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Front Page

Genetic Battleground Marked Between HIV and Host

There are two sides to every infection. The pathogen that is deadly to one person may only be a nuisance to another, depending on the immunological weapons each host carries. In HIV infection, some are better equipped to fight the virus than others, and characterizing this advantage is the best chance for identifying new approaches to making vaccines. A study in the Dec. 9 Nature provides a large-scale snapshot of how genetic differences translate into a faster or slower course of disease in HIV infection. It points to a specific genetic region—the human leukocyte antigen B (HLA-B) class I gene—as having a dominant role in shaping both the body’s response to HIV and the virus’s countermeasures. The study, led by Philip Goulder, HMS assistant professor of medicine at Massachusetts General Hospital, was conducted by a multi-institutional team in the United States, the United Kingdom, and South Africa, and demonstrates that slight differences in HLA-B proteins can noticeably influence disease outcome.

A large-scale analysis in South Africa led by Philip Goulder shows how evolution is driving both HIV and those infected by it. (Photo by Victoria Goulder)

Class Act

HLA class I molecules stud the surface of cells and act as warning beacons for roving killer T cells. When a cell is infected by a virus, the viral peptides churned through the cell’s protein processing machinery are bound by HLA molecules, which bring the peptides to the surface of the cell like warning flags. Each type of HLA molecule is capable of binding to only a certain range of peptides.

Humans have three different sets of HLA class I genes—A, B, and C—and each comes in hundreds of possible varieties. “It’s been long recognized that this particular region of the human genome is more variable than any other region,” said Goulder, whose time is divided among Oxford, Boston, and Durban. Of the three sets of HLA class I genes, HLA-B is the most diverse, with more than 500 known variations. By keeping a long list of possible HLA molecules to choose from, humans are able to adapt their immune systems over time to meet new challenges from pathogens.

Previous research has suggested that a few specific HLA-B alleles protect certain HIV-infected people against developing AIDS. But the
current study shows that the HLA-B genes are a key driver in the success—or failure—of the immune response to HIV in a large population of infected people.

“This work illustrates the potential of microscopy to go beyond a description of what something looks like to being a detailed quantitation of what's going on in the cell.”

Profiling The team studied a group of 375 HIV-infected South Africans who were not being treated for HIV. Using blood samples, the researchers measured the immune responses to more than 400 synthetic peptides that together represent all of HIV’s proteins. The analysis showed a wide diversity of responses; many of the peptides caused no response, and only five were recognized by more than 25 percent of the subjects. Many of the peptide responses could be matched to the occurrence of particular HLA alleles, and HLA-B contributed to more of the associations than did HLA-A or -C.

The team also looked at how the different HLA alleles that people carry can affect the progress of HIV infection to disease. In a group of 700 infected people, the team found that the viral load of the patients varied significantly according to which HLA-B alleles they carried, but not according to their HLA-A or -C alleles. Most of the variants that could be associated with viral load that was better or worse than expected were HLA-B. Certain HLA-B alleles also correlated closely with differences in CD4 T cell counts, used as an additional measure of disease progression since CD4 cells are the target of HIV and are slowly decimated over the course of infection, if left untreated.

The Pressure Point

The study “shows us where the action is—it’s happening at HLA-B,” Goulder said. The researchers also analyzed whether HLA-B alleles were exerting a greater evolutionary pressure on the virus. When they looked at all the viral proteins in a cohort of infected people from Perth, Australia, they found a significantly higher rate of viral mutations associated with specific HLA-B alleles than with HLA-A variants.

The evolutionary pressure works both ways; the study found evidence that the Durban population is adapting in response to the pressures of the virus. There was a higher rate of protective HLA-B alleles in HIV-infected mothers than in infants who are infected, suggesting that women with protective alleles are less likely to pass the virus to their offspring.

The study was a multisite undertaking, with researchers at Harvard, Oxford, and the University of KwaZuluNatal in South Africa, among other institutions. The findings are the fruit of a unique program led by Bruce Walker, Howard Hughes investigator and HMS professor of medicine at MGH, through the Partners AIDS Research Center and the HMS Division of AIDS. By creating the Doris Duke Medical Research Institute at KwaZuluNatal, the program has allowed South Africans to conduct basic research into HIV. The paper’s first author is South African scientist Photini Kiepiela, who had not conducted research on HIV before the facilities opened. “One of the things that I feel most excited about is that South African researchers, with support from Harvard Medical School, have been able to make a really significant contribution to our understanding of HIV,” Walker said.

One of the implications of the study is that not all immune responses are equal, and it may be that particular responses must be achieved over others. Nor is it known how certain HLA molecules offer better protection against HIV. Though the findings will not translate immediately into a new vaccine strategy, Walker said that the study “gives us much better insight into that battleground between the virus and the host and where the effective skirmishes are taking place.”

—Courtney Humphries