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  1. Gill MSA, Hassan SS, Ahemad N
    Eur J Med Chem, 2019 Oct 01;179:423-448.
    PMID: 31265935 DOI: 10.1016/j.ejmech.2019.06.058
    HIV infection is a major challenge to mankind and a definitive cure or a viable vaccine for HIV is still elusive. HIV-1 is constantly evolving and developing resistant against clinically used anti-HIV drugs thus posing serious hurdles in the treatment of HIV infection. This prompts the need to developed new anti-HIV drugs; preferentially adopting intelligent ways to counteract an evolving virus. Highly Active Anti-Retroviral Therapy (HAART): a strategy involving multiple targeting through various drugs has proven beneficial in the management of AIDS. However, it is a complex regimen with high drug load, increased risk of drug interactions and adverse effects, which lead to poor patient compliance. Reverse transcriptase (RT) and Integrase (IN) are two pivotal enzymes in HIV-1 lifecycle with high structural and functional analogy to be perceived as drug-able targets for novel dual-purpose inhibitors. Designed multi-functional ligand (DML) is a modern strategy by which multiple targets can be exploited using a single chemical entity. A single chemical entity acting on multiple targets can be much more effective than a complex multi-drug regimen. The development of such multifunctional ligands is highly valued in anti-HIV drug discovery with the proposed advantage of being able to stop two or more stages of viral replication cycle. This review will encompass the evolution of the RT-IN dual inhibitory scaffolds reported so far and the contribution made by the leading research groups over the years in this field.
    Matched MeSH terms: HIV Reverse Transcriptase/antagonists & inhibitors*; HIV Reverse Transcriptase/metabolism
  2. Chander S, Tang CR, Al-Maqtari HM, Jamalis J, Penta A, Hadda TB, et al.
    Bioorg Chem, 2017 06;72:74-79.
    PMID: 28371664 DOI: 10.1016/j.bioorg.2017.03.013
    In the present study, a series of fourteen 5-benzoyl-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one derivatives were designed, synthesized and characterized by appropriate spectral analysis. Further, titled compounds were in-vitro screened against wild HIV-1 RT enzyme using ELISA based colorimetric assay, in which four compounds significantly inhibited the RT activity with IC50≤25µM. Moreover, two significantly active compounds of the series, A10 and A11 exhibited IC50 values 8.62 and 6.87µM respectively, during the in-vitro assay. Structure Activity Relationship (SAR) studies were performed for the synthesized compounds in order to estimate the effect of substitution pattern on the RT inhibitory potency. The cytotoxicity of the synthesized compounds was evaluated against T lymphocytes. Further, putative binding modes of the significantly active (A11) and the least active (A4) compounds with wild HIV-1 RT were also investigated using docking studies.
    Matched MeSH terms: HIV Reverse Transcriptase/antagonists & inhibitors*; HIV Reverse Transcriptase/metabolism
  3. Veerasamy R, Subramaniam DK, Chean OC, Ying NM
    J Enzyme Inhib Med Chem, 2012 Oct;27(5):693-707.
    PMID: 21961709 DOI: 10.3109/14756366.2011.608664
    A linear quantitative structure activity relationship (QSAR) model is presented for predicting human immunodeficiency virus-1 (HIV-1) reverse transcriptase enzyme inhibition. The 2D QSAR and 3D-QSAR models were developed by stepwise multiple linear regression, partial least square (PLS) regression and k-nearest neighbor-molecular field analysis, PLS regression, respectively using a database consisting of 33 recently discovered benzoxazinones. The primary findings of this study is that the number of hydrogen atoms, number of (-NH2) group connected with solitary single bond alters the inhibition of HIV-1 reverse transcriptase. Further, presence of electrostatic, hydrophobic and steric field descriptors significantly affects the ability of benzoxazinone derivatives to inhibit HIV-1 reverse transcriptase. The selected descriptors could serve as a primer for the design of novel and potent antagonists of HIV-1 reverse transcriptase.
    Matched MeSH terms: HIV Reverse Transcriptase/antagonists & inhibitors*
  4. Wang B, Lau KA, Ong LY, Shah M, Steain MC, Foley B, et al.
    Virology, 2007 Oct 25;367(2):288-97.
    PMID: 17604072
    The HIV protease-reverse transcriptase (PR-RT) (1047 bp), gp120-env (891 bp) and gp41-env (547 bp) regions from the plasma of 115 HIV-1-infected patients in Kuala Lumpur (KL), Malaysia were sequenced. Detailed phylogenetic and bootscanning analyses were performed to determine the mosaic structure of the HIV-1 strains and their recombination breakpoint(s). Among the 50 patient samples in which all three regions could be amplified, the HIV-1 CRF01_AE subtype (46%) was predominant followed by subtypes B (10%) and B' (6%). A total of 9/50 (18%) patients were infected with a CRF01_AE/B inter-subtype recombinant, displaying a recombinant form (RF)(PR-RT), CRF01_AE(gp120-env) and CRF01_AE(gp41-env). This RF was derived from the Thai variants of CRF01_AE and B' subtype, with two distinct B' subtype segments in the backbone of CRF01_AE, similar to the newly identified CRF33_01B. In addition, one sample demonstrated a close structural relationship with the new CRF33_01B in the PR-RT region but displayed B' segment in part of the env region (RF(PR-RT), CRF01_AE/B'(gp120-env) and B'(gp41-env)) indicating continuing evolution of CRF33_01B. The remaining 18% of samples were identified as unique recombinant forms (URFs).
    Matched MeSH terms: HIV Reverse Transcriptase/genetics*
  5. Rhee SY, Blanco JL, Jordan MR, Taylor J, Lemey P, Varghese V, et al.
    PLoS Med, 2015 Apr;12(4):e1001810.
    PMID: 25849352 DOI: 10.1371/journal.pmed.1001810
    BACKGROUND: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.

