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1.  HIV-1 Subtype C Reverse Transcriptase and Protease Genotypes in Zimbabwean Patients Failing Antiretroviral Therapy 
AIDS research and human retroviruses  2002;18(18):1407-1413.
HIV-1 drug resistance mutations have been identified and characterized mostly in subtype B HIV-1 infection. The extent to which antiretroviral drugs select for drug resistance mutations in non-subtype B HIV-1 is not known. We obtained HIV-1 reverse transcriptase (RT) and protease sequences from 21 Zimbabwean patients failing antiretroviral drug therapy. We compared these sequences with 56 published RT and protease subtype C sequences from untreated patients, 990 RT and 1140 protease subtype B sequences from treated patients, and 340 RT and 907 protease subtype B sequences from untreated patients and identified four mutation categories of subtype C HIV-1. Seventeen of the 21 patients (81%) had known drug resistance mutations. Mutations at 15 RT and 11 protease positions were more common in subtype C isolates than in subtype B isolates. HIV-1 subtype C-infected individuals receiving antiretroviral therapy develop many of the known subtype B drug resistance mutations. Comparison of subtype C RT and protease sequences with a large database of subtype B sequences identified subtype C-specific polymorphisms and candidate drug resistance mutations.
doi:10.1089/088922202320935483
PMCID: PMC2573400  PMID: 12512512
2.  Identification of Ugandan HIV Type 1 Variants with Unique Patterns of Recombination in pol Involving Subtypes A and D 
Most HIV-1 infections in Uganda are caused by subtypes A and D. The prevalence of recombination and the sites of specific breakpoints between these subtypes have not been reported. HIV-1 pol sequences encoding protease (amino acids 1-99) and reverse transcriptase (amino acids 1-324) from 102 pregnant Ugandan women were analyzed by the Recombinant Identification Program, SimPlot, and examination of phylogenetically informative sites to identify sites of recombination between sequence segments belonging to different subtypes. Thirteen percent (13 of 102) of the pol sequences contained strong evidence of recombination between subtypes A and D. At least nine different patterns of recombination were observed. Five women infected with a recombinant virus transmitted the recombinant virus perinatally. In this population-based study, intersubtype recombinants were common. The large number of different types of pol recombinants identified suggests that recombination occurs readily in the pol region. Perinatal transmission of the recombinant viruses demonstrates their evolutionary stability.
doi:10.1089/088922202317406655
PMCID: PMC2573392  PMID: 12015904
3.  N88D Facilitates the Co-occurrence of D30N and L90M and the Development of Multidrug Resistance in HIV Type 1 Protease following Nelfinavir Treatment Failure 
AIDS research and human retroviruses  2006;22(12):1300-1305.
Nelfinavir was once one of the most commonly used protease inhibitors (PIs). To investigate the genetic mechanisms of multidrug resistance in protease isolates with the primary nelfinavir resistance mutation D30N, we analyzed patterns of protease mutations in 582 viruses with D30N from 460 persons undergoing HIV-1 genotypic resistance testing at Stanford University Hospital from 1997 to 2005. Three patterns of mutational associations were identified. First, D30N was positively associated with N88D but negatively associated with N88S. Second, D30N and L90M were negatively associated except in the presence of N88D, which facilitated the cooccurrence of D30N and L90M. Third, D30N + N88D + L90M formed a stable genetic backbone for the accumulation of additional protease inhibitor (PI) resistance mutations. In 16 patients having isolates with more than one combination of mutations at positions 30, 88, and 90, all exhibited one of the steps in the following progression: D30N → D30N + N88D → D30N + N88D + L90M → D30N + N88D + L90M + (L33F ± I84V or M46I/L ± I54V). Although nelfinavir is now used less frequently than other PIs, the well-delineated mutational pathway we describe is likely to influence patterns of cross-resistance in viruses from persons who experience virologic failure while receiving this PI.
doi:10.1089/aid.2006.22.1300
PMCID: PMC2573402  PMID: 17209774
4.  Protease and Reverse Transcriptase Mutation Patterns in HIV Type 1 Isolates from Heavily Treated Persons 
We compared HIV-1 subtype B reverse transcriptase (RT) and protease mutation patterns in isolates from heavily treated persons in Northern California with those from persons described in the published literature predominantly from other parts of the United States and Europe. There were few differences in the prevalence of single, double, and triple mutations between the two sets of sequences. More complex patterns of mutations could be characterized by clustering the sequences into eight groups of RT sequences and nine groups of protease sequences according to the presence of known drug-resistance mutations. This clustering accounted for 63% of the variation at RT inhibitor-resistance positions and 68% of the variation at protease inhibitor-resistance positions. The majority of clusters contained Northern California and literature sequences in similar proportions.
doi:10.1089/088922203322493085
PMCID: PMC2547469  PMID: 14601580

Results 1-4 (4)