HIV-1 diversity and the implementation of integrase strand-transfer inhibitors as part of combination antiretroviral therapy

: The integrase (IN) strand-transfer inhibitor (InSTI) dolutegravir (DTG) is now recommended by the World Health Organization as part of salvage and/or first-line combination antiretroviral therapy (cART).[1] DTG has a high genetic barrier against developing resistance and is effective against all strains that previously exhibited resistance-associated mutations (RAMs) against other cART regimens.[2] Recommendations to use DTG were delayed owing to preliminary findings from Botswana that indicated potential safety concerns in pregnancy, with a small increased risk of neural tube defects.[3] Studies that investigated the safety and efficacy of DTG now support its use in all populations, including pregnant women and those of childbearing potentia

Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors

CITATION: Isaacs, Darren et al. 2020. Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors. Viruses, 12(9):936, doi:10.3390/v12090936.The original publication is available at: https://www.mdpi.comENGLISH ABSTRACT: The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.Publisher's versio

Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors

The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance

Fas mediated(CD95L) periferal T-cell Apotosis marker in monitoring HIV-1 disease progression in adults in Yaoundé, Cameroon

CITATION: Ikomey, G. M. et al. 2016. Fas mediated(CD95L) periferal T-cell Apotosis marker in monitoring HIV-1 disease progression in adults in Yaoundé, Cameroon. International Journal of Immunology, 4(1): 1-5, doi:10.11648/j.iji.20160401.11.The original publication is available at http://www.sciencepublishinggroup.com/j/ijisFas (CD95) / FasL are hallmarks of apoptosis involvement in pathogenesis of HIV. We assess changes in soluble Fas /FasL, CD4 % and HIV-1 viral load in patients prior to the initiation of antiretroviral therapy (ART) and 6 months thereafter. A prospective longitudinal study on sixty consented HIV-1 positive adults. sFas and sFasL levels were measured by ELISA. CD4 cell counts and HIV-1 viralloads were measured using standard methods. Samples were analysed according to the manufacturers’ guidelines.There was a significant positive correlation between HIV-1 viral load and FasL at six months (M6) on treatment [r = +0.49, (0.03)]. There were no correlation between sFas/FasL and CD4 cell counts [ r = -33 (0.16), -31 (0.17) - 23 (0.03) respectively]. The significant correlation between sFasL and HIV-1 viral load at six months of ART suggests that sFasL could be a signal biomarker for HIV-1 disease progression. We have shown in this study that high levels of sFasL depict high HIV-1 viral loads and advance state of the HIV disease. These biomarker should be investigated further in other settings.http://www.sciencepublishinggroup.com/home/indexhttp://article.sciencepublishinggroup.com/html/10.11648.j.iji.20160401.11.htmlPublisher's versio

Chronic obstructive pulmonary disease (COPD) : neutrophils, macrophages and lymphocytes in patients with anterior tuberculosis compared to tobacco related COPD

CITATION: Guiedem, E., et al. 2018. Chronic obstructive pulmonary disease (COPD): neutrophils, macrophages and lymphocytes in patients with anterior tuberculosis compared to tobacco related COPD. BMC Research Notes, 11:192, doi:10.1186/s13104-018-3309-6.The original publication is available at https://bmcresnotes.biomedcentral.comObjective: The inflammatory profile of chronic obstructive pulmonary disease (COPD) related to tobacco is known in certain studies while that of the post tuberculosis form is not yet known. This study aimed to evaluate the levels of neutrophils, macrophages and lymphocytes cells in sputum of COPD patients with history of smoking or anterior tuberculosis. Enumeration of cells in samples was analyzed using standard microscopy. Results: We enrolled 92 participants, 46 (50%) were COPD subjects comprising 22 (47.83%) smokers and 24 (52.17%) with anterior tuberculosis while 46 (50%) healthy persons constituted the control group. The levels of neutrophils, lymphocytes and monocytes were statistically higher in COPD patients compared to the control group with p-values of 0.0001 respectively. Neutrophils levels were higher in COPD patients with history of tobacco than in COPD patients with anterior tuberculosis with a mean rate of 4.72 × 106/ml and 2.48 × 106/ml respectively (p = 0.04). The monocytes and lymphocytes levels were not statistically different between the two sub-groups of COPD patients with p-value of 0.052 and 0.91 respectively. Neutrophils are the only inflammatory cells that were significantly higher in COPD patients with history of smoking as compared to COPD patients with anterior tuberculosis.https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-018-3309-6Publisher's versio

Kinetics of CD4+ T-cell recovery amongst HIV load suppressed patients on first-line antiretroviral therapy in Yaoundé, Cameroon

