Drug Resistance Mutation Profile and Accumulation Kinetics in Human Immunodeficiency Virus-Positive Individuals Infected with Subtypes B and F Failing Highly Active Antiretroviral Therapy Are Influenced by Different Viral Codon Usage Patterns

Waléria-Aleixo, A.; Martins, Angélica N.; Arruda, Monica Barcelos; Brindeiro, Rodrigo M.; Da-Silva, R. M.; Nobre, Flávio Fonseca; Greco, Dirceu Bartolomeu; Tanuri, Amílcar

doi:10.1128/aac.00820-08

Cited by 9 publications

(5 citation statements)

References 39 publications

(34 reference statements)

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“…2 Because subtype B accounts for less than 10% of the world-wide infections, 7 concerns arise regarding the effectiveness of current HAART treatment against other subtypes, with questions centered on variations in drug susceptibility, emergence patterns of drug pressure selected mutations, viral replicative capacity and dynamics of resistance emergence. 2,3,5,7,44,[48][49][50][51][52][53][54][55][56][57][58][59][60] Many of the natural polymorphisms in HIV-1PR that are found in non-B sequences correspond to secondary mutations that arise in subtype B, 37 possibly indicating that drug resistance against current PIs in non-B subtypes of HIV-1PR will advance more rapidly. 3,8,38,48,49,61,62 For example, Fig.…”

Section: Introductionmentioning

confidence: 99%

Pulsed EPR characterization of HIV-1 protease conformational sampling and inhibitor-induced population shifts

Liu

Casey

Blackburn

et al. 2016

Phys. Chem. Chem. Phys.

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The conformational landscape of HIV-1 protease (PR) can be experimentally characterized by pulsed-EPR double electron-electron resonance (DEER). For this characterization, nitroxide spin labels are attached to an engineered cysteine residue in the flap region of HIV-1 PR. DEER distance measurements from spin-labels contained within each flap of the homodimer provide a detailed description of the conformational sampling of apo-enzyme as well as induced conformational shifts as a function inhibitor binding. The distance distribution profiles are further interpreted in terms of a conformational ensemble scheme that consists of four unique states termed “curled/tucked”, “closed”, “semi-open” and “wide-open” conformations. Reported here are the DEER results for a drug-resistant variant clinical isolate sequence, V6, in the presence of FDA approved protease inhibitors (PIs) as well as a non-hydrolyzable substrate mimic, CaP2. Results are interpreted in the context of the current understanding of the relationship between conformational sampling, drug resistance, and kinetic efficiency of HIV-1PR as derived from previous DEER and kinetic data for a series of HIV-1PR constructs that contain drug-pressure selected mutations or natural polymorphisms. Specifically, these collective results support the notion that inhibitor-induced closure of the flaps correlates with inhibitor efficiency and drug resistance. This body of work also suggests DEER as a tool for studying conformational sampling in flexible enzymes as it relates to function.

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Section: Introductionmentioning

confidence: 99%

Pulsed EPR characterization of HIV-1 protease conformational sampling and inhibitor-induced population shifts

Liu

Casey

Blackburn

et al. 2016

Phys. Chem. Chem. Phys.

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“…). Moreover, in the CoRIS cohort, patients infected by non‐B subtypes were at 73% of lower risk of having resistance to the NRTIs class [Walèria‐Aleixo et al, ; Monge et al, ]. It has been proposed that changing features in the HIV‐1 epidemic in European countries, characterized by a significant increase in non‐B subtypes from populations migrating from countries with more limited access to ART, may partially justify the finding of a reduced prevalence of some TDR during the last years [Bracciale et al, ; De Mendoza et al, ].…”

Section: Discussionmentioning

confidence: 99%

“…This is the case of the extraordinary genetic variability which characterizes HIV infection with a potential impact on disease progression, diagnosis, therapy, and epidemiology [De Felipe et al, 2011]. HIV epidemic is characterized by a high genotypic diversity and several HIV subtypes and circulating recombinant forms (CRFs) have been described [Walèria-Aleixo et al, 2008;Luft et al, 2011;Schrrer et al, 2011]. HIV-1 subtype B is predominant in North America and Western Europe, including Spain, although is responsible for only 10% of global infections [Luft et al, 2011;Scherrer et al, 2011].…”

Section: Introductionmentioning

confidence: 99%

Trends on epidemiological, virological, and clinical features among newly diagnosed HIV‐1 persons in Northwest Spain over the last 10 years

