High prevalence of primary Enfuvirtide (ENF) resistance-associated mutations in HIV-1-infected patients in Hong Kong

Leung, Polly H.M.; Chen, J.H.K.; Wong, Ka-Hing; Chan, Kenny Chi Wai; Lam, Hoyin; Cheng, Vincent Chi-Chung; Yuen, Kwok‐Yung; Yam, Wing Cheong

doi:10.1016/j.jcv.2010.01.002

Cited by 10 publications

(10 citation statements)

References 17 publications

(21 reference statements)

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“…But we did not find any substitutions in the GIV motif and the residues 547–556 region in NHR related to viral resistance to enfuvirtide [18], [29]–[32], which is contrary to the report by Leung et al [34] who identified the G36D mutation in 19.4% of HARRT-experienced patients and 20.5% of ART-naïve patients in Hong Kong. The only polymorphism in this region is N553S, which was shown to be present in about 15% of HIV-1 isolates with non-decreased enfuvirtide susceptibility [35].…”

Section: Discussioncontrasting

confidence: 99%

Susceptibility of HIV-1 Subtypes B′, CRF07_BC and CRF01_AE that Are Predominantly Circulating in China to HIV-1 Entry Inhibitors

Lin

Huang

et al. 2011

PLoS ONE

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BackgroundThe B′, CRF07_BC and CRF01_AE are the predominant HIV-1 subtypes in China. It is essential to determine their baseline susceptibility to HIV entry inhibitors before these drugs are used in China.Methodology/Principal FindingsThe baseline susceptibility of 14 representative HIV-1 isolates (5 CRF07_BC, 4 CRF01_AE, and 5 B′), most of which were R5 viruses, obtained from drug-naïve patients to HIV entry inhibitors, including two fusion inhibitors (enfuvirtide and C34), two CCR5 antagonists (maraviroc and TAK779) and one CXCR4 antagonist (AMD3100), were determined by virus inhibition assay. The sequences of their env genes were amplified and analyzed. These isolates possessed similar susceptibility to C34, but they exhibited different sensitivity to enfuvirtide, maraviroc or TAK779. CRF07_BC isolates, which carried polymorphisms of A578T and V583I in the N-terminal heptad repeat and E630Q, E662A, K665S, A667K and S668N in the C-terminal heptad repeat of gp41, were about 5-fold less sensitive than B′ and CRF01_AE isolates to enfuvirtide. Subtype B′ isolates with a unique polymorphism site of F317W in V3 loop, were about 4- to 5-fold more sensitive than CRF07_BC and CRF01_AE isolates to maraviroc and TAK779. AMD3100 at the concentration as high as 5 µM exhibited no significant inhibitory activity against any of the isolates tested.ConclusionOur results suggest that there are significant differences in baseline susceptibility to HIV entry inhibitors among the predominant HIV-1 subtypes in China and the differences may partly result from the naturally occurring polymorphisms in these subtypes. This study provides useful information for rational design of optimal therapeutic regimens for HIV-1-infected patients in China.

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Section: Discussioncontrasting

confidence: 99%

Susceptibility of HIV-1 Subtypes B′, CRF07_BC and CRF01_AE that Are Predominantly Circulating in China to HIV-1 Entry Inhibitors

Lin

Huang

et al. 2011

PLoS ONE

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“…Notably, these mutations in HR2 domain may dramatically reduce ENF susceptibility about 100-1000-fold, in combination with substitutions in HR1 domain (amino acid positions: 36-45) [43,44]. In addition, a lot of minor mutations and polymorphisms (A30V, Q32L, L33V, L34M, S35A/F/T, Q39H, R46K/M/Q, E49D/K/Q, Q52H, H53N/Q/R, Q56K/R, I62V) associated with potential resistance ENF were discovered in our study have reported in previous studies [16,25,45,46].…”

Section: Discussionsupporting

confidence: 62%

“…ENF was the first HIV fusion inhibitor based on the amino acid sequence of the heptad repeat-2 (HR2) in the glycoprotein 41 (gp41) of HIV-1 envelope (env) protein, which blocks HIV-1 entry and restrict HIV-1 replication, used in combination with other antiretroviral drugs as an alternative to the ordinary ART [9,10]. HR1 region substitutions in HIV-1 env gp41, including A30V, L33V, L34M, G36D/S, I37V, V38A, Q39H/R, Q40H, N42T/D, N43D, L44M, L45M, R46M, L54M and et al, have been proved to be associated with ENF resistance in vitro and vivo [11][12][13][14][15][16]. The major ENF resistance-associated mutations were identified in amino acid position 36-45 of HR1 domain.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 gp41 genetic diversity and enfuvirtide resistance-associated mutations among enfuvirtide-naïve patients in southern China

