scholarly journals HIV Capsid Inhibitors Beyond PF74

Diseases ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 56 ◽  
Author(s):  
Carole McArthur ◽  
Fabio Gallazzi ◽  
Thomas P. Quinn ◽  
Kamal Singh
Keyword(s):  
Therapeutic Strategy ◽  
Infectious Virus ◽  
Binding Pocket ◽  
Host Factors ◽  
Structural Studies ◽  
Resistance Mutations ◽  
Double Stranded Dna ◽  
Immunodeficiency Virus ◽  
The Status ◽  
Multiple Stages

Human immunodeficiency virus (HIV) capsid plays important roles at multiple stages of viral replication. At the initial stages, controlled uncoating (disassembly) of the capsid ensures efficient reverse transcription of the single-stranded RNA genome, into the double-stranded DNA. Whereas at later stages, a proper assembly of capsid ensures the formation of a mature infectious virus particle. Hence, the inhibition of capsid assembly and/or disassembly has been recognized as a potential therapeutic strategy, and several capsid inhibitors have been reported. Of these, PF-3450074 (PF74) has been extensively studied. Recently reported GS-CA inhibitors (GS-CA1 and GS-6207), have shown a strong potential and appear to contain a PF74 scaffold. The location of resistance mutations and the results of structural studies further suggest that GS-CA compounds and PF74 share the same binding pocket, which is located between capsid monomers. Additionally, phenylalanine derivatives containing the PF74 scaffold show slightly enhanced capsid inhibiting activity. A comparison of capsid structures in complex with host factors and PF74, reveals the presence of common chemical entities at topologically equivalent positions. Here we present the status of capsid inhibitors that contain PF74 scaffolds and propose that the PF74 scaffold may be used to develop strong and safe capsid inhibitors.

scholarly journals Analysis of the Zidovudine Resistance Mutations T215Y, M41L, and L210W in HIV-1 Reverse Transcriptase

2015 ◽  
Vol 59 (12) ◽  
pp. 7184-7196 ◽  
Author(s):  
Paul L. Boyer ◽  
Kalyan Das ◽  
Eddy Arnold ◽  
Stephen H. Hughes
Keyword(s):  
Reverse Transcriptase ◽  
Drug Targets ◽  
Resistance Mutation ◽  
Resistance Mutations ◽  
Primary Resistance ◽  
Double Stranded Dna ◽  
Resistance Pathway ◽  
Immunodeficiency Virus ◽  
Sugar Ring ◽  
Hiv 1

ABSTRACTAlthough anti-human immunodeficiency virus type 1 (HIV-1) therapies have become more sophisticated and more effective, drug resistance continues to be a major problem. Zidovudine (azidothymidine; AZT) was the first nucleoside reverse transcriptase (RT) inhibitor (NRTI) approved for the treatment of HIV-1 infections and is still being used, particularly in the developing world. This drug targets the conversion of single-stranded RNA to double-stranded DNA by HIV-1 RT. However, resistance to the drug quickly appeared both in viruses replicating in cells in culture and in patients undergoing AZT monotherapy. The primary resistance pathway selects for mutations of T215 that change the threonine to either a tyrosine or a phenylalanine (T215Y/F); this resistance pathway involves an ATP-dependent excision mechanism. The pseudo-sugar ring of AZT lacks a 3′ OH; RT incorporates AZT monophosphate (AZTMP), which blocks the end of the viral DNA primer. AZT-resistant forms of HIV-1 RT use ATP in an excision reaction to unblock the 3′ end of the primer strand, allowing its extension by RT. The T215Y AZT resistance mutation is often accompanied by two other mutations, M41L and L210W. In this study, the roles of these mutations, in combination with T215Y, were examined to determine whether they affect polymerization and excision by HIV-1 RT. The M41L mutation appears to help restore the DNA polymerization activity of RT containing the T215Y mutation and also enhances AZTMP excision. The L210W mutation plays a similar role, but it enhances excision by RTs that carry the T215Y mutation when ATP is present at a low concentration.

scholarly journals Influence of naturally occurring insertions in the fingers subdomain of human immunodeficiency virus type 1 reverse transcriptase on polymerase fidelity and mutation frequencies in vitro

2006 ◽  
Vol 87 (2) ◽  
pp. 419-428 ◽  
Author(s):  
Kenneth Curr ◽  
Snehlata Tripathi ◽  
Johan Lennerstrand ◽  
Brendan A. Larder ◽  
Vinayaka R. Prasad
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleoside Analogue ◽  
Binding Pocket ◽  
Resistance Mutations ◽  
Immunodeficiency Virus