    METHODS AND FINDINGS: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.

    CONCLUSIONS: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

    Matched MeSH terms: HIV Reverse Transcriptase/antagonists & inhibitors; HIV Reverse Transcriptase/genetics*
  6. Kharkwal H, Kumar BK, Murugesan S, Singhvi G, Avasthi P, Goyal A, et al.
    Future Med Chem, 2021 02;13(3):269-286.
    PMID: 33399497 DOI: 10.4155/fmc-2020-0257
    Reverse transcriptase and integrase are key enzymes that play a pivotal role in HIV-1 viral maturation and replication. Reverse transcriptase consists of two active sites: RNA-dependent DNA polymerase and RNase H. The catalytic domains of integrase and RNase H share striking similarity, comprising two aspartates and one glutamate residue, also known as the catalytic DDE triad, and a Mg2+ pair. The simultaneous inhibition of reverse transcriptase and integrase can be a rational drug discovery approach for combating the emerging drug resistance problem. In the present review, the dual inhibition of RNase H and integrase is systematically discussed, including rationality of design, journey of development, advancement and future perspective.
    Matched MeSH terms: HIV Reverse Transcriptase/antagonists & inhibitors; HIV Reverse Transcriptase/metabolism
  7. Saepuloh U, Iskandriati D, Pamungkas J, Solihin DD, Mariya SS, Sajuthi D
    Trop Life Sci Res, 2020 Oct;31(3):47-61.
    PMID: 33214855 DOI: 10.21315/tlsr2020.31.3.4
    Simian betaretrovirus serotype-2 (SRV-2) is an important pathogenic agent in Asian macaques. It is a potential confounding variable in biomedical research. SRV-2 also provides a valuable viral model compared to other retroviruses which can be used for understanding many aspects of retroviral-host interactions and immunosuppression, infection mechanism, retroviral structure, antiretroviral and vaccine development. In this study, we isolated the gene encoding reverse transcriptase enzyme (RT) of SRV-2 that infected Indonesian cynomolgus monkey (Mf ET1006) and predicted the three dimensional structure model using the iterative threading assembly refinement (I-TASSER) computational programme. This SRV-2 RT Mf ET1006 consisted of 547 amino acids at nucleotide position 3284-4925 of whole genome SRV-2. The polymerase active site located in the finger/palm subdomain characterised by three conserved catalytic aspartates (Asp90, Asp165, Asp166), and has a highly conserved YMDD motif as Tyr163, Met164, Asp165 and Asp166. We estimated that this SRV-2 RT Mf ET1006 structure has the accuracy of template modelling score (TM-score 0.90 ± 0.06) and root mean square deviation (RMSD) 4.7 ± 3.1Å, indicating that this model can be trusted and the accuracy can be seen from the appearance of protein folding in tertiary structure. The superpositionings between SRV-2 RT Mf ET1006 and Human Immunodeficiency Virus-1 (HIV-1) RT were performed to predict the structural in details and to optimise the best fits for illustrations. This SRV-2 RT Mf ET1006 structure model has the highest homology to HIV-1 RT (2B6A.pdb) with estimated accuracy at TM-score 0.911, RMSD 1.85 Å, and coverage of 0.953. This preliminary study of SRV-2 RT Mf ET1006 structure modelling is intriguing and provide some information to explore the molecular characteristic and biochemical mechanism of this enzyme.
    Matched MeSH terms: HIV Reverse Transcriptase
  8. Tee KK, Pon CK, Kamarulzaman A, Ng KP
    AIDS, 2005 Jan 28;19(2):119-26.
    PMID: 15668536
    OBJECTIVES: To investigate the molecular epidemiology of HIV-1 and to screen for the emergence of intersubtype recombinants in Kuala Lumpur, Malaysia.

