Principal Investigators:

Scientific Description:

Advanced genetic and genomic technologies promise to transform our understanding and approach to human health and disease. Such genomic analyses are now common in Western populations of European descent. Studies of host genetic factors underlying long-term non-progressors of HIV infection have led to new therapies through the identification of loci that are important to in vivo control of virus pathogenicity. Similar studies of host genetic factors influencing active TB infection have also identified important loci that could significantly impact the future development of more effective therapeutic and prophylactic strategies. Most of these studies were undertaken in non-African, adult populations, although there are more than 2 million new cases of HIV and HIV-TB in Sub-Saharan Africa every year, including more than half a million children. HIV-infected children – who differ from their adult counterparts in their route of acquisition, clinical course, and pathophysiology – have been conspicuously absent, although they potentially have more to ultimately contribute and gain from therapeutic advances.

The Collaborative African Genomics Network (CAfGEN) aims to redress this scientific imbalance by integrating genetic and genomics technologies to probe host factors that are important to the progression of HIV and HIV-TB infection in sub-Saharan African children. The network will incorporate five sites – the Botswana and the Uganda Children’s Clinical Centers of Excellence will provide clinical expertise for patient recruitment; Makerere University and the University of Botswana will provide local molecular genetic expertise; and Baylor College of Medicine will provide access to genomics expertise and resources that will ultimately be transitioned to African researchers and institutions in a sustainable manner. The CAfGEN research agenda includes the recruitment of prospective and retrospective cohorts of HIV and HIV-TB infected children; the development of core genomic facilities for sample processing and storage; candidate gene re-sequencing, HLA allelotyping and whole-exome sequencing of patients at the extremes of HIV disease progression; and integrated genomic analyses of active TB progression and associated clinical outcomes using expression quantitative trait loci. These projects will be undertaken through an extensive training and career development plan that will also see significant upgrades in local genomics infrastructure. In so doing, CAfGEN will create a unique, highly synergistic African alliance that can contribute novel and important mechanistic insights to pediatric HIV and HIV-TB disease progression while establishing sustainable genomics technology, expertise, and capacity on the African continent.

Updated Aims:

The Specific Aims of the network are:

Aim 1a:  Recruit a cohort of well-phenotyped pediatric HIV and HIV-TB infected patients. We will retrospectively recruit 1000 LTNPs and 1000 rapid progressor controls through the Electronic Medical Record (EMR).

Aim 1b: Create a DNA and RNA bioarchive of HIV- and HIV-TB infected pediatric patients from blood and sputum samples that will be de-identified and linked to a central clinical database.

Aim 2a: Evaluate the role of ‘established’ HIV disease progression susceptibility loci in pediatric HIV by undertaking gene sequencing and allelotyping of candidate loci in case-control genetic studies of LTNP status.

Aim 2b: Identify novel host alleles influencing pediatric HIV disease progression by conducting an efficient screening process for sequence variants enriched in LTNPs using whole-exome sequencing.

Aim 3a: Identify genes that show significant temporal differential expression with progression to active TB disease by performing RNA sequencing of paired samples taken from HIV co-infected children at baseline and at the time of active TB disease progression.

Aim 3b: Identify genes key to the progression to active TB by combining differential gene expression with SNP genotypes to identify expression quantitative trait loci (eQTL) and performing integrated genomic analyses of active TB disease and related clinical outcomes.

Aim 4: Establish and enhance undergraduate, graduate, and faculty education in genetics/genomics and provide opportunities for long- and short-term training of scientists and technicians from African universities.

Aim 5: Establish genetic and genomic technologies and supporting laboratory and physical infrastructure for large-scale genetic/genomic analyses of common diseases in Africa.

These strategic aims are designed to create independent, sustainable genomics facilities in Africa that will recruit and train new scientists in genomics, who can then apply these technologies to solve widespread relevant problems in human disease.