The fingers subdomain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a hotspot for nucleoside analogue resistance mutations. Some multi-nucleoside analogue-resistant variants contain a T69S substitution along with dipeptide insertions between residues 69 and 70. This set of mutations usually co-exists with classic zidovudine-resistance mutations (e.g. M41L and T215Y) or an A62V mutation and confers resistance to multiple nucleoside analogue inhibitors. As insertions lie in the vicinity of the dNTP-binding pocket, their influence on RT fidelity was investigated. Commonly occurring insertion mutations were selected, i.e. T69S-AG, T69S-SG and T69S-SS alone, in combination with 3′-azido-2′,3′-deoxythymidine-resistance mutations M41L, L210W, R211K, L214F, T215Y (LAGAZ and LSGAZ) or with an alternate set where A62V substitution replaces M41L (VAGAZ, VSGAZ and VSSAZ). Using a lacZα gapped duplex substrate, the forward mutation frequencies of recombinant wild-type and mutant RTs bearing each of the above sets of mutations were measured. All of the mutants displayed significant decreases in mutation frequencies. Whereas the dipeptide insertions alone showed the least decrease (4·0- to 7·5-fold), the VAG series showed an intermediate reduction (5·0- to 11·4-fold) and the LAG set showed the largest reduction in mutation frequencies (15·3- and 16·3-fold for LAGAZ and LSGAZ, respectively). Single dNTP exclusion assays for mutants LSGAZ and LAGAZ confirmed their large reduction in misincorporation efficiencies. The increased in vitro fidelity was not due to excision of the incorrect nucleotide via ATP-dependent removal. There was also no direct correlation between increased fidelity and template–primer affinity, suggesting a change in the active site that is conducive to better discrimination during dNTP insertion.

scholarly journals The Fitness Cost of Mutations Associated with Human Immunodeficiency Virus Type 1 Drug Resistance Is Modulated by Mutational Interactions

2006 ◽  
Vol 81 (6) ◽  
pp. 3037-3041 ◽  
Author(s):  
Mian-er Cong ◽  
Walid Heneine ◽  
J. Gerardo García-Lerma
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Fitness Cost ◽  
Resistance Mutations ◽  
Drug Pressure ◽  
Critical Determinant ◽  
Immunodeficiency Virus ◽  
Cost Of Resistance

ABSTRACT It is generally accepted that the fitness cost of resistance mutations plays a role in the persistence of transmitted drug-resistant human immunodeficiency virus type 1 and that mutations that confer a high fitness cost are less able to persist in the absence of drug pressure. Here, we show that the fitness cost of reverse transcriptase (RT) mutations can vary within a 72-fold range. We also demonstrate that the fitness cost of M184V and K70R can be decreased or enhanced by other resistance mutations such as D67N and K219Q. We conclude that the persistence of transmitted RT mutants might range widely on the basis of fitness and that the modulation of fitness cost by mutational interactions will be a critical determinant of persistence.

scholarly journals Drug‐Selected Resistance Mutations and Non‐B Subtypes in Antiretroviral‐Naive Adults with Established Human Immunodeficiency Virus Infection

2003 ◽  
Vol 188 (7) ◽  
pp. 986-991 ◽  
Author(s):  
George J. Hanna ◽  
Henri U. Balaguera ◽  
Kenneth A. Freedberg ◽  
Barbara G. Werner ◽  
Kathleen A. Steger Craven ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Infection ◽  
Human Immunodeficiency Virus Infection ◽  
Resistance Mutations ◽  
Immunodeficiency Virus

scholarly journals Selective Excision of AZTMP by Drug-Resistant Human Immunodeficiency Virus Reverse Transcriptase

2001 ◽  
Vol 75 (10) ◽  
pp. 4832-4842 ◽  
Author(s):  
Paul L. Boyer ◽  
Stefan G. Sarafianos ◽  
Edward Arnold ◽  
Stephen H. Hughes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Nucleoside Analogs ◽  
Azido Group ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Azt Resistance ◽  
Hiv 1

