HIV continues to be a major public health problem in Africa. Although combination antiretroviral therapy (cART) has reduced mortality and improved lifespan, it does not provide cure. Patients must take medications daily for the rest of their lives with side effects, unsustainable costs, and development of resistance. The main obstacle to HIV cure is the persistence of the provirus in resting CD4+ T cells, which act as a reservoir to produce virus once treatment is interrupted. Of the approaches being investigated to cure HIV, the 'shock and kill' approach is the most promising. This approach seeks to reactivate and kill the T cells harboring the virus, while patient are on cART, with the idea that patients could then stop treatment after the reservoir cells are eliminated. Despite some modest successes, this approach has not been able to reduce the size of the HIV reservoir, due to inefficient reactivation. Since HIV replication is controlled by surrounding chromatin (epigenetics), we hypothesize that epigenetic modifying compounds will be more effective reactivation agents. Here, we propose to screen an epigenetic library of compounds, select the most effective and evaluate them in resting T cells isolated from HIV patients on cART. To do this, we will follow a cohort of patients, measure their viral loads and select those who have virologic suppression for the reactivation studies. This study will provide useful information on virologic suppression among Ghanaian patients, effectiveness of current therapy and discover novel compounds for the 'shock and kill' approach to HIV cure.

Aim

1: To characterize a cohort of HIV patients and evaluate their knowledge and attitude towards participation in HIV cure research

2: To screen a panel of 150 epigenetic modifying compounds for ability to reactivate HIV from latency in a cell line and primary cell model of latency.

3: To evaluate top 10 lead compounds in resting CD4 T cells isolated from patients suppressed on cART for more than 6 months

4: To assemble a well-characterized HIV patient’s biobank to serve as a repository of samples for future research and student training.

Collaborating Institutions:

University of Ghana Hospital, Legon, Accra Ghana

LEKMA Hospital, Teshie, Accra Ghana

Korle-Bu Teaching Hospital, Korle - Bu, Accra Ghana

West African Centre for Cell Biology of Infectious Pathogens, University of Ghana

Washington University in St. Louis, USA

Research Progress

Ethical Issues 

Ethical clearance for the study has been obtained from the ethical/institutional review boards of: 

• Noguchi Memorial Institute for Medical Research, University of Ghana, Legon
• Korle -Bu Teaching Hospital Accra 
• Ghana Health Service

Recruitment of project staff 

The project has successfully recruited two postdoctoral fellows, one PhD student and an Mphil student and identified project nurses at the collaborating hospitals to help with the recruitment of the study cohort.

Patient Recruitment and Sample processing 

A well-characterized cohort has been set up to answer the first objective. A total of three hundred and ninety patients (390), consisting 250 from the Korle-Bu Teaching Hospital, 70 from the University of Ghana hospital and 70 from LEKMA hospitals have been recruited into the study. Blood samples have been collected from the patients, processed into plasma and peripheral blood mononuclear cells and stored at -80^oC for further analysis. 

Achievements 

Cell passaging, expansion and freezing of cell lines; Optimization of cell cultures and other assays are ongoing. 

One manuscript has been drafted on the perception of HIV has been submitted to the journal of Virus Eradication

Sponsors

This project is part of the EDCTP2 programme

supported by the European Union.