Pernas

Mena

Cañizares

et al. 2015

Journal of Medical Virology

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To describe temporal trend and characteristics of newly HIV-diagnosed patients in a medical care area in Northwest Spain over the last 10 years. All newly diagnosed patients for HIV-infection from 2004 to 2013 at a reference medical care area in Northwest of Spain were identified. Epidemiological, virological, immunological, and clinical data, as well as HIV genotype and drug resistance information were recorded. A total of 565 newly HIV-diagnosed patients were identified. The number of new cases increased in the last 5 years (66 cases/year). Overall, 53.1% had a median CD4 counts < 350 cells/µl and 33.6% had an AIDS defining criteria. Non-B variants were found in 34.4% of patients being subtype F (25.8%) the most common non-B subtype. The rate of transmitted drug resistance (TDR) over the study period was 3.7%, but a decreased to 2.6% was observed in the last 5 years. The most prevalent TDR mutations were: T215 revertants (1.5%), K219QENR (1.2%), for NRTIs; K103N (1.9%), for NNRTIs; L90M (0.3%), for PIs. Overall, 73.2% of patients started antiretroviral treatment and 9.9% of patients died during follow-up. The number of newly HIV diagnosed patients increased since year 2009. There is a high prevalence of late diagnosis (53%) and 33% had an AIDS defining criteria. Interestingly, the most prevalent non-B subtype in our population was F (25.8%). These findings support the need to facilitate the access for HIV testing to reduce the rate of late HIV diagnosis, improve the clinical outcome and prevent HIV transmission.

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“…Genotype resistance tests do not provide any strong information because their reliability is limited by technical problems of amplifying and interpreting amino acid sequences, although there is no evidence that non‐B subtypes develop different drug resistance mutations or have different phenotype susceptibility [Visco‐Comandini and Balotta, 2003]. According to the International AIDS Society algorithm used in this study [Johnson et al, 2008], the amino acid substitutions may be clinically irrelevant, but it should be noted that the most frequent substitution (36I in the pol region, which has a prevalence of 85.7%) is one of the eight differences in protease protein between the subtype F and US subtype B consensus sequences [Waléria‐Aleixo et al, 2008].…”

Section: Discussionmentioning

confidence: 99%

A cluster of patients with recombinant B/F HIV‐1 infection: Epidemiological, clinical, and virological aspects

Rossotti¹,

Foglieni²,

Molteni³

et al. 2011

Journal of Medical Virology

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Migratory processes have caused changes in human immunodeficiency virus (HIV) epidemiology and non‐B subtypes are now playing an increasing role. In a cohort of 553 HIV‐infected outpatients tested to identify non‐B isolates, the largest group consisted of 13 subjects with a recombinant B/F form (prevalence 2.4%). Sequencing and phylogenetic analyses described a B/F recombinant clade with anomalous breakpoints that did not allow it to be classified as CRF12_BF. Viral load was not quantified efficiently because of a mismatch in the primers and probes used by commercial assays. An assessment of the clinical management, and epidemiological, immunological, and virological characteristics of these patients, who were receiving non‐nucleoside reverse transcriptase inhibitor (NNRTI)‐ or protease inhibitor (PI)‐based regimens, showed that the immunological and virological mismatch delayed the start of treatment by a mean of 6.8 months. Therapy was started in nine patients. Both NNRTI‐ and PI‐based regimens led to full virological suppression after a mean 36 weeks of treatment; the PI‐based regimens proved to be more effective in terms of immunological recovery (1,341 vs. 544 CD4+ cells/mm3). The spread of non‐B subtypes is increasing throughout the world but their response to treatment is still unclear. PIs and NNRTIs are effective but further tests are needed to allow the more efficient recognition of these viral strains and establish how they should be treated. J. Med. Virol. 83:1493–1498, 2011. © 2011 Wiley‐Liss, Inc.

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Drug Resistance Mutation Profile and Accumulation Kinetics in Human Immunodeficiency Virus-Positive Individuals Infected with Subtypes B and F Failing Highly Active Antiretroviral Therapy Are Influenced by Different Viral Codon Usage Patterns

Cited by 9 publications

References 39 publications

Pulsed EPR characterization of HIV-1 protease conformational sampling and inhibitor-induced population shifts

Pulsed EPR characterization of HIV-1 protease conformational sampling and inhibitor-induced population shifts

Trends on epidemiological, virological, and clinical features among newly diagnosed HIV‐1 persons in Northwest Spain over the last 10 years

A cluster of patients with recombinant B/F HIV‐1 infection: Epidemiological, clinical, and virological aspects

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