Resistance Mutations in Protease and Reverse Transcriptase Genes of Human Immunodeficiency Virus Type 1 Isolates from Patients with Combination Antiretroviral Therapy Failure

Young, Benjamin; Johnson, Steven C.; Minoo, Bahktiari; Shugarts, David; Young, Russell; Allen, Michael; Ramey, Rob Roy; Kuritzkes, Daniel R.

doi:10.1086/314437

Cited by 53 publications

(40 citation statements)

References 11 publications

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“…The M46I mutation was seen in four patients, while V82A/F and I84V mutations were each observed in two treated patients, but these last two mutations were only seen in association with the L90M mutation. The prevalence of the L90M mutation is similar to that observed in patients infected with subtype B who failed combination therapy, but the prevalence of the V82A/T/F mutation (Ͻ10%) is much lower (15).…”

supporting

confidence: 62%

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

Cane

Ruiter²,

Rice³

et al. 2001

J Clin Microbiol

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This work reports the variability of human immunodeficiency virus type 1 (HIV-1) protease from treated and untreated patients infected with HIV-1 subtype C in the United Kingdom. The most common primary mutation observed in treated patients was L90M. D30N, M46I, V82A/F, and I84V were seen rarely. M36I and I93L mutations were observed in nearly all samples from both treated and untreated patients and so cannot be considered as resistance-associated mutations in this subtype.

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supporting

confidence: 62%

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

Cane

Ruiter²,

Rice³

et al. 2001

J Clin Microbiol

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“…HIV-1 variants frequently evolve that escape HAART by developing resistance to the inhibitors used (4,15,19,28,40,42). Of patients first treated with a single drug regimen and then going onto HAART, as many as 40% have a viral rebound within the first 3 years, and this number is likely to be higher outside of controlled studies (20,35).…”

mentioning

confidence: 99%

Viral Evolution in Response to the Broad-Based Retroviral Protease Inhibitor TL-3

Bühler¹,

Lin²,

Morris³

et al. 2001

J Virol

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TL-3 is a protease inhibitor developed using the feline immunodeficiency virus protease as a model. It has been shown to efficiently inhibit replication of human, simian, and feline immunodeficiency viruses and therefore has broad-based activity. We now demonstrate that TL-3 efficiently inhibits the replication of 6 of 12 isolates with confirmed resistance mutations to known protease inhibitors. To dissect the spectrum of molecular changes in protease and viral properties associated with resistance to TL-3, a panel of chronological in vitro escape variants was generated. We have virologically and biochemically characterized mutants with one (V82A), three (M46I/F53L/V82A), or six (L24I/M46I/F53L/L63P/V77I/V82A) changes in the protease and structurally modeled the protease mutant containing six changes. Virus containing six changes was found to be 17-fold more resistant to TL-3 in cell culture than was wild-type virus but maintained similar in vitro replication kinetics compared to the wild-type virus. Analyses of enzyme activity of protease variants with one, three, and six changes indicated that these enzymes, compared to wild-type protease, retained 40, 47, and 61% activity, respectively. These results suggest that deficient protease enzymatic activity is sufficient for function, and the observed protease restoration might imply a selective advantage, at least in vitro, for increased protease activity.

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“…Highly active antiretroviral therapies (HAART) combining various drug regimens have decreased the occurrence of such mutations by reducing levels of virus replication, but they concomitantly decrease the intensity of the HIV-specific CTL responses (10,15,29). Currently viral replication is efficiently controlled in only 50% of patients receiving HAART; frequency of treatment failures is increasing and correlates with high levels of drug-induced mutations (56). In industrialized countries, approximately 15% of new cases of HIV primary infection involve strains that show primary drug-induced mutations transmitted by treated individuals (3,27,55).…”

mentioning

confidence: 99%

“…Alternatively, the coexistence of other class I loci could have negatively selected the appropriate CD8 ϩ T-lymphocyte response. It is only in the case of mutation T215Y, which is frequently observed within the AZT-induced mutations (35,56), that predicted epitopes failed to be recognized, suggesting a poor immune control of this region. Thus, both predictive model and ELISPOT analyses confirm the poor immunogenicity of the RT region surrounding mutation 215.…”

mentioning

confidence: 99%

Immunogenicity of Mutations Induced by Nucleoside Reverse Transcriptase Inhibitors for Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Cells

Samri¹,

Haas

Duntze³

et al. 2000

J Virol

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The impact of drug resistance mutations induced by nucleoside reverse transcriptase (RT) inhibitors (NRTI) on cytotoxic T-lymphocyte (CTL) recognition of human immunodeficiency virus type 1 strain LAI (HIV-1 LAI )RT was addressed in 35 treated or untreated patients. Two HIV-1 LAI RT regions encompassing mutation M41L, L74V, M184V, and T215Y/F were recognized in 75 and 83% mutated and in 33 and 42% unmutated samples, respectively. A total of 41 new CTL epitopes overlapping these mutations were predicted. Mutations enhanced HLA-binding scores of 17 epitopes, decreased scores of 5, and had no effect in 19. Four predicted epitopes containing mutations 41, 74, and 184 were tested and recognized by CD8 cells from mutated or unmutated samples, with frequencies up to 270 gamma interferon spot-forming cells per 10 6 peripheral blood mononuclear cells. Therefore, RT mutations induced by NRTI can increase the immunogenicity of RT for CTL and might allow a better immune control of resistant viruses in vivo, suggesting that specific immune therapy might help prevent these mutations.Cytotoxic T lymphocytes (CTL) specific for human immunodeficiency virus (HIV) or simian immunodeficiency virus are considered the most efficient virus-specific immune responses (4,26,29,39). The strength and the diversity of CTL responses (16, 54) have been proposed, together with reverse transcriptase (RT) infidelity (7,33,37), as an important factor for virus variability at time of asymptomatic disease and strong immune functions. Some viral mutations can decrease immunogenicity by interfering with the intracellular processing or with the HLA binding of viral peptides, thereby resulting in a lack of CTL recognition (5,11,13,14,22,30,32,34). In contrast, new HIV variants that do not interfere with such processes can be immunogenic for specific new CTL clones (16), a fact which contributes to some extent to determining HIV variability (54).The high level of HIV type 1 (HIV-1) RT sequence conservation among different HIV isolates (25) makes RT one of the most frequent targets for CTL recognition; indeed, 80% of HIV-infected individuals have specific RT-specific CTL (17). Prolonged antiviral mono-or bitherapy with nucleoside RT inhibitors (NRTI), however, results in selection of HIV-1 strains containing mutations in the RT gene (36). These mutations often have an impact on the enzymatic activity of RT and on the fitness of the virus (2, 45). These drug-induced mutations are highly standardized and characteristic of the various NRTI used (28, 38). Highly active antiretroviral therapies (HAART) combining various drug regimens have decreased the occurrence of such mutations by reducing levels of virus replication, but they concomitantly decrease the intensity of the HIV-specific CTL responses (10,15,29). Currently viral replication is efficiently controlled in only 50% of patients receiving HAART; frequency of treatment failures is increasing and correlates with high levels of drug-induced mutations (56). In industrialized countries, approximately 15% ...

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Resistance Mutations in Protease and Reverse Transcriptase Genes of Human Immunodeficiency Virus Type 1 Isolates from Patients with Combination Antiretroviral Therapy Failure

Cited by 53 publications

References 11 publications

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

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

Viral Evolution in Response to the Broad-Based Retroviral Protease Inhibitor TL-3

Immunogenicity of Mutations Induced by Nucleoside Reverse Transcriptase Inhibitors for Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Cells

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