For reasons largely unknown, a small number of HIV-infected individuals remain symptom-free long after AIDS normally would have appeared. Scientists from the National Institute of Allergy and Infectious Diseases (NIAID) and their co-workers now report how a small subgroup of these so-called long-term nonprogressors (LTNPs) may avoid disease. Their research, which appears in the March 14 Proceedings of the National Academy of Sciences,* provides new information that one day may be used in developing vaccines or other therapies to control HIV infection.
"This discovery applies to only a very small subset of long-term nonprogressors, but it identifies a feature common to the immune systems of these individuals that likely enables them to resist disease," notes Anthony S. Fauci, M.D., director of NIAID. "Although it does not explain all cases of long-term nonprogression, the discovery should provide insight into the mechanisms of immune defense against HIV."
Mark Connors, M.D., of NIAID's Laboratory of Immunoregulation, led a team from the United States and Australia in investigating the immune responses to HIV in a subgroup of 13 LTNPs. The investigators selected these patients because they represented the healthiest LTNPs - people with normal CD4+ T-cell counts and extremely low levels of HIV in the blood. This "elite" group of nonprogressors in many cases had virus levels below the level of detection even though they had been HIV-positive for 15 years and had not received antiretroviral therapy.
The research team looked at specific immune system genes in these patients and compared them with those from normal progressors. These so-called human leukocyte antigen (HLA) genes encode proteins that attach to pieces of microbes and subsequently signal the immune system to respond. In HIV and other viral infections, HLA proteins attach to virus fragments within infected cells. These HLA proteins then carry their viral captives to the cell surface where they display them to T cells, which destroy the diseased cell.
Virtually every cell in the body has HLA proteins, and these proteins differ according to type from person to person. Because one type of HLA protein may be better at attaching to fragments of a given microbe, individuals with certain HLA genes may be better at resisting selected infections, such as HIV.
In this study, Dr. Connors, lead author Stephen Migueles, M.D., and their colleagues found 11 of the 13 LTNP patients (85 percent) had a gene encoding an HLA variant called HLA B*5701, while only 19 of 200 progressors (9.5 percent) carried this gene. Furthermore, when the researchers looked at the T cells from LTNPs, they discovered that many of those cells recognized HLA B*5701 when it was attached to specific HIV protein fragments. These findings suggest that a property of the immune systems of these individuals, and not a weakened form of the virus, is the reason why some nonprogressors avoid disease.
Scientists have noticed connections between other HLA types and HIV disease progression in the past, but this is the first study to identify such an overwhelming correlation. "Some associations between HLA genes and disease resistance could be phenomena in which HLA isn't the key but is simply located near another important gene," explains Dr. Connors. "The functional studies included in our research indicate that this molecule is likely directly involved in restricting virus replication in this small subgroup of people."
Further studies will investigate in more detail how HLA B*5701 protects LTNPs from disease and why the protein does not appear to protect the small percentage of normal progressors who carry this gene variant. In addition, researchers will continue to look for HLA types that protect other nonprogressor subgroups in hopes of identifying additional factors used by the immune system to thwart AIDS progression.
NIAID is a component of the National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services. NIAID conducts and supports research to prevent, diagnose and treat illness such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.
Reference: SA Migueles et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci USA 97:2709-714 (2000).
* This article first appeared Feb. 29, 2000, in the PNAS Early Edition online.