ABSTRACT Two distinct mechanisms can be envisioned for resistance of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) to nucleoside analogs: one in which the mutations interfere with the ability of HIV-1 RT to incorporate the analog, and the other in which the mutations enhance the excision of the analog after it has been incorporated. It has been clear for some time that there are mutations that selectively interfere with the incorporation of nucleoside analogs; however, it has only recently been proposed that zidovudine (AZT) resistance can involve the excision of the nucleoside analog after it has been incorporated into viral DNA. Although this proposal resolves some important issues, it leaves some questions unanswered. In particular, how do the AZT resistance mutations enhance excision, and what mechanism(s) causes the excision reaction to be relatively specific for AZT? We have used both structural and biochemical data to develop a model. In this model, several of the mutations associated with AZT resistance act primarily to enhance the binding of ATP, which is the most likely pyrophosphate donor in the in vivo excision reaction. The AZT resistance mutations serve to increase the affinity of RT for ATP so that, at physiological ATP concentrations, excision is reasonably efficient. So far as we can determine, the specificity of the excision reaction for an AZT-terminated primer is not due to the mutations that confer resistance, but depends instead on the structure of the region around the HIV-1 RT polymerase active site and on its interactions with the azido group of AZT. Steric constraints involving the azido group cause the end of an AZT 5′-monophosphate-terminated primer to preferentially reside at the nucleotide binding site, which favors excision.

scholarly journals Beberapa Faktor yang Berhubungan dengan Kejadian HIV/AIDS pada Wanita (Studi Kasus di Kabupaten Kendal)

2017 ◽  
Vol 2 (1) ◽  
pp. 18
Author(s):  
Siti Musyarofah ◽  
Suharyo Hadisaputro ◽  
Budi Laksono ◽  
Muchlis Achsan Udji Sofro ◽  
Lintang Dian Saraswati
Keyword(s):  
Blood Donors ◽  
Sampling Technique ◽  
Host Factors ◽  
Level Of Education ◽  
Sexually Transmitted ◽  
Consecutive Sampling ◽  
The Status ◽  
Number Of Sexual Partners ◽  
History Of ◽  
Hiv Aids

Background: HIV/AIDS are major problem that threatens Indonesia and many countries around the world. In 2011 there were 17.3 million adults living with AIDS were women. The purpose of studies proved that host and environmental factors were associated the occurence of HIV/AIDS in women. Method: The research using case-control study, was supported by indepth interview. The target population were women in Kendal with a sample of 76 women consisted of 38 women with HIV/AIDS and 38 women negative HIV. Samples case with consecutive sampling technique, control with cluster sampling. Bivariate analysis using chi-square test and multivariate analysis used logistic regression. Results: Multivariate analysis showed that host factors significantly associated with the occurence of HIV/AIDS in women were the number of sexual partners more than 1 (p = 0,003), level of education was low ≤ 9 years (p = 0,049) and the first married age < 20 years (p = 0,03); environment factors significantly associated was history of HIV/AIDS on her husband (p=0,001). Host factors were not significantly associated with the occurence of HIV/AIDS in women were history of receiving blood donors,  history of sexually transmitted diseases, the status of drug users, the habit of drinking alcohol, violence, type of job, and socioeconomic. Conclusion: Host factors significantly associated with the occurence of HIV/AIDS in women were the number of sexual partners more than 1, level of education was low ≤ 9 years, and the first married age <20 years; environment factors significantly associated was history of HIV/AIDS on her husband. Background:HIV/AIDSaremajorproblemthatthreatensIndonesiaandmanycountriesaround theworld.In2011therewere17.3millionadultslivingwithAIDSwerewomen.Thepurposeof studiesprovedthathostandenvironmentalfactorswereassociatedtheoccurenceofHIV/AIDS inwomen.Method:Theresearchusingcase-controlstudy,wassupportedbyindepthinterview.Thetarget population were women in Kendal with a sample of 76 women consisted of 38 women with HIV/AIDSand 38 women negative HIV. Samples case with consecutive sampling technique, controlwithclustersampling.Bivariateanalysisusingchi-squaretestandmultivariateanalysis usedlogisticregression.Results:    Multivariateanalysisshowedthathostfactorssignificantlyassociatedwiththe occurenceofHIV/AIDSinwomenwerethenumberofsexualpartnersmorethan1(p=0,003), levelofeducationwaslow≤9years(p=0,049)andthefirstmarriedage<20years(p=0,03); environmentfactorssignificantlyassociatedwashistoryofHIV/AIDSonherhusband(p=0,001).HostfactorswerenotsignificantlyassociatedwiththeoccurenceofHIV/AIDSinwomen were history of receiving blood donors,  history of sexually transmitted diseases, the status of drugusers,thehabitofdrinkingalcohol,violence,typeofjob,andsocioeconomic.Conclusion: Host factors significantly associated with the occurence of HIV/AIDS in women werethenumberofsexualpartnersmorethan1,levelofeducationwaslow≤9years,andthefirst marriedage<20years;environmentfactorssignificantlyassociatedwashistoryofHIV/AIDSon herhusband.

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