Chang

Zhao

Zhang

et al. 2020

Preprint

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Background: Human immunodeficiency virus (HIV) increasing molecular diversity and emergence of drug resistant mutants remain a major concern in Southern China, enfuvirtide (ENF/T-20) is the first entry inhibitor used in patients failing highly active antiretroviral therapy (HAART). However, data on HIV-1 gp41genetic diversity and primary ENF resistance-associated mutations among treatment-naïve patients in southern China is limited. The objective was to identify molecular diversity and ENF resistance patterns of HIV-1 in southern China, using envelop (env) gp41 sequences and bioinformatics tools, which may help optimize ART. Methods: From December 2018 to January 2019, 439 blood plasma samples from ENF-naïve HIV-1 patients were collected from Shenzhen, Wuhan and Chongqing, of which, 396 HIV env regions were sequenced and subtyped, and were performed the analysis of drug resistance-associated mutations (DRMs). Results: The main subtypes were circulating recombinant form (CRF) 01_AE (30.6%) and CRF07_BC (48.7%), CRF55_01B had been the fourth subtype in our work, many rare CRFs were observed. Notably, CRF02_AG and CRF_BF strains typically found in Africa and US respectively were identified amongst Chinese HIV-1 patients. Known DRMs were detected in 27.5% (109/396) of ENF treatment-naïve patients. One major DRM (L44M), many secondary DRMs including (N126K, E137K, S138A) and lots of polymorphisms were found in the study, which have been proved to elevate resistance to ENF. Conclusion: HIV-1 molecular diversity among people in southern China observed in the work indicates that HIV-1 variability is becoming increasingly complex in the south of China. A diverse set of primary DRMs discovered in this study described the serious threat to ART, which remind us the urgent need of timely surveillance of HIV-1 viral diversity and drug resistance in China.

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“…25 In contrast, Leung et al found a high level of G36D mutation in naïve patients from Hong Kong. 26 Thus, understanding the discrepancies between the studies is important to have a clear view of primary resistance to this antiretroviral.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Primary Resistance to HIV Entry Inhibitors Among Brazilian Patients Failing Reverse Transcriptase/Protease Inhibitors Treatment Reveal High Prevalence of Maraviroc Resistance-Related Mutations

Alencar

Nishiya

Ferreira

et al. 2010

AIDS Research and Human Retroviruses

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Entry inhibitor is a new class of drugs that target the viral envelope protein. This region is variable; hence resistance to these drugs may be present before treatment. The aim of this study was to analyze the frequency of patients failing treatment with transcriptase reverse and protease inhibitors that would respond to the entry inhibitors Enfuvirtide, Maraviroc, and BMS-806. The study included 100 HIV-1 positive patients from one outpatient clinic in the city of Sao Paulo, for whom a genotype test was requested due to treatment failure. Proviral DNA was amplified and sequenced for regions of gp120 and gp41. A total of 80 could be sequenced and from those, 73 (91.3%), 5 (6.3%) and 2 (2.5%) were classified as subtype B, F, and recombinants (B/ F and B/C), respectively. CXCR4 co-receptor use was predicted in 30% of the strains. Primary resistance to Enfuvirtide was found in 1.3%, following the AIDS Society consensus list, and 10% would be considered resistant if a broader criterion was used. Resistance to BMS-806 was higher; 6 (7.5%), and was associated to non-B strains. Strikingly, 27.5% of samples harbored one or more mutation among A316T, I323V, and S405A, which have been related to decreased susceptibility of Maraviroc; 15% of them among viruses predictive to be R5. A more common mutation was A316T, which was associated to the Brazilian B strain harboring the GWGR motif at the tip of V3 loop and their derivative sequences. These results may be impact guidelines for genotype testing and treatment in Brazil.

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High prevalence of primary Enfuvirtide (ENF) resistance-associated mutations in HIV-1-infected patients in Hong Kong

Cited by 10 publications

References 17 publications

Susceptibility of HIV-1 Subtypes B′, CRF07_BC and CRF01_AE that Are Predominantly Circulating in China to HIV-1 Entry Inhibitors

Susceptibility of HIV-1 Subtypes B′, CRF07_BC and CRF01_AE that Are Predominantly Circulating in China to HIV-1 Entry Inhibitors

HIV-1 gp41 genetic diversity and enfuvirtide resistance-associated mutations among enfuvirtide-naïve patients in southern China

Evaluation of Primary Resistance to HIV Entry Inhibitors Among Brazilian Patients Failing Reverse Transcriptase/Protease Inhibitors Treatment Reveal High Prevalence of Maraviroc Resistance-Related Mutations

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