A Phase IIb, Randomized, Double-blind, Parallel-group Study to Assess the Efficacy, Safety, Tolerability, and Resistance Profile of GSK3640254 in Combination With Dolutegravir Compared to Dolutegravir Plus Lamivudine in HIV-1 Infected, Treatment-naïve Adults

The purpose of this study was to evaluate the efficacy of GSK3640254 + DTG relative to lamivudine (3TC) + DTG in treatment-naïve adult participants living with human immunodeficiency virus (HIV)-1. The participants were randomized to one of the three doses of blinded GSK3640254 (100, 150, or 200 milligrams [mgs]) or a reference arm of blinded 3TC-each in combination with open label DTG.

Start Date18 Aug 2021

Sponsor / Collaborator

ViiV Healthcare Ltd.

[+1]

NCT04857892

/ CompletedPhase 1

A Two-Part, Randomized, Open-Label, Single Dose, Crossover Clinical Study to Assess the Relative Bioavailability of Fixed-Dose Combinations of GSK3640254 and Dolutegravir and to Assess the Effect of Food on the Select Fixed Dose Combination of GSK3640254 and Dolutegravir in Healthy Participants

This is a two part study to compare the relative bioavailability (BA) of 2 fixed dose combinations (FDCs) of GSK3640254/DTG with GSK3640254 and DTG administered together as single agents (Part 1) and to assess the effect of food on the pharmacokinetic (PK) of the selected FDC of GSK3640254/DTG (Part 2).

Start Date21 Apr 2021

Sponsor / Collaborator

ViiV Healthcare Ltd.

NCT04425902

/ CompletedPhase 1

Effects of GSK3640254 on the Single-Dose Pharmacokinetics of Probe Substrates (Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, Midazolam, Digoxin, and Pravastatin) in Healthy Subjects

This is an open-label, single sequence study that is being conducted to investigate the potential drug-drug interaction (DDI) when GSK3640254 is co-administered with a cocktail of cytochrome P450 (CYP) enzymes and transporter probe substrates in healthy participants. This study will aid in understanding these interactions and resulting changes in exposure (if any) when drugs that are metabolized via these pathways are given in combination with GSK3640254. The study will consist of a Screening period and 3 sequential treatment regimens. Participants will be administered a single dose of probe substrate drugs (caffeine 200 milligram (mg), metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg and pravastatin 40 mg) on Day 1. Participants will then receive GSK3640254 200 mg once daily on Days 11 to 20 followed by co-administration of probe substrate drugs with GSK3640254 on Day 21.

Start Date16 Dec 2020

Sponsor / Collaborator

ViiV Healthcare Ltd.

100 Clinical Results associated with HIV-1 maturation

100 Translational Medicine associated with HIV-1 maturation

0 Patents (Medical) associated with HIV-1 maturation

Literatures (Medical) associated with HIV-1 maturation

01 Jan 2021·Journal of Biological ChemistryQ2 · BIOLOGY

Ceramide synthase 2 deletion decreases the infectivity of HIV-1

Q2 · BIOLOGY

Article

Author: Kyle, Jennifer E ; Petty, R Max ; Barklis, Eric ; Barklis, Robin Lid ; Bloodsworth, Kent J ; Bramer, Lisa M ; Zelnik, Iris D ; Futerman, Anthony H ; Leier, Hans C ; Alfadhli, Ayna ; Tafesse, Fikadu G ; Metz, Thomas O

The lipid composition of HIV-1 virions is enriched in sphingomyelin (SM), but the roles that SM or other sphingolipids (SLs) might play in the HIV-1 replication pathway have not been elucidated. In human cells, SL levels are regulated by ceramide synthase (CerS) enzymes that produce ceramides, which can be converted to SMs, hexosylceramides, and other SLs. In many cell types, CerS2, which catalyzes the synthesis of very long chain ceramides, is the major CerS. We have examined how CerS2 deficiency affects the assembly and infectivity of HIV-1. As expected, we observed that very long chain ceramide, hexosylceramide, and SM were reduced in CerS2 knockout cells. CerS2 deficiency did not affect HIV-1 assembly or the incorporation of the HIV-1 envelope (Env) protein into virus particles, but it reduced the infectivites of viruses produced in the CerS2-deficient cells. The reduced viral infection levels were dependent on HIV-1 Env, since HIV-1 particles that were pseudotyped with the vesicular stomatitis virus glycoprotein did not exhibit reductions in infectivity. Moreover, cell-cell fusion assays demonstrated that the functional defect of HIV-1 Env in CerS2-deficient cells was independent of other viral proteins. Overall, our results indicate that the altered lipid composition of CerS2-deficient cells specifically inhibit the HIV-1 Env receptor binding and/or fusion processes.

