Scientists Report New Lead in the Genetics of HIV Resistance
Over the last three years, scientists have discovered a number of relatively common gene changes that can influence how fast or slow a person develops AIDS. To date, most of these alterations involve genes that HIV-1 needs to infect human immune cells. Still left to be found are inherited variations in other human genes that actually drive the immune response against the virus, changes that should also influence the rate at which some people progress to AIDS.
Now, a leading group of scientists in the genetics of HIV resistance says it has identified differences in certain immune response genes that show the strongest genetic effect yet on how fast people infected with HIV-1 progress to AIDS*. The scientists also say their data provide powerful new evidence to support a Nobel Prize-winning theory on how the immune system works.
Reporting in the March 12 issue of the journal Science, the researchers show that variations from person to person in genes that signal immune T cells to attack HIV-1 have a strong influence on the course of HIV-1 disease. In fact, the group notes that 30 percent to 40 percent of the almost 500 people in the study had distinct inherited patterns of these so-called HLA Class I genes that correlated with slow progression. Conversely, they could pick out other patterns, or genotypes, in about 45 percent of HIV-positive individuals that led to rapid progression to AIDS. Slow progression is defined as avoiding AIDS six to 12 years after infection, while rapid progression is defined developing AIDS in three years or less.
According to Stephen O'Brien, Ph.D., leader of the AIDS genetics research group at the National Cancer Institute's (NCI) Frederick Cancer Research and Development Center and senior author on the paper, this finding highlights the growing need to factor genetics into AIDS treatment and diagnostics.
"The virulence of HIV-1 is just one part of the equation in understanding why some people progress faster or slower to AIDS than others," said O'Brien, whose group has identified four other gene changes that inhibit HIV-1's ability to infect immune cells. "The genetic machinery that powers our cells also is a major factor, and the collective strength of this machinery at controlling HIV-1 varies from person to person.
"This finding shows us that natural variability has important implications for HIV-1 diagnostics, particularly in evaluating the results of therapy and vaccine clinical trials and teasing out the modifying effects of these genetic influences," added O'Brien.
Unlike most human gene discoveries, which tend to focus on disease- causing mutations, the data published this week also point to the total number of unique HLA types as a key determinant in the course of HIV-1 infection. The point being, people inherit two copies of each of the three HLA Class I genes, representing a total of six possible unique types. According to Mary Carrington, Ph.D., lead author on the paper and a scientist with Science Applications International Corporation at NCI-Frederick, her group's data show that people who inherit two different types of each HLA gene (six different Class I types) tend to fare better than those who inherit matching copies (three different Class I types).
For those who are familiar with HLA genes, this should ring a bell. HLA stands for Human Leukocyte Antigen, a part of the larger Major Histocompatability Complex, or MHC, that allows the immune system to distinguish "self" from "non-self", such as an invading virus. Researchers noted long ago that HLA genes are probably the most widely diverse in sequence of all genes in humans. In fact, scientists have found as many as 200 sequence combinations, or types, for one HLA gene alone.
Given this natural variability, scientists Peter Doherty, Ph.D., and Rolf Zinkernagel, Ph.D., theorized that HLA genes are diverse within a species to maximize its potential to survive periodic exposures to new and potentially devastating pathogens, such as HIV. "The more unique genes a person has, the greater the chance will be that the immune system will find an escape route to control the virus and get it under control," said Carrington.
Though this theory has become a cornerstone of modern immunology and earned the 1996 Nobel Prize in Medicine and Physiology for Doherty and Zinkernagel, their hypothesis -- called "heterozygote advantage"-- has for technical reasons remained largely theoretical. However a widespread epidemic, like AIDS, offers large numbers of people to test the effects of genetic variability.
But, not only has the virus spread throughout the world, it also seems to put the theory of heterozygote advantage to the ultimate test. "The virus can generate up to a billion copies of mutation-derived variant virus daily," said O'Brien. "The immune system would seem only to be effective in clearing these HIV variants if it carried maximal HLA variation."
About five years ago, O'Brien, Carrington, and their colleagues decided to apply their expertise in genetic diversity and immunology to several large, well-established AIDS cohorts that chronicle the natural history of HIV-1 positive people. They hypothesized that in these cohorts, overall genetic variability in the HLA or also specific configurations of a gene might be involved in resistance to AIDS progression.
According to this week's paper, their hypothesis was correct -- and, by association, so was the theory of heterozygote advantage. In the study, Carrington et al. examined the genotypes of three HLA Class I genes in 498 people who had documented dates of HIV-1 infection and whose health has been tracked over time. HLA Class I genes encode proteins whose task it is to present bits of viral proteins to immune T cells, which then can recognize the foreign material and kill the cell to stop the infection from spreading.
The researchers found that people who had only three or four different Class I types out of a possible total of six unique types, were rapid progressors to AIDS. In fact, about 75 percent of those who developed AIDS in less than one year of becoming HIV positive had identical copies at one or more HLA genes. Conversely, people who had maximal HLA diversity avoided AIDS for longer than 10 to 12 years.
In general, Carrington et al. found that maximal HLA diversity was more important in predicting the course of the disease than which particular HLA types were present. But they did note two key exceptions. Regardless of a person's HLA diversity, individuals who carried even a single version of the so-called gene types HLA-B*35 or HLA-Cw*04 were rapid progressors to AIDS. In fact, one patient who had dual copies of these HLA types developed CD4 cell counts below 200 within a few months of infection and developed clinical AIDS in 10 months. By 13 months, the patient died.
The work involved the cooperation of volunteers involved in five AIDS cohort studies: Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, ALIVE Study, Multicenter Hemophilia Cohort Study, and San Francisco City Clinic Cohort. These cohorts are supported by various National Institutes of Health institutes including the National Institute of Allergy and Infectious Diseases, the NCI, and the National Institute of Child Health and Human Development.
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* The title of the study is "HLA and HIV-1: Heterozygote Advantage and B*35-Cw*04 Disadvantage." The authors are Mary Carrington, George W. Nelson, Maureen P. Martin, Teri Kissner, David Vlahov, James J. Goedert, Richard Kaslow, Susan Buchbinder, Keith Hoots, and Stephen J. O'Brien.