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Research into elite suppressors offers clues to new treatments
A therapeutic vaccine might be possible
Investigators studying "elite suppressors," this unique group of HIV-infected individuals who can ward off illness from HIV for years or even decades, have found clues that might lead to powerful new treatments.
Elite suppressors, also referred to as true long-term nonprogressors (LTNPs), HIV controllers, or elite controllers, might be described as a heterogeneous group of HIV-infected patients who maintain suppressed viral loads and normal CD4 T-cell counts without the benefit of antiretroviral therapy (ART).
"Many investigators study elite suppressors as a group, but how heterogeneous these patients are remains unclear," says Una O'Doherty, MD, PhD, an assistant professor in the department of pathology and division of transfusion medicine at the University of Pennsylvania in Philadelphia, PA.
"The cohort we recently studied was shown to have better HIV specific killer CD8 T-cells by our colleagues Migueles and Connors," O'Doherty says.
"We then showed that this cohort of elite suppressors has much lower levels of integrated HIV DNA compared to treated and untreated progressors," she adds. "Our work is consistent with other studies suggesting that elite suppressors have smaller reservoirs."
Understanding why these individuals have smaller reservoirs is an important question that might offer clues to new treatments, O'Doherty notes.
Elite suppressors/controllers are different from the classically-defined long-term nonprogressors, who have detectable viral loads, and from the small fraction of people who resist HIV infection entirely. Long-term nonprogressors are people who can maintain high CD4 cell counts for 10 years or longer, despite having detectable viral loads, says Robert Buckheit, III, a graduate student researcher at the Johns Hopkins University School of Medicine in Baltimore, MD.
The small population that has inherited the Delta 32 mutation of the C-C chemokine receptor type 5 (CCR5) protein are resistant to certain types of HIV-1 infection. But this population also is different from elite suppressors because elite suppressors become infected but then are able to control HIV infection indefinitely.
One National Institutes of Health (NIH) cohort has a LTNPs/elite controllers who have a median duration with HIV infection of 19.5 years.
Plus, there are two individuals who have controlled their HIV infection for 33 years, says Stephen A. Migueles, MD, CAPT, USPHS, senior clinical investigator and staff clinician in the HIV-Specific Immunity Section of the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH in Bethesda, MD.
These people were part of a hepatitis study from the 1970s. Although their HIV diagnosis didn't occur until the 1980s, the physicians who referred them to Migueles and co-investigators confirmed that the men had been infected since 1978. Even after more than three decades of infection, the men maintained viral loads of less than 50 copies, and they never developed opportunistic infections, Migueles notes.
"They have stable, non-declining CD4 T cell counts," he says.
Different research has suggested different ideas about what makes an elite suppressor.
One theory, supported by many studies, is that elite suppressors have a very good host immunity, O'Doherty says.
Other theories have suggested that the host cell is resistant, so the cells of elite suppressors do not become as infected as the cells of typical HIV patients. This area of investigation remains controversial because some groups have found evidence of host cell resistance, while other scientists have found opposite results, O'Doherty says.
A third theory is that elite suppressors have defective virus.
"Defective virus is very hard to prove," O'Doherty says. "Studies have shown that cloned viral sequences from elite suppressors are more often phenotypically defective than in progressors, but it may be that the immune system selected for these mutant sequences."
The theory that would be the easiest to turn into a therapy would be the one involving the host immune response.
"If we determine what is essential for a good immune response maybe we could immunize already-infected people and convert the average HIV-infected individual into an elite suppressor," O'Doherty explains.
When Migueles and co-investigator Mark Connors, MD, first began collaborating in the 1990s, scientists and clinicians grouped all HIV-infected individuals who had not progressed typically with their disease in one category of long-term nonprogressors.
Migueles and Connors were the first to include viral load measurements in their case definition and began to subdivide the group into two groups: a group of slow progressors with viral loads in the 5,000-10,000 copies/ml range and the true LTPNs/elite controllers. The slow progressors are people who begin to have gradual declines in their CD4+ T cell counts, but they do better off therapy for a longer period of time than typical progressors, Migueles explains.