01 Jul 2019·Journal of Pharmaceutical Sciences

DNA Quadruplex–Based Inhibitor With Flexible Fragments at the 3′ Terminal Shows Enhanced Anti–HIV-1 Fusion Activity

Article

Author: Xu, Liang ; Ren, Hongqian ; Tang, Yongjia ; Han, Zeye ; Liu, Keliang

Chemically optimizing the molecular structure of aptamers may enhance properties such as biological activity or metabolic stability. DNA quadruplex-based HIV-1 fusion inhibitors were found to interact with HIV-1 surface glycoprotein in aptamer mode. In this work, a series of quadruplex-based HIV-1 fusion inhibitors with flexible oligodeoxynucleotide fragments at the 3' terminal was discovered. The flexible extension did not greatly influence quadruplex formation at the 5'-end. Increasing the length of the flexible fragment may increase antifusion activity. Compared with a traditional inhibitor, d(⁵^'TGGGAG^3')₄, these novel inhibitors showed enhanced interaction with HIV-1 glycoproteins gp120 and gp41, which increased inhibition of 6-helical bundle formation during the course of virus fusion. These inhibitors also showed improved stability, compared with natural oligodeoxynucleotide. This work may inform the design of anti-HIV-1 DNA helix-based inhibitors with new structures or mechanisms.

01 Jan 2014·The Journal of Infectious DiseasesQ2 · MEDICINE

HIV Type 1 Polymerase Gene Polymorphisms Are Associated With Phenotypic Differences in Replication Capacity and Disease Progression

Q2 · MEDICINE

Article

Author: Supriya Munshaw ; Mark C. Evans ; Ronald H. Gray ; Agnes C. Paquet ; Andrew D. Redd ; Merlin L. Robb ; Steven J. Reynolds ; Oliver Laeyendecker ; Wei Huang ; Mojgan Haddad ; Mary K. Grabowski ; Oon Tek Ng ; Susan H. Eshleman ; Thomas C. Quinn ; David Serwadda ; Maria J. Wawer

BACKGROUNDDeterminants of intersubtype differences in human immunodeficiency virus type 1 (HIV-1) clinical disease progression remain unknown.METHODSHIV-1 subtype was independently determined for 5 separate genomic regions in 396 HIV-1 seroconverters from Rakai, Uganda, using a multiregion hybridization assay. Replication capacities (RC) in samples from a subset of 145 of these subjects were determined. HIV-1 genomic regions and pol RC were examined for association with disease progression. Amino acid polymorphisms were examined for association with pol RC.RESULTSIn multivariate analyses, the hazard for progression to the composite end point (defined as a CD4(+) T-cell count <250 cells/mm(3), antiretroviral therapy initiation, or death) among patients with subtype D pol infection was 2.4 times the hazard for those infected with subtype A pol infection (P = .001). Compared with subtype A pol (the reference group), the hazard for progression to the composite end point for subtype D pol infection with a pol RC >67% (ie, the median pol RC) was significantly greater (HR, 4.6; 95% confidence interval [CI], 1.9-11.0; P = .001), whereas the hazard for progression to the composite end point for subtype D pol infection with a pol RC ≤67% was not significantly different (HR, 2.2; 95% CI, 1.0-4.9; P = .051). Amino acid substitutions at protease positions 62 and 64 and at reverse transcriptase position 272 were associated with significant differences in pol RC.CONCLUSIONSHIV-1 pol gene intersubtype and RC differences are associated with disease progression and may be influenced by amino acid polymorphisms.

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