Low Accumulation of L90M in Protease from Subtype F HIV‐1 with Resistance to Protease Inhibitors Is Caused by the L89M Polymorphism

Calazans, Alexandre; Brindeiro, Rodrigo M.; Brindeiro, Patrícia A.; Verli, Hugo; Arruda, Monica Barcelos; Gonzalez, Luis M. F.; Guimarães, Jorge A.; Diaz, Ricardo Sobhie; Antunes, Octávio Augusto Ceva; Tanuri, Amílcar

doi:10.1086/430002

Cited by 53 publications

(45 citation statements)

References 47 publications

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“…Patients who fail protease therapy and harbor subtype F isolates do not acquire D30N and accumulate L90M only infrequently (25). This appears to be due to the fact that accumulation of L90M in subtype F is dependent on first acquiring L89M.…”

Section: Mutational Interactions That Affect Fitness Intragenic Intermentioning

confidence: 99%

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Dykes

Demeter

2007

Clin Microbiol Rev

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SUMMARY The relative fitness of a variant, according to population genetics theory, is that variant's relative contribution to successive generations. Most drug-resistant human immunodeficiency virus type 1 (HIV-1) variants have reduced replication fitness, but at least some of these deficits can be compensated for by the accumulation of second-site mutations. HIV-1 replication fitness also appears to influence the likelihood of a drug-resistant mutant emerging during treatment failure and is postulated to influence clinical outcomes. A variety of assays are available to measure HIV-1 replication fitness in cell culture; however, there is no agreement regarding which assays best correlate with clinical outcomes. A major limitation is that there is no high-throughput assay that incorporates an internal reference strain as a control and utilizes intact virus isolates. Some retrospective studies have demonstrated statistically significant correlations between HIV-1 replication fitness and clinical outcomes in some patient populations. However, different studies disagree as to which clinical outcomes are most closely associated with fitness. This may be in part due to assay design, sample size limitations, and differences in patient populations. In addition, the strength of the correlations between fitness and clinical outcomes is modest, suggesting that, at present, it would be difficult to utilize these assays for clinical management.

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Section: Mutational Interactions That Affect Fitness Intragenic Intermentioning

confidence: 99%

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Dykes

Demeter

2007

Clin Microbiol Rev

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“…H69K mutacija, kartu su mutacijomis M36I ir L89M, dažniau-sia lemia atsparumą TPV (16). Mutaciją L89M kai kurie autoriai sieja su atsparumu SQV, NFV, RTV, APV ir LPV (17). Mutacijų M36I, H69K ir L89M derinys siejamas su padidėjusia rizika perduodamo atsparumo PI pacientams su viruso potipiu CRF02_AG (16).…”

Section: Mutacijomis Ir Lėmė Atsparumą Efv Etr Nvp Rvp; O Septintaunclassified

ŽIV-1 dažniausios mutacijos ir atsparumas antiretrovirusiniams vaistams

Subočiūtė-Stuliova¹,

Griskevicius²,

Gorobecas³

et al. 2015

AML

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Tyrimo tikslas. Įvertinti ŽIV infekuotiems pacientams skirtingų ŽIV-1 mutacijų pasiskirstymą ir jų nulemtą atsparumą antiretrovirusiniams vaistams (ARV). Metodai. Mutacijų tipai ir atsparumas vaistams buvo tiriami 149 ŽIV-1 infekuotiems pacientams, kurių kraujo plazmos mėginiai 2011– 2013 m. ištirti Nacionalinėje visuomenės sveikatos priežiūros laboratorijoje. ŽIV-1 genotipas ir atsparumas vaistams tirtas pacientams, kurių plazmos virusinis krūvis buvo ne mažesnis 2 000 kopijų/ml. Nustatytų ŽIV-1 mutacijų, sukeliančių atsparumą specifiniams ARV preparatams, duomenys buvo vertinami „HIV-1 Genotyping System Software v2.8“, tiesiogiai prisijungus prie „Stanford HIV Drug Resistance Database“ (http://hivdb.stanford.edu), kur buvo tikrinama sekų kokybė ir nustatomas viruso potipis. Rezultatai. Su atsparumu ARV susiję mutacijos buvo aptiktos 84 pacientams, o iš jų atsparumas vaistams (tiek faktinis, tiek potencialus) – 37 pacientams. Dažniausia aptiktos mutacijos, lemiančios atsparumą proteazių inhibitoriams (PI), buvo L10V, L10IV, L10N, L10I, A71V. Šios mutacijos buvo nustatytos kartu su atsparumo nukleozidiniams atvirkštinės transkriptazės inhibitoriams (NATI) ir nenukleozidiniams atvirkštinės transkriptazės inhibitoriams (NNATI) mutacijomis. Dažniausios atsparumo NATI mutacijos buvo A62V ir V75L, o NNATI mutacijos – V179D, G190S, K103N ir E138A, kurios ir pavienės, ir kartu su kitomis mutacijomis lemia tam tikro lygio atsparumą vaistams. Išvados. Lietuvoje gydomiems ŽIV infekuotiems asmenims būdinga šio viruso mutacijų įvairovė: su atsparumu susietos ir su nustatytu atsparumu vaistams (25 % tyrime dalyvavusių asmenų); su atsparumu susietos, bet be nustatyto atsparumo vaistams (32 % tyrime dalyvavusių asmenų). Prieš paskiriant gydymą ŽIV infekuotiems asmenims svarbu nustatyti atsparumą ARV lemiančias mutacijas ir tęsti atsparumo ARV tyrimus jau gydomiems pacientams.

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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%

“…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). Similarly, T74S, which is a polymorphism that occurs in 8% of subtype C sequences, but rarely in other subtypes, is associated with reduced susceptibility to nelfinavir (Deforche et al, 2007;Deforche et al, 2006;Rhee et al, 2006b).…”

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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Low Accumulation of L90M in Protease from Subtype F HIV‐1 with Resistance to Protease Inhibitors Is Caused by the L89M Polymorphism

Abstract: The L89M mutation in subtype F viruses is a high genetic barrier to the accumulation of the L90M resistance mutation and can function as a resistance mutation, depending on the presence of other polymorphisms in the subtype F PR backbone.

Cited by 53 publications

References 47 publications

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

ŽIV-1 dažniausios mutacijos ir atsparumas antiretrovirusiniams vaistams

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

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