Bio

Martin Mulinge CV

Publications


2021

Yang, X, He Z, Zheng Y, Wang N, Mulinge M, Schmit J-C, Steinmetz A, Seguin-Devaux C.  2021.  Chemical Constituents of and Their Anti-HIV-1 Activity., 2021 Apr 23. Molecules (Basel, Switzerland). 26(9) Abstract

Three new (-) and 25 known compounds were isolated from the crude extract of . The chemical structures of new compounds were established by extensive spectroscopic analyses including 1D and 2D NMR and HRESIMS. Cassiabrevone () is the first heterodimer of guibourtinidol and planchol A. Compound was a new chalcane, while was a new naphthalene. Cassiabrevone (), guibourtinidol-(4α→8)-epiafzelechin (), taxifolin (), oleanolic acid (), piceatannol (), and palmitic acid (), exhibited potent anti-HIV-1 activity with IC values of 11.89 µM, 15.39 µM, 49.04 µM, 7.95 µM, 3.58 µM, and 15.97 µM, respectively.

Zheng, Y, Yang X-W, Schols D, Mori M, Botta B, Chevigné A, Mulinge M, Steinmetz A, Schmit J-C, Seguin-Devaux C.  2021.  Active Components from Prevent HIV-1 Entry by Distinct Mechanisms of Action., 2021 May 10. International journal of molecular sciences. 22(9) Abstract

is widely used in Sub-Saharan Africa for treating many diseases, including HIV-1 infection. We have recently described the chemical structures of 28 compounds isolated from an alcoholic crude extract of barks and roots of , and showed that six bioactive compounds inhibit HIV-1 infection. In the present study, we demonstrate that the six compounds block HIV-1 entry into cells: oleanolic acid, palmitic acid, taxifolin, piceatannol, guibourtinidol-(4α→8)-epiafzelechin, and a novel compound named as cassiabrevone. We report, for the first time, that guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone inhibit HIV-1 entry (IC of 42.47 µM and 30.96 µM, respectively), as well as that piceatannol interacts with cellular membranes. Piceatannol inhibits HIV-1 infection in a dual-chamber assay mimicking the female genital tract, as well as HSV infection, emphasizing its potential as a microbicide. Structure-activity relationships (SAR) showed that pharmacophoric groups of piceatannol are strictly required to inhibit HIV-1 entry. By a ligand-based in silico study, we speculated that piceatannol and norartocarpetin may have a very similar mechanism of action and efficacy because of the highly comparable pharmacophoric and 3D space, while guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone may display a different mechanism. We finally show that cassiabrevone plays a major role of the crude extract of by blocking the binding activity of HIV-1 gp120 and CD4.

Scriven, YA, Mulinge MM, Saleri N, Luvai EA, Nyachieo A, Maina EN, Mwau M.  2021.  Prevalence and factors associated with HIV-1 drug resistance mutations in treatment-experienced patients in Nairobi, Kenya: A cross-sectional study., 2021 Oct 08. Medicine. 100(40):e27460. Abstract

An estimated 1.5 million Kenyans are HIV-seropositive, with 1.1 million on antiretroviral therapy (ART), with the majority of them unaware of their drug resistance status. In this study, we assessed the prevalence of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs), nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors, and the variables associated with drug resistance in patients failing treatment in Nairobi, Kenya.This cross-sectional study utilized 128 HIV-positive plasma samples obtained from patients enrolled for routine viral monitoring in Nairobi clinics between 2015 and 2017. The primary outcome was human immunodeficiency virus type 1 (HIV-1) drug resistance mutation counts determined by Sanger sequencing of the polymerase (pol) gene followed by interpretation using Stanford's HIV Drug Resistance Database. Poisson regression was used to determine the effects of sex, viral load, age, HIV-subtype, treatment duration, and ART-regimen on the primary outcome.HIV-1 drug resistance mutations were found in 82.3% of the subjects, with 15.3% of subjects having triple-class ART resistance and 45.2% having dual-class resistance. NRTI primary mutations M184 V/I and K65R/E/N were found in 28.8% and 8.9% of subjects respectively, while NNRTI primary mutations K103N/S, G190A, and Y181C were found in 21.0%, 14.6%, and 10.9% of subjects. We found statistically significant evidence (P = .013) that the association between treatment duration and drug resistance mutations differed by sex. An increase of one natural-log transformed viral load unit was associated with 11% increase in drug resistance mutation counts (incidence rate ratio [IRR] 1.11; 95% CI 1.06-1.16; P < .001) after adjusting for age, HIV-1 subtype, and the sex-treatment duration interaction. Subjects who had been on treatment for 31 to 60 months had 63% higher resistance mutation counts (IRR 1.63; 95% CI 1.12-2.43; P = .013) compared to the reference group (<30 months). Similarly, patients on ART for 61 to 90 months were associated with 133% higher mutation counts than the reference group (IRR 2.33; 95% CI 1.59-3.49; P < .001). HIV-1 subtype, age, or ART-regimen were not associated with resistance mutation counts.Drug resistance mutations were found in alarmingly high numbers, and they were associated with viral load and treatment time. This finding emphasizes the importance of targeted resistance monitoring as a tool for addressing the problem.

