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A Genetic Knack for Tackling HIV
 
 
  By Jon Cohen
ScienceNOW Daily News
19 July 2007
 
The study, published by the journal Science yesterday, coincides with the largest scientific gathering on HIV ever held in Australia. About 6500 delegates are due to attend the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Sydney which starts tomorrow.
 
Geneticists have uncovered intriguing new clues about why some people battle HIV more effectively than others. The findings, published online 19 July in Science, may ultimately reveal why these people tend to develop AIDS more slowly.
 
The body's first response to HIV strongly influences how fast the virus will destroy the immune system. Shortly after infection, HIV levels skyrocket, but then the immune system and other antiviral factors produced by cells drive down the amount of virus in the blood--the so-called viral load--and establish a "set point." The lower the set point, the longer the immune system can function effectively. These set points vary widely, and researchers with the U.S.-based Center for HIV-AIDS Immunology and European collaborators hunted for a genetic explanation.
 
The team studied 486 patients infected with HIV who had not received treatment and had known dates of infection and accurate set points. Then they checked blood samples against half a million known variations in DNA sequences, or single-nucleotide polymorphisms, which recently were identified by the International HapMap Project that looked for differences in the genomes of people from many populations. "We've approached this as a straight, quantitative genetic problem," explains David Goldstein, a geneticist at Duke University in Durham, North Carolina, who led the study. The researchers say this is the first study to ever do such a genome-wide association analysis for an infectious disease.
 
Goldstein and co-workers unearthed two polymorphisms in genes that explain 15% of the variation seen in viral set points. The effects of the polymorphisms were independent of one another, and both correlated with lowered set points. The more powerful one occurred within a stretch of DNA, or locus, that contains the HCP5 gene, which codes for a human endogenous retrovirus--a genetic fossil of a virus that wove itself into human chromosomes long ago but no longer produces infectious progeny.
 
Intriguingly, the researchers found that the people who had the HCP5 polymorphism often had a rare gene that can powerfully thwart HIV. That gene, HLA-B*5701, codes for a protein on immune cells that plays a central role in clearing the body of HIV-infected cells. "This research is very important, but it remains to be clarified what the role of these two loci are," says Mark Connors, an immunologist at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, whose lab first reported that HIV-infected people who remain unharmed by the virus for many years often have the HLA-B*5701 allele.
 
The second implicated polymorphism is in the HLA-C gene, which plays a similar role to HLA-B in mounting an effective immune response. The researchers do not know the mechanisms through which these polymorphisms lower viral set points but suggest that if they can be unraveled, the findings may lead to new targets for anti-HIV drugs and new vaccine strategies.
 
AIDS researcher Steven Wolinsky of Northwestern University Medical School in Chicago, Illinois, cautions that this study largely focused on Caucasians: "I would have more confidence in the data if they could replicate the results in the context of a different genetic background." Wolinsky notes that similar findings in the past have turned out to appear in some cohorts but not others: "It's an interesting association, but it really needs to be validated."
 
Science July 19
Published Online July 19, 2007
Science DOI: 10.1126/science.1143767
 
A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1
 
Jacques Fellay 1, Kevin V. Shianna 2, Dongliang Ge 1, Sara Colombo 3, Bruno Ledergerber 4, Mike Weale 1, Kunlin Zhang 3, Curtis Gumbs 1, Antonella Castagna 5, Andrea Cossarizza 6, Alessandro Cozzi-Lepri 7, Andrea De Luca 8, Philippa Easterbrook 9, Patrick Francioli 10, Simon Mallal 11, Javier Martinez-Picado 12, Jose M. Miro 13, Niels Obel 14, Jason P. Smith 2, Josiane Wyniger 3, Patrick Descombes 15, Stylianos E. Antonarakis 16, Norman L. Letvin 17, Andrew J. McMichael 18, Barton F. Haynes 19, Amalio Telenti 3*, David B. Goldstein 1*
 
1 Center for Population Genomics and Pharmacogenetics, Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710, USA.
2 Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710, USA.
3 Institute of Microbiology, University Hospital Center and University of Lausanne, 1011 Lausanne, Switzerland.
4 Division of Infectious Diseases, University Hospital, 8091 Zurich, Switzerland.
5 Clinic of Infectious Diseases, IRCCS San Raffaele Hospital, 20127 Milan, Italy.
6 Department of Biomedical Sciences, Section of General Pathology, University of Modena and Reggio Emilia, School of Medicine, 41100 Modena, Italy.
7 Department of Primary Care and Population Sciences, Royal Free and University College Medical School, UCL London NW3 2PF, UK.
8 Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, 00168 Rome, Italy.
9 Academic Department of HIV/GUM, Kings College London, at Guy's, King's, and St Thomas' Hospitals, London SE5 9RJ, UK.
10 Service of Infectious Diseases, Department of Medicine and Service of Hospital Preventive Medicine, University Hospital Center, 1011 Lausanne, Switzerland.
11 Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, WA 6000, Australia. 12 irsiCaixa Foundation and Hospital Germans Trias i Pujol, 08916 Badalona, Spain, and Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain. 13 Hospital Clinic - IDIBAPS, University of Barcelona, 08036 Barcelona, Spain. 14 Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark. 15 Genomics Platform, NCCR "Frontiers in Genetics," University of Geneva, 1211 Geneva, Switzerland. 16 Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland. 17 Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. 18 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. 19 Duke Human Vaccine Institute, Duke University, Durham, NC 27710, USA.
 
Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele HLA-B*5701, while a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated a third locus encoding a RNA polymerase subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.
 
 
 
 
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