    DESIGN: A molecular epidemiology study was conducted among HIV-1 seropositive patients attending the University Malaya Medical Center (UMMC) from July 2003 to June 2004.

    METHODS: Protease (PR) and reverse transcriptase (RT) gene sequences were derived from drug resistance genotyping assay of 100 newly diagnosed or antiretroviral-naive patients. These were phylogenetically analysed to determine the subtypes and recombination breakpoint analyses were performed on intersubtype recombinants to estimate the recombination breakpoint(s).

    RESULTS: CRF01_AE predominated in Kuala Lumpur with 65% in both PR and RT genes. B subtype was detected at 14% and 12% in PR and RT genes, respectively. C subtype was present at 1% in both genes. Overall, the concordance of PR and RT genes in discriminating subtypes/circulating recombinant forms (CRF) was high at 96%. In this study, novel CRF01_AE/B intersubtype recombinants were detected at high prevalence (22%), including those isolates with subtype discordance. Thai variants of CRF01_AE and B subtype were involved in the genesis of these unique recombinant forms (URF). Interestingly, 19 CRF01_AE/B intersubtype recombinant isolates shared similar recombination breakpoints in both PR and RT genes. Several distinct URF were also identified.

    CONCLUSION: PR and RT genes can be utilized for subtype/CRF assessment with high degree of agreement, allowing concurrent surveillance of circulating HIV-1 subtypes with antiretroviral drug resistance genotyping tests. The emergence of highly identical CRF01_AE/B intersubtype recombinants suggests the possibility of the appearance of a new circulating recombinant form in Kuala Lumpur.

