Major Genetic Factors for Control of HIV-1
An international collaboration between European, Australian and American researchers has unveiled some of the genetic mysteries explaining why some people naturally keep HIV levels almost undetectable, whereas others quickly lose control of the infection. Foundation irsiCaixa from the Hospital Germans Trias i Pujol, and Hospital Clínic are the two Catalan centres in this study, published in Science.
This international collaboration has been the largest ever to have taken place in a large scale study on genetic differences between patients infected by HIV, and is the first study of this kind in the field of infectious disease. Catalan participants have been coordinated by Javier Martínez-Picado, ICREA research professor in the Foundation irsiCaixa of Hospital Germans Trias i Pujol, and Josep M. Miró, consultant of the Unit of Infectious Diseases and AIDS of Hospital Clínic-IDIBAPS of Barcelona, and had the collaboration of Hospital de la Santa Creu i Sant Pau, and Hospital Mútua de Terrassa. Research has been conducted with the latest genomics and bioinformatics technologies, analysing 550,000 variations of the complete human genome in 486 patients, mostly European, preselected from 30,000 potential candidates.These variations, known as simple nucleotide polymorphisms (SNPs), are single variations affecting only one nucleotide or base of the genomic sequence. Despite humans sharing 99.9% of the genome sequence, there are still 3 million genetic variations –which make us different from one another– 90% of which are due to SNPs. Hence, a good knowledge of these variations is highly valuable for the determination of the progression of AIDS.
During the present study, obtained genetic data was compared to blood virus load in patients during the first two years after the infection, and also to the rhythm of immune degradation as a result of the infection. This type of comparison, known as association study, permitted to deduct main genetic variations playing a central role in the control of viral infection.
Results point to two gene variants related to the immune system. More precisely, these variations are in a genetic region responsible for the determination of immune response capacity against a number of infectious diseases, including AIDS. These variations are located in the short arm of chromosome 6 in genes controlling HLA-B and HLA-C molecular systems, responsible for the activation of the immune system so that it is able to locate and destroys cells infected by HIV. This study has also identified a third genetic variation involved in immune damage of patients, particularly in a gene encoding a protein which seemingly participates in viral replication, and is also located in chromosome 6.
Genetic variants associated to genes encoding HLA-B and HLA-C molecular systems would explain up to 15% of viral load variation among patients, whereas the third genetic variation would explain 5.8% of these differences. Further study of other genetic regions involved in this process is needed. Nevertheless, HLA-B variation presents the highest correlation with the immune response described until now.
Obtained information will be very useful in the long road to a more rational vaccine development. This and similar studies should push us toward more personalised medicine, where the most suitable drugs for each individual would be determined on the basis of their gene characteristics.
Science. 2007 Jul 19; [Epub ahead of print]
A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1.
Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, Zhang K, Gumbs C, Castagna A, Cossarizza A, Cozzi-Lepri A, De Luca A, Easterbrook P, Francioli P, Mallal S, Martinez-Picado J, Miro JM, Obel N, Smith JP, Wyniger J, Descombes P, Antonarakis SE, Letvin NL, McMichael AJ, Haynes BF, Telenti A, Goldstein DB.
Center for Population Genomics and Pharmacogenetics, Duke Institute for Genome Sciences and Policy, 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.
PMID: 17641165 [PubMed – as supplied by publisher]