2016

Santos da Silva, E, Mulinge M, Lemaire M, Masquelier C, Beraud C, Rybicki A, Servais J-Y, Iserentant G, Schmit J-C, Seguin-Devaux C, Perez Bercoff D.  2016.  The Envelope Cytoplasmic Tail of HIV-1 Subtype C Contributes to Poor Replication Capacity through Low Viral Infectivity and Cell-to-Cell Transmission., 2016. PloS one. 11(9):e0161596. Abstract

The cytoplasmic tail (gp41CT) of the HIV-1 envelope (Env) mediates Env incorporation into virions and regulates Env intracellular trafficking. Little is known about the functional impact of variability in this domain. To address this issue, we compared the replication of recombinant virus pairs carrying the full Env (Env viruses) or the Env ectodomain fused to the gp41CT of NL4.3 (EnvEC viruses) (12 subtype C and 10 subtype B pairs) in primary CD4+ T-cells and monocyte-derived-macrophages (MDMs). In CD4+ T-cells, replication was as follows: B-EnvEC = B-Env>C-EnvEC>C-Env, indicating that the gp41CT of subtype C contributes to the low replicative capacity of this subtype. In MDMs, in contrast, replication capacity was comparable for all viruses regardless of subtype and of gp41CT. In CD4+ T-cells, viral entry, viral release and viral gene expression were similar. However, infectivity of free virions and cell-to-cell transmission of C-Env viruses released by CD4+ T-cells was lower, suggestive of lower Env incorporation into virions. Subtype C matrix only minimally rescued viral replication and failed to restore infectivity of free viruses and cell-to-cell transmission. Taken together, these results show that polymorphisms in the gp41CT contribute to viral replication capacity and suggest that the number of Env spikes per virion may vary across subtypes. These findings should be taken into consideration in the design of vaccines.

2014

Zheng, Y, Mulinge M, Counson M, Yang X, Steinmetz A, Schmit J-C, Devaux C.  2014.  Anti-HIV activities in an African plant extract. Planta Medica. 80(10)

2013

Mulinge, M, Lemaire M, Servais J-Y, Rybicki A, Struck D, Santos da Silva E, Verhofstede C, Lie Y, Seguin-Devaux C, Schmit J-C, Perez Bercoff D.  2013.  HIV-1 tropism determination using a phenotypic Env recombinant viral assay highlights overestimation of CXCR4-usage by genotypic prediction algorithms for CRF01_AE and CRF02_AG [corrected]., 2013. PloS one. 8(5):e60566. Abstract

Human Immunodeficiency virus type-1 (HIV) entry into target cells involves binding of the viral envelope (Env) to CD4 and a coreceptor, mainly CCR5 or CXCR4. The only currently licensed HIV entry inhibitor, maraviroc, targets CCR5, and the presence of CXCX4-using strains must be excluded prior to treatment. Co-receptor usage can be assessed by phenotypic assays or through genotypic prediction. Here we compared the performance of a phenotypic Env-Recombinant Viral Assay (RVA) to the two most widely used genotypic prediction algorithms, Geno2Pheno[coreceptor] and webPSSM.

Santos da Silva, E, Mulinge M, Perez Bercoff D.  2013.  The frantic play of the concealed HIV envelope cytoplasmic tail., 2013 May 24. Retrovirology. 10:54. Abstract

Lentiviruses have unusually long envelope (Env) cytoplasmic tails, longer than those of other retroviruses. Whereas the Env ectodomain has received much attention, the gp41 cytoplasmic tail (gp41-CT) is one of the least studied parts of the virus. It displays relatively high conservation compared to the rest of Env. It has been long established that the gp41-CT interacts with the Gag precursor protein to ensure Env incorporation into the virion. The gp41-CT contains distinct motifs and domains that mediate both intensive Env intracellular trafficking and interactions with numerous cellular and viral proteins, optimizing viral infectivity. Although they are not fully understood, a multiplicity of interactions between the gp41-CT and cellular factors have been described over the last decade; these interactions illustrate how Env expression and incorporation into virions is a finely tuned process that has evolved to best exploit the host system with minimized genetic information. This review addresses the structure and topology of the gp41-CT of lentiviruses (mainly HIV and SIV), their domains and believed functions. It also considers the cellular and viral proteins that have been described to interact with the gp41-CT, with a particular focus on subtype-related polymorphisms.

2009

Ndung'u, K, Purity G, Martin M, Johnson K, J K, Lawrence M, Naomi M, John K, Grace M.  2009.  . A comparative study in direct cryopreservative efficacy between Triladyl® and EDTA saline glucose 10% glycerol cryopreservative media for human and non-human infective trypanosomes. J. Protozool. Res . 19:22-28.

2008

Coddens, A, Verdonck F, Mulinge M, Goyvaerts E, Miry C, Goddeeris B, Duchateau L, Cox E.  2008.  The possibility of positive selection for both F18(+)Escherichia coli and stress resistant pigs opens new perspectives for pig breeding., 2008 Jan 01. Veterinary microbiology. 126(1-3):210-5. Abstract

F18(+)Escherichia coli infections causing post-weaning diarrhoea and/or oedema disease are a major cause of economic losses in pig industry. To date, no preventive strategy can protect pigs from F18(+)E. coli infections. One of the most attractive approaches to eliminate F18(+)E. coli infections is the selection for pigs that are resistant to F18(+)E. coli infections. However, this strategy was not believed to be favourable because of reports of genetic association with the stress-susceptibility gene in the Swiss Landrace. To investigate this potential association more thoroughly, 131 randomly selected Belgian hybrid pigs were genotyped for both the F18(+)E. coli resistance alleles (FUT1(A)) and the stress-susceptibility alleles (RYR1(T)) and their association was investigated by determining the linkage disequilibrium. This linkage disequilibrium (LD=-0.0149) is close to zero and does not differ significantly from 0 (likelihood ratio test chi(1)(2)=1.123, P=0.29), demonstrating no association between the FUT1(A) and RYR1(T) alleles. Furthermore, only a small fraction (4.6%) of the Belgian pigs was found to be resistant to F18(+)E. coli infections. Our results suggest that selection for F18(+)E. coli resistant pigs might be an attractive approach to prevent pigs from F18(+)E. coli infections, unlike to what has previously been postulated.

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