Impact of baseline polymorphisms in RT and protease on outcome of highly active antiretroviral therapy in HIV-1-infected African patients

Frater, John; Beardall, A.; Ariyoshi, Koya; Churchill, Duncan; Galpin, S.; Clarke, John R.; Weber, Jonathan; McClure, Myra O.

doi:10.1097/00002030-200108170-00006

Cited by 88 publications

(75 citation statements)

References 18 publications

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“…In their study of patients of African origin who were infected with a non-B subtype of HIV-1 and were living in London, Frater et al 41 found no significant difference in the response to therapy among patients infected with subtype A, those infected with subtype C, and those infected with subtype D. In the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial, 62 there was no significant difference according to HIV-1 subtype in the virologic response to treatment or in the frequency of development of resistance among children. Overall, it appears that HIV-1 subtypes do not effect major differences in the response to antiretroviral therapy.…”

Section: Response To Therapymentioning

confidence: 99%

The Challenge of HIV-1 Subtype Diversity

et al. 2008

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Section: Response To Therapymentioning

confidence: 99%

The Challenge of HIV-1 Subtype Diversity

et al. 2008

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“…The V6 54 variant showed a lesser effect on nelfinavir and AG1776 with an 18-and 8-fold increase in the K i value, respectively. Variant V6 84 showed a greater decrease in inhibitor susceptibility (235-fold) to ritonavir than did V6 46 and V6 54 . To our surprise, the addition of mutation I84V decreased the binding affinity of indinavir to a lesser extent than M46I and I54V, 540-and 34-fold less, respectively, and the affinity of nelfinavir was 96-fold less than that of the mutation M46I.…”

Section: Resultsmentioning

confidence: 90%

“…The K m , k cat , and k cat /K m parameters were determined for LAI, a pretherapy isolated protease (wild type), and seven variants, V6, V6 46 , V6 54 , V6 84 , V6 46/84 , V6 54/84 , and V6 46/54/84 , using a synthetic substrate that mimics the CA-p2 site of Gag (Table 3). The V6, V6 46 , V6 54 , and V6 84 variants all experienced a decrease in k cat /K m of 2-, 2-, 3-, and 10-fold, respectively, when compared to LAI ( Table 2). Variants V6 46/84 , V6 54/84 , and V6 46/54/84 showed a decrease in k cat /K m of 5-, 8-, and 6-fold, respectively, when compared to LAI.…”

Section: Resultsmentioning

confidence: 99%

Comparing the Accumulation of Active- and Nonactive-Site Mutations in the HIV-1 Protease

et al. 2004

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Protease inhibitor resistance still poses one of the greatest challenges in treating HIV. To better design inhibitors able to target resistant proteases, a deeper understanding is needed of the effects of accumulating mutations and the contributions of active-and nonactive-site mutations to the resistance. We have engineered a series of variants containing the nonactive-site mutations M46I and I54V and the active-site mutation I84V. These mutations were added to a protease clone (V6) isolated from a pediatric patient on ritonavir therapy. This variant possessed the ritonavir-resistance-associated mutations in the active-site (V32I and V82A) and nonactive-site mutations (K20R, L33F, M36I, L63P, A71V, and L90M). The I84V mutation had the greatest effect on decreasing catalytic efficiency, 10-fold when compared to the pretherapy clone LAI. The decrease in catalytic efficiency was partially recovered by the addition of mutations M46I and I54V. The M46I and I54V were just as effective at decreasing inhibitor binding as the I84V mutation when compared to V6 and LAI. The V6 54/84 variant showed over 1000-fold decrease in inhibitor-binding strength to ritonavir, indinavir, and nelfinavir when compared to LAI and V6. Crystalstructure analysis of the V6 54/84 variant bound to ritonavir and indinavir shows structural changes in the 80's loops and active site, which lead to an enlarged binding cavity when compared to pretherapy structures in the Protein Data Bank. Structural changes are also seen in the 10's and 30's loops, which suggest possible changes in the dynamics of flap opening and closing.The development of resistance to protease inhibitors (PI) 1 during treatment of infection by the Human Immunodeficiency Virus (HIV) still poses one of the greatest challenges in the struggle to limit the virus replicative capacity. After initiation of therapy with single or multiple protease inhibitors, resistance mutations in the protease can appear within weeks. Under a constant drug selection pressure, resistant mutations continue to accumulate. It is clear that there is a correlation between the number of resistance mutations and the level of resistance and cross resistance to multiple protease inhibitors. It is of great interest to understand the level of contributions made by active-and nonactive-site mutations to the development of a high level of resistance (1-6). The HIV protease is a symmetric dimer composed of two 99-residue polypeptides (Figure 1). The dimerization region comprises the floor of the active site, which includes two catalytic aspartic acids (Asp25), one provided by each polypeptide. Unlike the human aspartic proteases that have one flap, two flaps completely cap the active site of the HIV protease. A more detailed description of HIV-1 protease structure, inhibitor binding, and resistance can be found in reviews by Wlodawer and Gustchina, Tomasselli and Heinrikson,.In this study, we analyze the effect of adding the nonactive-site mutations M46I and I54V and the active-site mutation I84V to a post...

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“…A French cohort study of 416 adult patients, 24% of whom carried non-B subtypes, showed that at 3, 6 and 12 months after initiation of ARV therapy (first line (Bocket et al, 2005). Frater et al studied patients of African origin who were infected with a non-B subtype of HIV-1 and were living in London, and found no significant difference in the response to therapy (first line regimens, 50% PI-based regimens, 50% NNRTI-based regimens) among patients infected with subtypes A, C and D (Frater et al, 2001). Geretti and collaborators reported that patients infected with subtypes A, C, D and CRF02_AG were as likely to achieve viral load suppression (NRTI backbone: AZT+3TC or TDF+FTC or TDF+3TC or 3TC+d4T or d4T+ddI or ABC+3TC; third drug: EFV or NVP or RTV boosted PI) as those infected with subtype B and showed comparable rates of CD4 cell count recovery (Geretti et al, 2009).…”

Section: Impact Of Hiv-1 Diversity In Response To Antiretroviral Therapymentioning

confidence: 99%

HIV-1 Diversity and Its Implications in Diagnosis, Transmission, Disease Progression, and Antiretroviral Therapy

Bártolo¹,

Taveira²

2012

Genetic Diversity in Microorganisms

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Impact of baseline polymorphisms in RT and protease on outcome of highly active antiretroviral therapy in HIV-1-infected African patients

Cited by 88 publications

References 18 publications

The Challenge of HIV-1 Subtype Diversity

The Challenge of HIV-1 Subtype Diversity

Comparing the Accumulation of Active- and Nonactive-Site Mutations in the HIV-1 Protease

HIV-1 Diversity and Its Implications in Diagnosis, Transmission, Disease Progression, and Antiretroviral Therapy

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