Genetic variant linked to lower levels of HIV virus in people of African ancestry
An international team of researchers has found a genetic variant that may explain why some people of African ancestry have naturally lower viral loads of HIV, reducing their risk of transmitting the virus and slowing progress of their own illness.
Reported today in Nature, this is the first new genetic variant related to HIV infection discovered in nearly 30 years of research. It could, in the future, help direct the development of new treatments approaches for those living with HIV.
HIV remains a major threat to global health. According to UNAIDS, there were 38.4 million people living with HIV globally in 2021. A combination of pre-exposure drugs and medicines that dramatically reduce viral loads has had a major impact on transmission, yet 1.5 million people were newly infected in 2021. And while treatments have improved dramatically since the virus was first identified, 650,000 people still died from AIDS-related illnesses in that year.
Viral load is the amount of a virus in a patient’s system. Higher levels are known to correlate with faster disease progression and increased risk of transmission. But viral load varies widely among infected individuals, influenced by a number of factors including an individual’s genetic makeup.
Most of what we know about the relationship between our DNA and HIV comes from studies among European populations. But given that HIV disproportionately affects people on the African continent – more than 25 million people who are HIV-positive live on the continent – it’s important to better understand the role of genetics in HIV infection in African populations.
To investigate this question, researchers analysed the DNA of almost 4,000 people of African ancestry living with HIV-1, the most common type of the virus. They identified a variant within a region on chromosome 1 containing the gene CHD1L which associated with reduced viral load in carriers of the variant. Between 4% and 13 % of people of African origin are thought to carry this particular variant.
Paul McLaren from the Public Health Agency of Canada’s National Microbiology Laboratory, joint first author, said: “African populations are still drastically underrepresented in human DNA studies, despite experiencing the highest burden of HIV infection. By studying a large sample of people of African ancestry, we’ve been able to identify a new genetic variant that only exists in this population and which is linked to lower HIV viral loads.”
CHD1L is known to play a role in repairing damaged DNA, though it is not clear why the variant should be important in reducing viral load. However, as HIV attacks immune cells, researchers at the University of Cambridge’s Department of Medicine, led by Dr Harriet Groom and Professor Andrew Lever, used stem cells to generate variants of cells that HIV can infect in which CHD1L had either been switched off or its activity turned down.
HIV turned out to replicate better in a type of immune cell known as a macrophage when CHD1L was switched off. In another cell type, the T cell, there was no effect – perhaps surprising since most HIV replication occurs in the latter cell type.
Dr Groom said: “This gene seems to be important to controlling viral load in people of African ancestry. Although we don’t yet know how it’s doing this, every time we discover something new about HIV control, we learn something new about the virus and something new about the cell. The link between HIV replication in macrophages and viral load is particularly interesting and unexpected.”
Co-author Professor Manjinder Sandhu from the Faculty of Medicine at Imperial College London said: “With more than a million new HIV infections a year, it’s clear that we still have a long way to go in the fight against HIV – we are yet to have a vaccine to prevent infection, have yet to find a cure and still see drug resistance emerging in some individuals. The next step is to fully understand exactly how this genetic variant controls HIV replication.”
The research in Cambridge was largely funded by the Medical Research Council. A full list of funders can be found in the research paper.
Reference
McLaren, PJ; Porreca, I; Iaconis, G; Mok, HP, Mukhopadhyay, Sl; Karakoc, E et al. Africa-specific human genetic variation near CHD1L associates with HIV-1 load. Nature; 2 Aug 2023; DOI: 10.1038/s41586-023-06370-4
JOURNAL
Nature
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Africa-specific human genetic variation near CHD1L associates with HIV-1 load
ARTICLE PUBLICATION DATE
2-Aug-2023
Learning how to control HIV from African genomes
“We searched for human genetic variation that associates with spontaneous control of HIV and identified a novel region in the genome that is only variable in populations of African ancestries,” says Professor Jacques Fellay at EPFL’s School of Life Sciences. “We used a combination of computational and experimental approaches to explore the biological mechanism behind the genetic association and provide evidence that the gene CHD1L acts to limit HIV replication in a subset of white blood cells.”
HIV is still a problem
Despite significant advances in treatment and access to therapy, the human immunodeficiency virus remains a global health challenge with almost 40 million affected individuals, no vaccine and no cure. The virus attacks the person’s immune cells (helper T cells, macrophages, and dendritic cells) damaging their ability to mount an immune response. Without treatment, the infected person grows more susceptible to opportunistic infections and cancer, and can develop acquired immunodeficiency syndrome, the well-known AIDS.
Although annual HIV infections have been declining because of widespread antiretroviral therapies, the trend has slowed substantially since 2005, and there are now alarming increases in the number of newly infected adults in some regions.
HIV and studies on the human genome
The way to therapies involves fundamental research, including studies into the relationship between the human genome and the progression of HIV infection, which can reveal possible therapeutic targets.
These Genome-Wide Association Studies, or GWAS, analyze the entire genome of a large number of individuals to identify genetic variants associated with a clinical outcome, such as the ability to naturally control viral replication.
Measuring HIV replication control: not enough in African populations
The degree of viral infection is measured by the virus’ “setpoint viral load” (spVL), which refers to the relatively stable level of HIV replication in the body after the initial, acute phase of infection in untreated individuals.
A critical determinant of HIV infection progression and transmissibility, spVL is expressed as the number of viral copies per milliliter of plasma. The spVL of HIV varies widely in the infected population, depending on the ability of every individual's immune system to control viral replication without antiretroviral drugs.
