Gene variants predict HIV viral levels

Variations in three genes help set the viral level of HIV, according to a study published in this week's Science. The findings help explain why viral load differs dramatically between individuals, and pinpoint genes that may regulate the mechanism of the disease. The study, the first genome-wide search for genes involved in HIV control, "raises new questions about the mechanisms via which the genes identified affect viral load and disease progression at the cellular and molecular level," said David Camerini of the University of California, Irvine, who was not involved in the work. "It also suggests new avenues to manipulate the immune response to HIV-1 with vaccines." Viral titer differs dramatically from patient to patient-in some the virus is almost undetectable, while others host as many as one million copies in a milliliter of blood. To find out if genetic differences between patients make them more vulnerable to viral proliferation, Jacques Fellay and David B. Goldstein of Duke University in Chapel Hill, North Carolina and colleagues traced levels of the virus in 486 HIV patients over the first 3 years of infection, and conducted a genome-wide analysis of single nucleotide polymorphisms. The group found that patients with low viral counts frequently had at least one of three single nucleotide differences in immune-related genes. "All of the genes affiliated with variation in viral number are located in the HLA region of Chromosome 6, which is known to play a major role in immunity," Fellay said. Each of the three polymorphisms was located on or near one of four different genes. One of the genes, Human Leukocyte Antigen-C (HLA-C), is a member of the HLA gene family. Most HLA genes encode cell surface proteins that recognize pathogens and alert the immune system. "It's surprising that [HLA-C] may in fact be involved in virus restriction," Fellay told The Scientist. Most HLA genes are thought to play a role in detecting pathogens, but only HLA-A and HLA-B are known to trigger an immune response against viruses. "By showing that HLA-C is involved in controlling HIV, our results also suggest a new potential target for vaccines," said Fellay. Efforts at vaccine development have focused on designing HIV-look-alikes that trigger HLA-A and HLA-B to raise the red flag to the immune system. "Tricking HLA-C to invoke the immune response might have the same potential as HLA-A and HLA-B-based approaches," said Fellay. A second polymorphism was associated with a gene called HCP5. "Because portions of the HCP5 gene mimic the sequence of HIV, it's thought to have a role in viral immunity," said Fellay. Earlier studies had examined only its sequence, "but our findings are the first to show a direct link between HCP5 and HIV control," he said. Two other genes, which were linked to a single polymorphism, code for transcription factors that have no known role in viral defense.Although the study uncovers variability in human responses to infection, it does not provide clues about the mechanism through which these genes control viral load, said Judy Lieberman of Harvard University, who was not a co-author. "The influence of these candidate genes on disease pathogeneses will need to be understood via future in vitro experiments," she said. Amy Coombs mail@the-scientist.comLinks within this article:Fellay, Jacques, "A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1," Science, published online July 19, 2007. http://www.sciencemag.orgJ. Roberts, "Looking at Variation in Numbers," The Scientist, March 14, 2005. http://www.the-scientist.com/article/display/15302/N. Johnston, "HIV/Host Interaction Elucidated," The Scientist, January 17. 2005. http://www.the-scientist.com/article/display/15184/David Camerini http://www.faculty.uci.edu/scripts/UCIFacultyProfiles/detailMBB.cfm?ID=4930E. Talor, "The vaccine conundrum," The Scientist, April 1, 2007. http://www.the-scientist.com/2007/4/1/48/1/S.E. Langford, "Predictors of disease progression in HIV infection," AIDS Res. Ther., May, 2007. http://www.the-scientist.com/pubmed/17502001David B. Goldstein http://www.genome.duke.edu/people/faculty/goldsteinT. Toma, "HLA influences AIDS response," The Scientist, June 23, 2003, http://www.the-scientist.com/article/display/21403/C.C. Choi, "How monkeys block HIV," The Scientist, November 1, 2006. http://www.the-scientist.com/article/display/24082'Judy Lieberman http://www.cbrinstitute.org/labs/lieberman/index.html

Gene variants predict HIV viral levels

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