    Matched MeSH terms: HIV Reverse Transcriptase/genetics
  9. Peksheva O, Kuzovatova E, Parfenova O, Zaytseva N
    Viruses, 2022 Aug 27;14(9).
    PMID: 36146704 DOI: 10.3390/v14091898
    The increasing number of HIV-infected people who are receiving ART, including those with low adherence, is causing the spread of HIV drug resistance (DR). A total of 1396 plasma samples obtained from treatment-experienced patients from the Volga federal district (VFD), Russia, were examined to investigate HIV DR occurrence. The time periods 2008−2015 and 2016−2019 were compared. Fragmentary Sanger sequencing was employed to identify HIV resistance to reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) using an ABI 3500XL genetic analyzer, a ViroSeq™ HIV-1 genotyping system (Alameda, CA, USA) and AmpliSense HIV-Resist-Seq reagent kits (Moscow, Russia). In 2016−2019, HIV DR was detected significantly more often than in 2008−2015 (p < 0.01). Mutations to RTIs retained leading positions in the structure of DR. Frequencies of resistance mutations to nucleoside and non-nucleoside RTIs (NRTIs and NNRTIs) in the spectra of detected mutations show no significant differences. Resistance to NRTIs after 2016 began to be registered more often as a part of multidrug resistance (MDR), as opposed to resistance to a single class of antiretrovirals. The frequency of DR mutations to PIs was low, both before and after 2016 (7.9% and 6.1% in the spectrum, respectively, p > 0.05). MDR registration rate became significantly higher from 2008 to 2019 (17.1% to 72.7% of patients, respectively, p < 0.01). M184V was the dominant replacement in all the years of study. A significant increase in the frequency of K65R replacement was revealed. The prevalence of integrase strand transfer inhibitor (INSTI) resistance mutations remains to be investigated.
    Matched MeSH terms: HIV Reverse Transcriptase/genetics
  10. Mohamad S, Deris ZZ, Yusoff NK, Ariffin TA, Shueb RH
    Braz J Infect Dis, 2012 May-Jun;16(3):284-8.
    PMID: 22729198
    Antiretroviral (ARV) therapy has dramatically reduced morbidity and mortality in human immunodeficiency virus 1 (HIV-1) infected children. However, development of ARV resistance in these children is a major public health problem due to lack of availability of and access to new drugs. This study was conducted in order to identify circulating HIV subtypes and recombinant forms and evaluate the drug resistance mutation patterns in 18 HIV-1 infected children failing ARV treatment in Kelantan, Malaysia. Genotyping for codon 1-99 of protease (PR) and 1-250 of reverse transcriptase (RT) were performed by polymerase chain reaction (PCR) amplification and DNA sequencing. Subsequently, these were phylogenetically analyzed to determine the subtypes. CRF33_01B (44.4%) was found to be the predominant HIV subtype, followed by B (27.8%), CRF15_01B (16.7%) and CRF01_AE (11.1%) subtypes. The most prevalent RT mutations were T215F/V/Y (66.7%), D67G/N (55.6%), K219Q/E/R (44.4%), M184V/I (38.9%), K70R/E (27.8%) and M41L (27.8%), associated with nucleoside reverse transcriptase inhibitors (NRTI) resistance; and K103N (55.6%), G190A (33.3%), and K101P/E/H (27.8%) associated with non-nucleoside reverse transcriptase inhibitors (NNRTI) resistance. The results showed a possible emergence of CRF33_01B as current predominant subtypes/circulating recombinant forms (CRFs), and a high frequency of primary mutations among HIV-1 infected children after failure of ARV therapy in Kelantan, Malaysia.
    Matched MeSH terms: HIV Reverse Transcriptase/genetics*
  11. Cain LE, Phillips A, Lodi S, Sabin C, Bansi L, Justice A, et al.
    AIDS, 2012 Aug 24;26(13):1691-705.
    PMID: 22546987
    OBJECTIVE: To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV-infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes.

    DESIGN: Prospective studies of HIV-infected individuals in Europe and the US included in the HIV-CAUSAL Collaboration.

    METHODS: Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started an NRTI, efavirenz or nevirapine, classified as following one or both types of regimens at baseline, and censored when they started an ineligible drug or at 6 months if their regimen was not yet complete. We estimated the 'intention-to-treat' effect for nevirapine versus efavirenz regimens on clinical, immunologic, and virologic outcomes. Our models included baseline covariates and adjusted for potential bias introduced by censoring via inverse probability weighting.

    RESULTS: A total of 15 336 individuals initiated an efavirenz regimen (274 deaths, 774 AIDS-defining illnesses) and 8129 individuals initiated a nevirapine regimen (203 deaths, 441 AIDS-defining illnesses). The intention-to-treat hazard ratios [95% confidence interval (CI)] for nevirapine versus efavirenz regimens were 1.59 (1.27, 1.98) for death and 1.28 (1.09, 1.50) for AIDS-defining illness. Individuals on nevirapine regimens experienced a smaller 12-month increase in CD4 cell count by 11.49 cells/μl and were 52% more likely to have virologic failure at 12 months as those on efavirenz regimens.

    CONCLUSIONS: Our intention-to-treat estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a larger 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with nevirapine.

