A new study has suggested that it is the proteins which help some HIV infected people not end up having AIDS.
A large-scale genetic analysis has suggested that tiny changes in the structure of a protein help the immune system to recognize and destroy infected cells, reports Nature.
Most people who contract HIV eventually end up with full-blown AIDS as the virus replicates in their cells, reaching very high levels and damaging their immune systems.
However, the virus does not progress to this stage in about 1 out of every 300 infected people. These 'HIV controllers' do not require treatment, because their bodies suppress the replication of the virus.
Bruce Walker of the Harvard University in Charlestown, first thought of carrying out the study when he recognized the clinical value of such HIV controllers.
"I realized that we could create a cohort by going directly to physicians around the world, and I thought we should figure out what is genetically unique about people who do well compared with people who do badly," he said.
Walker and his colleagues sampled the DNA of more than 900 HIV controllers. They compared it with the genetic code of 2,600 individuals with normal HIV infections, using a technique called a genome-wide association study (GWAS).
The GWAS tested single nucleotide polymorphism (SNP) variations - changes in one letter of DNA - at a million points in the genomes of these individuals, and found more than 300 sites that were statistically associated with control of HIV.
All the sites identified are in a region of the genome that codes for proteins involved in immune response, called HLA proteins. The researchers used regression analyses to narrow their search down to the four sites most strongly linked to HIV immunity.
It isn't possible to tell from the statistics alone whether these sites cause HIV immunity themselves or are simply closely associated with others that do. But using a detailed map of the HLA regions of the genome, created as part of an earlier diabetes study2, the team pinpointed specific amino acids in the protein HLA-B that differed between controllers and people with normal infections.
These amino acids seemed to be behind the ability to control the virus.
"Out of the three billion nucleotides [that make up the human genome], we narrowed it down to a handful of amino acids that define the difference, each coded for by just three nucleotides," said Walker.
Changes in the amino acids identified by Walker's team altered how HLA-B presents viral peptides from HIV to the immune system, but how this process differs between controllers and people with normal HIV infections remains unclear.