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CAfGEN Collaborative Makes Headway in Work on Pediatric HIV Genomics in Africa


NEW YORK (GenomeWeb) – The Collaborative African Genomics Network (CAfGEN), an initiative tasked with using genomics technologies to probe host factors important to the progression of HIV and HIV-tuberculosis infection in sub-Saharan African children, is entering its third and final year of research under a $3 million National Institutes of Health grant.  

CAfGEN is made up of the Botswana-Baylor Children's Clinical Centre of Excellence, the University of Botswana, the Baylor Uganda Children's Foundation, Makerere University, and Baylor College of Medicine. The network's mission is to establish a collaborative network of scientists and physicians in Africa with genomics expertise to aid with more advanced understanding and diagnosis of diseases in African populations.

One way CAfGEN is doing this is by training African scientists/researchers. The network has six trainees from Uganda and Botswana learning about using genomics techniques and tools at Baylor College of Medicine so that they can create genetics laboratories in their respective countries.

The overarching three-year NIH grant was awarded in 2014 to the Botswana-Baylor Children's Clinical Hospital of Excellence and is part of the Human Heredity and Health in Africa (H3Africa) Initiative, which aims to facilitate a contemporary research approach to the study of genomics and environmental determinants of common diseases with the goal of improving the health of African populations.

Graeme Mardon, professor of molecular and human genetics at Baylor College of Medicine and co-principal investigator on the grant, told GenomeWeb last week that the outfit has hit nearly all of the milestones it laid out in its grant.

Before any research with human DNA could start, all of the CAfGEN collaborators had to get approval from the Institutional Review Boards (IRBs) in Uganda, Botswana, and the US. While this was a challenge, Mardon told GenomeWeb, all the CAfGEN institutions received IRB approvals over a year ago.

Once they received approval they began to recruit African children to participate in two separate studies to help gain a deeper understanding of HIV infection in those patients on the genetic level. One study is comparing the genetics of disease-resistant children and  those that get sick with HIV in HIV-positive children to better understand the disease progression. The second study is following the progression of tuberculosis (TB) as it affects children who are HIV positive.

To take a closer look at different genetic factors involved in HIV disease progression in children they had to look at two different sub-groups of children. "Some kids who are HIV positive get sick very quickly, who we call rapid progressors, and there are other kids who in spite of never being treated never got the disease [within a 10-year period], who are called long-term non-progressors," Mardon said.

For the first study, the CAfGEN researchers are particularly interested in comparing the difference between these two sub-groups to try and understand the mechanism of HIV disease progression. They were particularly interested to see if there were mutations in the CCR5 gene, such as the delta-32 allele present in European populations, that prevents HIV disease progression, Mardon said. This particular allele isn't present in African populations, he said, but it's possible that there are either different alleles of CCR5 or rare variants in other genes that influence disease progression.

To look for such differences, CAfGEN researchers recruited 1,000 HIV-positive children (500 long-term non-progressors and 500 rapid progressors) in Uganda and Botswana. They collected and prepared more than 900 DNA samples on site, then sent them off to the Baylor College of Medicine for whole exome sequencing on the facility's Illumina HiSeq platform. To date, 215 of those samples have been sequenced with 110 in the pipeline in coming weeks, Mardon told GenomeWeb. He also noted that the African scientists currently being trained at Baylor College of Medicine are the ones who are conducting the data analysis, not the Baylor scientists.

It's too early to say if the researchers have found anything useful, since they only analyzed a portion of their samples, Mardon said, but the initial analysis seems to fit.

The second project has meet with a few more pitfalls. Initially, they went into the project with the expectation that 10 percent of the children would convert to active TB disease within a year of observation based on past statistics in Botswana and Uganda for TB diagnosis, Mardon said.

CAfGEN researchers were able to recruit 1,200 HIV-positive, sick children and collect initial samples for them. However, protocol changes to how they treated children in Uganda and Botswana that were exposed to TB changed their expected result. "The good news is that the kids aren't getting TB," said Mardon, "but it means that the science hasn't progressed."

Fortunately, Mardon and his colleagues have been able to recruit children from neighboring African countries that better fit the requirements for the study, which they hope will allow them to make progress over the next year.

CAfGEN plans to continue the work on both current projects. It expects to be able to do a more comprehensive comparative analysis between rapid progressors and long-term non-progressors. Additionally, CAfGEN plans to be able to make more headway on the research involving TB now that it has a more promising recruitment cohort.

There has been some talk that NIH plans to renew another round of funding for projects that fall within the H3Africa project, Mardon said. While nothing has been finalized yet, if this is the case, CAfGEN plans to submit a new grant application that will help fund this project for an additional five years.