P18-13 LB. Immunogenicity of an autologous dendritic cell anti-HIV therapy in HIV-1 infected individuals

Here we present new derivatives of nucleoside reverse transcriptase inhibitors with a C20 fullerene. The computational chemistry methods used in this study evaluate affinity of designed compounds towards the HIV-1 reverse transcriptase (RT) binding site and select the most active ones. The best of the designed compounds have superior or similar affinity to RT active site in comparison to most active test compounds, including drugs used in anti-HIV therapy.

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Plant-made HIV vaccines and potential candidates

10.31221/osf.io/2d6qk ◽

2020 ◽

Author(s):

Jocelyne Tremouillaux-Guiller ◽

Khaled Moustafa ◽

Kathleen Hefferon ◽

Goabaone Gaobotse ◽

Abdullah Makhzoum

Keyword(s):

Neutralizing Antibodies ◽

Opportunistic Infections ◽

Broadly Neutralizing Antibodies ◽

Hiv Vaccines ◽

Therapeutic Vaccines ◽

Hiv Therapy ◽

The Past ◽

Health Burdens ◽

Anti Hiv ◽

Hiv 1

Millions of people around the world suffer from heavy social and health burdens related to HIV/AIDS and its associated opportunistic infections. To reduce these burdens, preventive and therapeutic vaccines are required. Effective HIV vaccines have been under investigation for several decades using different animal models. Potential plant-made HIV vaccine candidates have also gained attention in the past few years. In addition to this, broadly neutralizing antibodies produced in plants which can target conserved viral epitopes and neutralize mutating HIV strains have been identified. Numerous epitopes of glycoproteins and capsid proteins of HIV-1 are a part of HIV therapy. Here, we discuss some recent findings aiming to produce anti-HIV-1 recombinant proteins in engineered plants for AIDS prophylactics and therapeutic treatments.

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Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

Molecules ◽

10.3390/molecules25051050 ◽

2020 ◽

Vol 25 (5) ◽

pp. 1050 ◽

Cited By ~ 1

Author(s):

Yuan Lei ◽

Sheng Han ◽

Yang Yang ◽

Christophe Pannecouque ◽

Erik De Clercq ◽

...

Keyword(s):

Resistant Mutant ◽

Molecular Hybridization ◽

Binding Modes ◽

Wild Type ◽

Hiv Therapy ◽

Mutant Strains ◽

Drug Resistant Mutant ◽

New Compounds ◽

Anti Hiv ◽

Hiv 1

The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a molecular hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC50 value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure–activity relationship (SAR) of these new compounds was concluded. The molecular modeling predicted the binding modes of the new compounds with RT, providing molecular insight for further drug design.

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Molecular insight on the binding of NNRTI to K103N mutated HIV-1 RT: molecular dynamics simulations and dynamic pharmacophore analysis

Molecular BioSystems ◽

10.1039/c6mb00428h ◽

2016 ◽

Vol 12 (11) ◽

pp. 3385-3395 ◽

Cited By ~ 19

Author(s):

Bilal Nizami ◽

Dominique Sydow ◽

Gerhard Wolber ◽

Bahareh Honarparvar

Keyword(s):

Molecular Dynamics ◽

Drug Resistance ◽

Hiv Infection ◽

Molecular Dynamics Simulations ◽

Rapid Onset ◽

Hiv Therapy ◽

Dynamics Simulations ◽

Anti Hiv ◽

Hiv 1

Regardless of advances in anti-HIV therapy, HIV infection remains an immense challenge due to the rapid onset of mutation instigating drug resistance.

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P18-07. Ex vivo production of autologous HIV-1 to be used as immunogen in autologous dendritic cell-based therapeutic vaccine (clinical trial DCV02)

Retrovirology ◽

10.1186/1742-4690-6-s3-p316 ◽

2009 ◽

Vol 6 (S3) ◽

Author(s):

C Gil ◽

N Climent ◽

C Hurtado ◽

S Nieto ◽

F García ◽

...

Keyword(s):

Clinical Trial ◽

Dendritic Cell ◽

Ex Vivo ◽

Therapeutic Vaccine ◽

Autologous Dendritic Cell ◽

Vaccine Clinical Trial ◽

Hiv 1

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Dual Mechanisms of Action of Self-Delivering, Anti-HIV-1 FANA Oligonucleotides as a Potential New Approach to HIV Therapy

Molecular Therapy — Nucleic Acids ◽

10.1016/j.omtn.2019.07.001 ◽

2019 ◽

Vol 17 ◽

pp. 615-625 ◽

Cited By ~ 3

Author(s):

Mayumi Takahashi ◽

Haitang Li ◽

Jiehua Zhou ◽

Pritsana Chomchan ◽

Veenu Aishwarya ◽

...