Although there have been large studies of spVL control in populations of European descent, much less has been done in populations of African ancestries, which are still drastically underrepresented in human genomic studies. This is both a significant problem considering the disproportionate HIV burden in Africa and a missed opportunity given the high genome diversity among people of African descent, which fosters a high probability of genetic discoveries.
A key gene for resistance to HIV replication in people of African ancestries
To address this disparity, a large international collaboration of scientists and clinicians has now performed large-scale GWAS using data from diverse populations of African ancestries. In total, the scientists analyzed the genomes from 3,879 individuals living with HIV-1. Using computational analysis and fine-mapping techniques, they identified a novel region in the genome that shows a strong association with spVL control.
The study was co-led by Jacques Fellay at EPFL, Paul McLaren at the Public Health Agency of Canada’s National Microbiology Laboratory, and Manjinder Sandhu at Imperial College London. It is now published in Nature.
This region corresponds to a gene known as CHD1L (for “Chromodomain Helicase DNA Binding Protein 1 Like”), which encodes a protein that helps DNA unwind after it has been damaged, allowing it to be repaired. But in this study, the CHD1L gene showed genetic variation specific to populations of African ancestries, and that was linked to the spontaneous control of the most common and virulent type of HIV, called HIV-1.
Having identified CHD1L as a potential modulator of HIV-1 infection, the researchers explored the biological mechanism behind the genetic association and determined that CHD1L plays a role in limiting HIV replication in a subset of white blood cells.
The discovery of CHD1L's role in limiting HIV replication could lead to improved treatment options for infected individuals. “Our findings provide insights into potential therapeutic targets, which are needed to continue the fight against HIV-1,” says Fellay. “In addition, our results underscore the importance of performing genomic studies in diverse ancestral populations to better address their specific medical needs and global health inequities.”
List of other contributors
- Public Health Agency of Canada
- University of Manitoba
- Wellcome Trust Sanger Institute
- University of Cambridge
- King's College London
- Lausanne University Hospital (CHUV) and University of Lausanne
- Swiss Institute of Bioinformatics
- The Jackson Laboratory for Genomic Medicine
- Stanford University
- Northwestern University
- Ragon Institute of MGH, MIT and Harvard
- Frederick National Laboratory for Cancer Research
- San Francisco Department of Public Health
- University of Modena and Reggio Emilia
- Siena University Hospital
- University of Siena
- National Institutes of Health
- Columbia University
- Vanderbilt University School of Medicine
- University of Washington
- London School of Hygiene and Tropical Medicine
- Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine
- Zambia Emory HIV Research Project
- Johns Hopkins University
- University of Amsterdam
- RTI International
- Université Paris Saclay
- Bicêtre Hospital
- Murdoch University and Pathwest
- IrsiCaixa AIDS Research Institute
- University of Vic – Central University of Catalonia
- CIBERINFEC, Instituto de Salud Carlos III
- University of Barcelona
- National Health Laboratory Service, South Africa and University of KwaZulu-Natal
- Copenhagen University Hospital
- San Raffaele Scientific Institute
- Vita-Salute San Raffaele University, School of Medicine Milan
- International AIDS Vaccine Initiative
- University of California, San Francisco
- Inselspital – University Hospital Bern
- Hôpital Saint-Louis
- University of Zurich
- Howard Hughes Medical Institute
- Frederick National Laboratory
- Conservatoire national des arts et métiers
- National University of Singapore
- Queen Mary University of London
- Imperial College London
- Omnigen Biodata
Reference
Paul J. McLaren, Immacolata Porreca, Gennaro Iaconis, Hoi P. Mok, Subhankar Mukhopadhyay, Emre Karakoc, Sara Cristinelli, Cristina Pomilla, István Bartha, Christian W. Thorball, Riley H. Tough, Paolo Angelino, Cher S. Kiar, Tommy Carstensen, Segun Fatumo, Tarryn Porter, Isobel Jarvis, William C Skarnes, Andrew Bassett, Marianne K. DeGorter, Mohana P.S. Moorthy, Jeffrey F. Tuff, Eun-young Kim, Miriam Walter, Lacy M Simons, Arman Bashirova, Susan Buchbinder, Mary Carrington, Andrea Cossarizza, Andrea De Luca, James J. Goedert, David B. Goldstein, David W. Haas, Joshua T. Herbeck, Eric O. Johnson, Pontiano Kaleebu, William Kilembe, Gregory D. Kirk, Neeltje A. Kootstra, Alex H. Kral, Olivier Lambotte, Ma Luo, Simon Mallal, Javier Martinez-Picado, Laurence Meyer, José M. Miro, Pravi Moodley, Ayesha A. Motala, James I. Mullins, Niels Obel, Fraser Pirie, Francis A. Plummer, Guido Poli, Matthew A. Price, Andri Rauch, Ioannis Theodorou, Alexandra Trkola, Bruce D. Walker, Cheryl A. Winkler, Jean-François Zagury, Stephen B. Montgomery, Angela Ciuffi, Judd F. Hultquist, Steven M. Wolinsky, Gordon Dougan, Andrew M.L. Lever, Deepti Gurdasani, Harriet Groom, Manjinder S. Sandhu, Jacques Fellay. Africa-specific human genetic variation near CHD1L associates with HIV-1 load. Nature 02 August 2023. DOI: 10.1038/s41586-023-06370-4
JOURNAL
Nature
ARTICLE TITLE
Africa-specific human genetic variation near CHD1L associates with HIV-1 load.
ARTICLE PUBLICATION DATE
2-Aug-2023
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