    Matched MeSH terms: HIV Reverse Transcriptase/antagonists & inhibitors*
  12. Tee KK, Kamarulzaman A, Ng KP
    Med Microbiol Immunol, 2006 Jun;195(2):107-12.
    PMID: 16404607
    To assess the prevalence of major drug resistance mutations in antiretroviral (ARV)-treated patients with detectable viral load (VL) in Kuala Lumpur, Malaysia, genotypic resistance testing was performed among treated human immunodeficiency virus type 1 (HIV-1) patients attending the University Malaya Medical Center between July 2003 and November 2004. The reverse transcriptase (RT) and protease genes from 36 plasma samples with detectable VL were examined for major mutations associated with ARV resistance as reported by the International AIDS Society-USA Drug Resistance Mutations Group. The prevalence of patients with at least one major mutation conferring drug resistance to nucleoside RT inhibitors (NRTIs), non-NRTIs (NNRTIs) or protease inhibitors (PIs) was 77.8%. In the RT gene, the frequency of mutations associated with NRTIs and NNRTIs resistance was 52.8 and 63.9%, respectively, with M184V and K103N mutations being selected most frequently by these drugs. A patient with Q151M mutation complex was also detected. Twenty-two percent of the patients had mutations associated with PIs. The following pattern of prevalence of ARV-resistant HIV-1 variants was observed: NNRTI-resistant > NRTI-resistant > PI-resistant. The prevalence of major drug resistance mutations among ARV-treated patients with detectable VL is high in Kuala Lumpur. Genotypic drug resistance testing is therefore important for monitoring patients experiencing ARV regimen failure.
    Matched MeSH terms: HIV Reverse Transcriptase/genetics
  13. Patil AD, Freyer AJ, Eggleston DS, Haltiwanger RC, Bean MF, Taylor PB, et al.
    J Med Chem, 1993 Dec 24;36(26):4131-8.
    PMID: 7506311
    As part of a search for novel inhibitors of HIV-1 reverse transcriptase, the acetone extract of the giant African snail, Achatina fulica, was shown to be active. Fractionation of the extract yielded inophyllums A, B, C, and E and calophyllolide (1a, 2a, 3a, 3b, and 6), previously isolated from Calophyllum inophyllum Linn., a known source of nutrition for A. fulica. From a methanol/methylene chloride extract of C. inophyllum, the same natural products in considerably greater yield were isolated in addition to a novel enantiomer of soulattrolide (4), inophyllum P (2b), and two other novel compounds, inophyllums G-1 (7) and G-2 (8). The absolute stereochemistry of inophyllum A (1a) was determined to be 10(R), 11(S), 12(S) from a single-crystal X-ray analysis of its 4-bromobenzoate derivative, and the relative stereochemistries of the other inophyllums isolated from C. inophyllum were established by a comparison of their 1H NMR NOE values and coupling constants to those of inophyllum A (1a). Inophyllums B and P (2a and 2b) inhibited HIV reverse transcriptase with IC50 values of 38 and 130 nM, respectively, and both were active against HIV-1 in cell culture (IC50 of 1.4 and 1.6 microM). Closely related inophyllums A, C, D, and E, including calophyllic acids, were significantly less active or totally inactive, indicating certain structural requirements in the chromanol ring. Altogether, 11 compounds of the inophyllum class were isolated from C. inophyllum and are described together with the SAR of these novel anti-HIV compounds.
    Matched MeSH terms: HIV Reverse Transcriptase
  14. Ariffin TA, Mohamad S, Yusuf WN, Shueb RH
    J Infect Dev Ctries, 2014 Aug;8(8):1063-7.
    PMID: 25116676 DOI: 10.3855/jidc.4095
    INTRODUCTION: The widespread use of highly active antiretroviral therapy (HAART) and continuous reports of HIV-1 strains developing resistance to these drugs is rather alarming, as transmission of resistant viruses to newly infected persons is possible. This study aimed to determine HIV-1 subtypes and the prevalence of primary mutations associated with antiretroviral (ARV) resistance among treatment-naive prisoners on the east coast of Malaysia.
    METHODOLOGY: Viral RNA was extracted from plasma samples of 21 treatment-naive prisoners. Protease (PR) and reverse transcriptase (RT) regions were amplified and sequenced. Stanford HIV database algorithms were used for interpretation of resistance, and phylogenetic analysis was performed for subtype assignment.