HIV infected patients on Antiretroviral Therapy (ART) are exposed to various immunological disorders. Immune reconstitution is one of the most challenging problem linked to morbidity and mortality in HIV patients. This study aimed at evaluating the kinetics of CD4+ T-cell recovery amongst HIV load suppressed patients on first-line ART in Yaoundé, Cameroon. This was a retrospective cohort study performed at the care and treatment units of the Yaoundé University Teaching Hospital and Essos Hospital Center, with viral suppressed patients initiated on ART between March and July 2015. Data were collected using a standard form and analyzed using R.3.6.2 software. A p<0.05 was considered statistically significant for a 95%CI. Of the 499 viral suppressed participants, 32% (n=160) were male and 68% (n=339) female; 33% and 40% had severe and moderate immunodepression at baseline, respectively; 9% and 28% remain respectively on the same immunological state. CD4+ T-cell count increased by 73%, 49% and 29% for patients that started treatment, with CD4+ <150 cells/ml, 150<CD4+<350 cells/ml and 350<CD4+<500 cells/ml, respectively and 14%, 34% and 40% reached a target of 500 cells/ml or more after 4 years of treatment. Elder patients and males were likely to have CD4+ T-cells less than 350 Cells/ml. Approximately 35% of patient started treatment with CD4+ T-cells <350 Cells/ml. CD4+ T-cells increased significantly during 4 years of treatment but, just 29% in average achieved CD4+ ≥ 500 cells/ml. CD4 T-cells recovery represent and important challenge in the immunological monitoring of long-term HIV infected patients on ART

The disproportionate effect of COVID-19 mortality on ethnic minorities : genetics or health inequalities?

CITATION: El-Khatib, Z. et al. 2020. The disproportionate effect of COVID-19 mortality on ethnic minorities : genetics or health inequalities? EClinicalMedicine, 23:100430, doi:10.1016/j.eclinm.2020.100430.The original publication is available at https://www.thelancet.com/journals/eclinm/homeThe cases of novel coronavirus disease 2019 (COVID-19) continue to increase across the world, infecting nearly 5.5 million individuals and more than 350,000 death. The earlier studies indicate that significant risk factors for severe COVID-19 are older adults, and people with co-morbidities (regardless of age) including chronic lung diseases, heart diseases, severe obesity (body mass index 40 or higher), and diabetes. When it comes to the role of race/ethnicity, the data is limited, which could be disproportionately affecting ethnic minorities as observed in England during 2009 Influenza A (H1N1) pandemic [1 ]. Earlier reports from the United Kingdom indicated black, Asian and minority ethnic (BAME) are the hardest hit with COVID-19 both in terms of critically ill as well as higher mortality [2 ]Publisher's versio

Some cellular inflammatory characteristics in patients with chronic obstructive pulmonary disease (COPD) with anterior tuberculosis compared to tobacco related COPD

Background Although smoking is the main cause of the chronic obstructive pulmonary disease (COPD), previous tuberculosis (TB) infection can also induce the disease. While the management of COPD is mainly performed with anti-inflammatory molecules, inflammatory profile of post tuberculosis obstructive disease is not yet known. The purpose of this study was to compare certain inflammatory cells of post tuberculosis COPD to that of post tobacco COPD. Methods This cross-sectional study conducted at the Yaoundé Jamot hospital consisted of 92 participants comprising 22 post tobacco COPD patients (COPD/tobacco), 24 post tuberculosis COPD (COPD/TB) and 46 healthy individuals constituting the control group. Sputum and blood were collected for cells counts. Results In sputum, the mean count of neutrophils, lymphocytes and monocytes was statistically higher in COPD patients compared to the control group with p-values respectively of 0.0001, 0.0001 and 0.0001. Comparison of the two COPD groups showed that, neutrophils cells count is higher in COPD/tobacco than in COPD/TB patients (p = 0.04). Monocytes and lymphocytes counts were similar between the two groups of patients with COPD with p-value of 0.052 and 0.91respectivelly. In blood, the rate of CD4 cells was higher in COPD patients compared to controls with a significant p-value of 0.0006. The blood CD8 cell count was not statistically different between COPD patients and the controls group (p = 0.6). Comparing the two COPD groups together, we had a blood CD8 rate higher in COPD/tobacco than COPD/TB (p = 0.0043), and blood CD4 rate were not statistically different between the two COPD groups. Conclusions Neutrophils, monocytes and lymphocytes are involved both in the COPD/tobacco and COPD/TB, with high levels of sputum neutrophiles and blood CD8 cells in COPD/tobacco patients. In blood TCD8 and CD4 lymphocytes may be involved in the pathogenesis of COPD