Genetic Changes in HIV-1 Gag-Protease Associated with Protease Inhibitor-Based Therapy Failure in Pediatric Patients.
Studies have shown a low frequency of HIV-1 protease drug resistance mutations in patients failing protease inhibitor (PI)-based therapy. Recent studies have identified mutations in Gag as an alternate pathway for PI drug resistance in subtype B viruses. We therefore genotyped the Gag and protease genes from 20 HIV-1 subtype C-infected pediatric patients failing a PI-based regimen. Major protease resistance mutations (M46I, I54V, and V82A) were identified in eight (40%) patients, as well as Gag cleavage site (CS) mutations (at codons 373, 374, 378, 428, 431, 449, 451, and 453) in nine (45%) patients. Four of these Gag CS mutations occurred in the absence of major protease mutations at PI failure. In addition, amino acid changes were noted at Gag non-CS with some predicted to be under HLA/KIR immune-mediated pressure and/or drug selection pressure. Changes in Gag during PI failure therefore warrant further investigation of the Gag gene and its role in PI failure in HIV-1 subtype C infection.
1 Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) , Johannesburg, South Africa .|2 Faculty of Health Sciences, University of Witwatersrand , Johannesburg, South Africa .
Jennifer
J
Giandhari
1 Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) , Johannesburg, South Africa .|2 Faculty of Health Sciences, University of Witwatersrand , Johannesburg, South Africa .
Adriaan E
AE
Basson
3 Empilweni Services and Research Unit, Rahima Moosa Mother and Child Hospital, Faculty of Health Sciences, University of Witwatersrand , Johannesburg, South Africa .
Ashraf
A
Coovadia
4 Gertrude H. Sergievsky Center, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University , New York, New York.
Louise
L
Kuhn
5 International Center for AIDS Programs, Mailman School of Public Health, Columbia University , New York, New York.
Elaine J
EJ
Abrams
3 Empilweni Services and Research Unit, Rahima Moosa Mother and Child Hospital, Faculty of Health Sciences, University of Witwatersrand , Johannesburg, South Africa .
Renate
R
Strehlau
1 Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) , Johannesburg, South Africa .|2 Faculty of Health Sciences, University of Witwatersrand , Johannesburg, South Africa .
Lynn
L
Morris
1 Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) , Johannesburg, South Africa .|2 Faculty of Health Sciences, University of Witwatersrand , Johannesburg, South Africa .
Gillian M
GM
Hunt
D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1