    RESULTS: In the PR gene, no antiviral resistance-associated mutation was detected. For RT-associated mutations, K103N was the most prevalent in sequenced samples (14.3%). Genetic subtyping on the pol gene revealed that the majority of the prisoners were infected with subtype CRF33_01B (52.4%).
    CONCLUSION: Continuous surveillance of newly infected individuals is required to help strategize the best antiviral treatment for these patients.
    Matched MeSH terms: HIV Reverse Transcriptase/genetics
  15. Ong LY, Razak SN, Lee YM, Sri La Sri Ponnampalavanar S, Syed Omar SF, Azwa RI, et al.
    J Med Virol, 2014 Jan;86(1):38-44.
    PMID: 24127302 DOI: 10.1002/jmv.23772
    Expansion of antiretroviral treatment programs have led to the growing concern for the development of antiretroviral drug resistance. The aims were to assess the prevalence of drug resistant HIV-1 variants and to identify circulating subtypes among HAART-naïve patients. Plasma specimens from N = 100 HIV+ HAART-naïve adult were collected between March 2008 and August 2010 and viral RNA were extracted for nested PCR and sequenced. PR-RT sequences were protein aligned and checked for transmitted drug resistance mutations. Phylogenetic reconstruction and recombination analysis were performed to determine the genotypes. Based on the WHO consensus guidelines, none of the recruited patients had any transmitted drug resistance mutations. When analyzed against the Stanford guidelines, 35% of patients had at least one reported mutation that may reduce drug susceptibility to PI (24%), NRTI (5%), and NNRTI (14%). The commonly detected mutation that may affect current first line therapy was V179D (3%), which may lead to reduced susceptibility to NNRTI. The predominant circulating HIV-1 genotypes were CRF01_AE (51%) and CRF33_01B (17%). The prevalence of unique recombinant forms (URF) was 7%; five distinct recombinant structures involving CRF01_AE and subtype B' were observed, among them a cluster of three isolates that could form a novel circulating recombinant form (CRF) candidate. Transmitted drug resistance prevalence among HAART-naïve patients was low in this cohort of patients in Kuala Lumpur despite introduction of HAART 5 years ago. Owing to the high genetic diversity, continued molecular surveillance can identify the persistent emergence of HIV-1 URF and novel CRF with significant epidemiological impact.
    Matched MeSH terms: HIV Reverse Transcriptase/genetics
  16. Tee KK, Kamarulzaman A, Ng KP
    AIDS Res Hum Retroviruses, 2006 Feb;22(2):121-4.
    PMID: 16478392
    To assess the prevalence of mutations associated with drug resistance in antiretroviral-naive patients in Kuala Lumpur, Malaysia, genotypic resistance testing was conducted among drug-naive HIV-1 patients attending the University Malaya Medical Center (UMMC) between July 2003 and June 2004. Reverse transcriptase (RT) and protease genes of plasma virions were sequenced from 100 individuals. The majority of the patients were recently diagnosed. Codons 20-255 of the RT and 1-96 of the protease gene were examined for major and minor mutations associated with antiretroviral resistance reported by the International AIDS Society- USA (IAS-USA) Drug Resistance Mutations Group. The prevalence of patients with at least one major mutation conferring drug resistance was 1%, with only one patient having a Y181C amino acid substitution in the RT gene that confers high-level resistance to nevirapine and delavirdine. Minor mutations were detected in high prevalence in the protease gene. Amino acid substitutions I13V, E35D, and M36I were associated with CRF01_AE while L63P, V77I, and I93L were associated with subtype B. Baseline prevalence of major mutations associated with resistance to antiretroviral drugs was low among antiretroviral-naive HIV-1 patients, suggesting that routine drug resistance testing may be unnecessary for all individuals newly diagnosed with HIV or all patients beginning antiretroviral therapy.
    Matched MeSH terms: HIV Reverse Transcriptase/genetics
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