Keyword(s):

Mechanisms Of Action ◽

New Approach ◽

Hiv Therapy ◽

Anti Hiv ◽

Hiv 1

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Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance

Communications Biology ◽

10.1038/s42003-019-0706-x ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 3

Author(s):

Magdeleine Hung ◽

E. John Tokarsky ◽

Leanna Lagpacan ◽

Lijun Zhang ◽

Zucai Suo ◽

...

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Structural Basis ◽

Binding Affinities ◽

Resistance Mutations ◽

Hiv Therapy ◽

And Shifts ◽

Anti Hiv ◽

Hiv 1 ◽

Therapy Treatment

AbstractEmtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (−)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (−)-FTC-TP and (−)-3TC-TP and drug resistance by M184V. (−)-FTC-TP and (−)-3TC-TP have higher binding affinities (1/Kd) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (−)-FTC-TP and (−)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3′-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold) Kd for the L-nucleotides and moderately higher (>9-fold) Kd for the D-isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (−)-FTC-TP and shifts its triphosphate into a non-productive conformation.

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Effect upon the anti-HIV Activity of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine of Combination with anti-Herpes Nucleoside Analogues

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029300400105 ◽

1993 ◽

Vol 4 (1) ◽

pp. 41-47 ◽

Cited By ~ 1

Author(s):

S. Cox ◽

A. Vissgården ◽

B. Wahren

Keyword(s):

Aids Patients ◽

Hiv Therapy ◽

Immunodeficiency Virus ◽

Life Threatening ◽

The Individual ◽

Lower Ratio ◽

Hiv Drugs ◽

Anti Hiv ◽

Hiv 1 ◽

Antagonistic Interactions

The treatment of the severe and often life-threatening herpesvirus infections which commonly occur in AIDS patients is complicated by the need to treat simultaneously with drugs directed against the human immunodeficiency virus (HIV). Combining together different drugs in this way can lead to effects upon the activities of the individual drugs, such as synergism or antagonism. The effect upon the anti-HIV activity of 3′-azido-3′-deoxythymidine (AZT) and 3′-fluoro-3′-deoxythymidine (FLT) of combination with the anti-herpesvirus drugs 9-(1,3-dihydroxy-2-propoxymethyl-)guanine (DHPG; ganciclovir) and (-)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine ([-]-2HM-HBG) was investigated. Neither DHPG nor (-)-2HM-HBG showed antiviral activity against HIV-1 up to 50 [AM. When combined with AZT or FLT at ratios of antiherpes:anti-HIV drug of 10:1 or greater, both DHPG and (-)-2HM-HBG antagonized the anti-HIV activity of AZT and FLT. When combined at a lower ratio (1:1), there was no effect upon the anti-HIV activity of either AZT or FLT. The phosphorylation of FLT was found to be unchanged in the presence of DHPG or (-)-2HM-HBG, indicating that the mechanism of the antagonism was not owing to an effect of DHPG or (-)-2HM-HBG upon the metabolism of the anti-HIV drugs. The results suggest that combination chemotherapy with the anti-herpes drugs DHPG/(-)-2HM-HBG and AZT/FLT should be used cautiously. The possibility of such antagonistic interactions should be borne in mind when considering the choice of drug and ratio for treatment of herpesvirus infections in AIDS patients on anti-HIV therapy.

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Inferring within-patient HIV-1 evolutionary dynamics under anti-HIV therapy using serial virus samples with vSPA

BMC Bioinformatics ◽

10.1186/1471-2105-10-360 ◽

2009 ◽

Vol 10 (1) ◽

pp. 360 ◽

Cited By ~ 3

Author(s):

Naoki Hasegawa ◽

Wataru Sugiura ◽

Junko Shibata ◽

Masakazu Matsuda ◽

Fengrong Ren ◽

...

Keyword(s):

Evolutionary Dynamics ◽

Hiv Therapy ◽

Anti Hiv ◽

Hiv 1

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Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors

eLife ◽

10.7554/elife.36340 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 29

Author(s):

Yang Yang ◽

Dongwei Kang ◽

Laura A Nguyen ◽

Zachary B Smithline ◽

Christophe Pannecouque ◽

...

Keyword(s):

Reverse Transcriptase ◽

Hydrophobic Interactions ◽

Binding Pocket ◽

Structural Features ◽

Hiv Treatment ◽

Structural Basis ◽

Drug Resistant ◽

Hiv Therapy ◽

Anti Hiv ◽

Hiv 1

Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 Å resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.

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