen in seven subtype C and two CRF_AE study sequences. Q56K was observed in a subtype A1 sequence. All the study sequences harbored N42S, a natural polymorphism associated with increased susceptibility to ENF. Of the mutations V38A and N140I, known to provide immunologic gain, the latter was observed in four subtype C sequences. This is the first study from India highlighting the presence of certain mutations in Indian subtype C env gp41, which may play a role in the evolution of subtype-specific variations in the resistance to ENF and associated immune response.
Subject(s)
HIV Envelope Protein gp41/genetics , HIV-1/genetics , Mutation, Missense , Proviruses/genetics , Amino Acid Substitution/genetics , Anti-HIV Agents/pharmacology , DNA, Viral/chemistry , DNA, Viral/genetics , Drug Resistance, Viral , Enfuvirtide , HIV Envelope Protein gp41/pharmacology , HIV-1/isolation & purification , Humans , India , Molecular Sequence Data , Peptide Fragments/pharmacology , Proviruses/isolation & purification , Sequence Analysis, DNAABSTRACT
We report one or more HIV resistance mutations in 81.81% of the 33 antiretroviral treatment-experienced study participants with evidence of virologic failure, with M184V being the most commonly observed resistance mutation (69.7%). Two out of four participants with protease inhibitors (PI) experience harbored multiple PI-associated resistance mutations. No resistance mutations were observed in 22 treatment-naive study plasma sequences. All the study pol sequences were subtype C, except one that was subtype A1. On analyzing paired plasma-proviral DNA sequences from 16 treatment-experienced patients, which harbored mutations at positions associated with antiretroviral drug resistance, an 87.5% discordance in reverse transcriptase mutations was seen between the two compartments. Our study highlights the high prevalence of HIV resistance mutations in treatment-experienced patients in Pune, with protease major resistance mutations being reported for the first time from India. The proviral DNA resistance mutation patterns may have an impact on the clinical management of HIV/AIDS.
Subject(s)
Drug Resistance, Viral , HIV Infections/drug therapy , HIV-1/drug effects , Mutation , Adolescent , Adult , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Child , Child, Preschool , Genes, pol , HIV Infections/virology , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/therapeutic use , HIV-1/genetics , Humans , India , Middle Aged , Molecular Sequence Data , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/therapeutic useABSTRACT
The prevalence of HIV drug resistance (HIVDR) mutations in the HIV protease (PR) and reverse transcriptase (RT) genes was estimated from peripheral blood mononuclear cells (PBMCs) in a study population of 25 antiretroviral (ARV) therapy-naive and 50 ARV-experienced chronically infected patients from Pune city, Maharashtra State, western India. Of the 75 study HIV-1 sequences, 73 belonged to subtype C and 2 to subtype A1. On phylogenetic analysis, the study subtype C sequences sub clustered randomly with different Indian and non-Indian subtype C sequences, emphasizing the HIV-1 subtype C pol gene diversity. The heterosexual route was the most common route of transmission (74.67%). There were no observable HIVDR mutations in ARV-naive patients. The ARV-experienced patients had a history of exposure to nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor combinations. At least one HIVDR mutation in RT was observed in 29 (80.55%) of ARV-experienced patients with evidence of failing therapy. M184V was the most common observed HIVDR mutation. No PR major mutations were observed among ARV-experienced patients. A higher prevalence of proviral HIVDR mutations in PBMCs was associated with irregular adherence to therapy (p < 0.05) and HIV-1 RNA levels > 1000 copies/ml (p < 0.001).
