Resistance-Associated Mutations in the Human Immunodeficiency Virus Type 1 Subtype C Protease Gene from Treated and Untreated Patients in the United Kingdom

Cane, Patricia A.; Ruiter, Annemiek de; Rice, Philip; Wiselka, Martin; Fox, R.; Pillay, Deenan

doi:10.1128/jcm.39.7.2652-2654.2001

Cited by 70 publications

(52 citation statements)

References 18 publications

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“…These findings are in accordance with the analyzed data reported in a recent study that compared the genotypic variation between the prevalent clades, B and C, in Israel (12), as well as in other studies reporting genotypic differences between clades only in the secondary resistance mutation patterns (4,6,10,11,12,17,27). A high frequency of ritonavir and nelfinavir resistance mutations was detected, in contrast to the low prevalence found by others in infants (9).…”

Section: Vol 40 2002 Drug Resistance Of Hiv-1 Clades B and Non-b Insupporting

confidence: 82%

Testing Genotypic and Phenotypic Resistance in Human Immunodeficiency Virus Type 1 Isolates of Clade B and Other Clades from Children Failing Antiretroviral Therapy

Brindeiro

Mortensen³

et al. 2002

J Clin Microbiol

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The emergence of resistance to antiretroviral drugs is a major obstacle to the successful treatment of human immunodeficiency virus type 1 (HIV-1)-infected patients. In this work, we correlate clinical and virological trends such as viral load (VL) and CD4 counts to genotypic and phenotypic antiretroviral (ARV) resistance profiles of HIV-1 isolates from the B and non-B subtypes found in vertically infected children failing ARV therapy. Plasma samples were collected from 52 vertically HIV-1-infected children failing different ARV therapies. Samples underwent HIV-1 pol sequencing and phenotyping and were clustered into subtypes by phylogenetic analysis. Clinical data from each patient were analyzed together with the resistance (genotypic and phenotypic) data obtained. Thirty-five samples were from subtype B, 10 samples were non-B (subtypes A, C, and F), and 7 were mosaic samples. There was no significant difference concerning treatment data between B and non-B clades. Prevalence of known drug resistance mutations revealed slightly significant differences among B and non-B subtypes: L10I, 21 and 64%, K20R, 13 and 43%, M36I, 34 and 100%, L63P, 76 and 36%, A71V/T, 24 and 0%, and V77I, 32 and 0%, respectively, in the protease (0.0001 < P < 0.0886), and D67N, 38 and 8%, K70R, 33 and 0%, R211K, 49 and 85%, and K219Q/E, 31 and 0%, respectively, in the reverse transcriptase (0.0256 < P < 0.0704). Significant differences were found only in secondary resistance mutations and did not reflect significant phenotypic variation between clade B and non-B.

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Section: Vol 40 2002 Drug Resistance Of Hiv-1 Clades B and Non-b Insupporting

confidence: 82%

Testing Genotypic and Phenotypic Resistance in Human Immunodeficiency Virus Type 1 Isolates of Clade B and Other Clades from Children Failing Antiretroviral Therapy

Brindeiro

Mortensen³

et al. 2002

J Clin Microbiol

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“…Other resistance mutations considered of a lesser significance are defined as secondary or minor. Although none of the primary mutations occur as polymorphisms in wild-type HIV-1, several secondary mutations contributing to reduced susceptibility (i.e., M36I and I93L) are found in nearly 100% of subtype C virus from drug-naive patients (5,10). Upon antiretroviral treatment, such differences in baseline polymorphisms among subtypes may result in the evolution of drug resistance along distinct mutational pathways, or in differences in the incidence of these specific pathways (1,4,9,12,16,25,28,29).…”

mentioning

confidence: 99%

Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Grossman

Paxinos

Averbuch

et al. 2004

Antimicrob Agents Chemother

109

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Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C-and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P ‫؍‬ 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC 50 ) change in susceptibility to nelfinavir only. Other mutations increased IC 50 correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ؎ 22% to 22% ؎ 15% (P ‫؍‬ 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.

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“…For example, the accessory PI resistance mutations I13V, K20I, M36I and I93L represent the consensus variant in one or more non-subtype B isolates (Rhee et al, 2006a). Furthermore, although both D30N and L90M mutations occur in non-subtype B viruses during nelfinavir therapy, D30N point mutation occurs more commonly in subtype B viruses; while L90M occurs more commonly in subtypes C, F, G and circulating recombinant form-AE (CRF-AE) viruses (Abecasis et al, 2005;Calazans et al, 2005;Cane et al, 2001;Grossman et al, 2004;Sugiura et al, 2002). The increased predilection for a certain subtype to develop L90M may relate to the presence of variants other than L, which is subtype B consensus, at position 89 (Abecasis et al, 2005;Calazans et al, 2005;Gonzalez et al, 2004).…”

Section: Point Mutations Associated With Resistance To Protease Inhibmentioning

confidence: 99%

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

Khati¹,

Millroy²

2012

Point Mutation

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Resistance-Associated Mutations in the Human Immunodeficiency Virus Type 1 Subtype C Protease Gene from Treated and Untreated Patients in the United Kingdom

Cited by 70 publications

References 18 publications

Testing Genotypic and Phenotypic Resistance in Human Immunodeficiency Virus Type 1 Isolates of Clade B and Other Clades from Children Failing Antiretroviral Therapy

Testing Genotypic and Phenotypic Resistance in Human Immunodeficiency Virus Type 1 Isolates of Clade B and Other Clades from Children Failing Antiretroviral Therapy

Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

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