HIV/AIDS remains a major cause of morbidity and mortality in sub-Saharan Africa and children are particularly vulnerable. The progression of HIV disease to AIDS is complex. Although studies in adult, mostly Western populations have clearly demonstrated a consistent role for host genetic factors in this progression, the host genetic factors influencing disease progression in sub-Saharan populations, and in particular, pediatric African populations, remains largely unknown. In the same way, tuberculosis (TB) remains a significant cause of morbidity and mortality in sub-Saharan Africa, particularly in those co-infected with HIV. Hence there is a pressing need to find new and effective strategies for managing and diagnosing TB infections. Exposure to M. tuberculosis ? the causative agent of TB ? typically results in either active TB disease (ATB), latent TB infection (LTBI), or no TB. The driving mechanisms behind these outcomes, however, are not well understood, making the diagnostics employed for their detection imprecise, particularly in children. Nonetheless, there is growing evidence that host genomic factors play a prominent role, and can be diagnostically exploited. The availability of advanced genomic technologies presents a valuable opportunity to investigate the host genetics of HIV and TB disease progression in sub-Saharan children, and this is at the scientific core of the Collaborative African Genomics Network (CAfGEN) ? an H3Africa Collaborative Center spanning six institutions in Uganda, Botswana, Swaziland, and the United States. During the previous award period, despite unavoidable challenges, CAfGEN was able to use next-generation sequencing to identify candidate genes influencing pediatric HIV progression and TB disease progression; leverage scientific studies to establish and develop genomics capacity, technology, and expertise in Uganda and Botswana; and effectively engage local communities in addressing ethical, legal and social issues (ELSI) related to genomics research. In the next grant period CAfGEN will build on these achievements by a) expanding genomics studies of pediatric HIV and TB disease progression in children to include new populations and new science; b) providing additional genomics and bioinformatics training on the continent; c) assisting the six PhD students who received two-years of graduate training in human genetics to transition into independent investigators in their home countries; and d) continuing the use of innovative approaches to engage local communities in addressing ELSI related to genomics research in Africa. In so doing, CAfGEN will contribute novel and important mechanistic insights to pediatric HIV and HIV-TB disease progression, whilst creating a sustainable, synergistic, knowledgeable African genomic alliance capable of transforming the future of health on the African continent ? the ultimate goal of the H3Africa Initiative.

Public Health Relevance

HIV and TB are important infections globally but Africa is disproportionately affected. HIV infection among children generally progresses very rapidly when compared to infection among adults but the underlying mechanisms of these phenomena have not been studied, especially in African children. Like HIV, TB is common in Africa and is particularly difficult to diagnose in children. People who contact the bacteria that cause TB may resist infection, develop active disease, or develop silent infection, but the underlying mechanisms are not well understood. The broad aims of this application are to use newer genomics technologies to better understand disease progression in childhood HIV and TB disease and provide a robust foundation for expanding the use and knowledge of genomics on the continent. We intend to build on the achievements of the previous award period by: a) expanding studies on the genomics of pediatric HIV progression and TB disease progression in children with HIV infection to include new populations; b) providing more long-term and short-term genomics and bioinformatics training while assisting the six African students that were trained to complete their PhDs and transition into independent investigators utilizing enabling technology provided during the previous award period; and c) continuing to engage local communities in addressing ethical, legal, and social issues related to genomics research through the use of a variety of approaches in Botswana, Uganda, and Swaziland.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHG1)
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Botswana Baylor Child/Clincal Center/Excell
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Retshabile, Gaone; Mlotshwa, Busisiwe C; Williams, Lesedi et al. (2018) Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana. Am J Hum Genet 102:731-743
Mlotshwa, Busisiwe C; Mwesigwa, Savannah; Mboowa, Gerald et al. (2017) The collaborative African genomics network training program: a trainee perspective on training the next generation of African scientists. Genet Med 19:826-833
Mokone, Gaonyadiwe G; Kebaetse, Maikutlo; Wright, John et al. (2014) Establishing a new medical school: Botswana's experience. Acad Med 89:S83-7
H3Africa Consortium (see original citation for additional authors) (2014) Research capacity. Enabling the genomic revolution in Africa. Science 344:1346-8