The LTPNs/ECs in this NIAID cohort appear to have active immune control mediated by CD8+ T cell responses. Investigators found a striking enrichment of particular HLA class alleles. This suggests that some CD8 responses, which recognize pieces of the virus in the binding groove of the encoded HLA class I proteins, are better than others and that the people who were doing well likely had superior HIV-specific CD8 T cell responses, he adds.
It was later demonstrated that the CD8+ T cells in these patients proliferate better and more efficiently kill HIV-infected CD4+ T cells.
"The best direct data supporting active immune control of the virus by CD8 T cells have been generated in an animal model with nonprogressor monkeys," Migueles says. "When you delete out their CD8 T cells with an antibody that takes them out for a period of time, the monkey's HIV viral load went up."
Migueles and Connors showed in a recent study that despite many demographic and other differences, the elite controller cohorts being studied at five cities around the world have similar HLA class I alleles, which are believed to offer protective qualities to people with HIV infection. These include the HLA B*57 and HLA B*27.1
The cohorts had a range of 68% to 95% of members with one of the protective alleles.1
While it appears that a few people do well because of attenuated virus, the majority of elite controllers appear to have an active immune control mediated by CD8 T cell responses, Migueles says.
In a recent study examining the transmission of HIV-1 from a long-term nonprogressor to an elite suppressor, investigators found that even with an attenuated HIV isolate, there was a difference in set point viral loads that suggested host factors contributed to determining elite suppressor status.2
The long-term nonprogressor was married to the elite suppressor in the study. The husband had a detectable viral load, but high CD4 T cell counts, and the wife had an undetectable viral load, Buckheit says.
Researchers have taken a comprehensive look at elite suppressors, conducting genotypic studies and isolating the virus in the lab. Everything they've found so far shows that the virus is replication competent, which means it's the host not the virus that causes the difference, says Joel N. Blankson, MD, PhD, an associate professor at the Johns Hopkins University School of Medicine.
HIV investigators continue to delve into what makes elite suppressors different. These differences could provide the answer to constructing a new type of therapy.
"We've looked at many different aspects of the host, including innate immunity and antibody responses and haven't found anything," Blankson says. "What's different is the HLA alleles are over-represented in these patients; they present antigens to CD8 T cells."
The research has progressed, sometimes one case at a time.
"We have even identified transmission pairs where there's discordance," Blankson says. "One patient has clinical AIDS and the other patient is an elite suppressor, and we've documented the virus is the same."
New research emerging
The recent 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, MA, featured a number of new studies about elite suppressors, including one in which a patient maintained elite suppression even after treatment with rituximab-based chemotherapy.3
The study concludes that humoral immunity may not play a central role in suppressing viral replication in elite suppression.3
"This was based on a one patient case report of a man who acquired HIV over 10 years ago," says Adam Spivak, MD, a clinical fellow at the Johns Hopkins University School of Medicine.
The patient had taken ART briefly when he was first diagnosed, but did not take it after that and yet his CD4 cell count remained high and his viral load was undetectable, Spivak says.
"So he fits into this category of elite suppressors or elite controllers, patients who control the virus without any medication," he adds.
What researchers are learning from cases like this one is that some rare individuals have immune systems that are able to control infection, Spivak says.
"When you put the CD8 T cells of an elite suppressor in a test tube with HIV, you will find there won't be any infected HIV cells anymore," he explains. "These CD8 T cells go in and kill HIV-infected cells."
While this is a simplified version of what occurs, it illustrates some exciting potential in HIV treatment. The potential is for development of a therapeutic vaccine that would assist individuals' immune systems to gain better control of the virus.
This is a more realistic scenario than the development of a drug that completely kills the virus.
"It's rare to have sterilizing immunity," Spivak says. "Think about chickenpox, an infection we all had in childhood: the itchy blisters went away, but everyone has the virus in them and their bodies are controlling it until many decades later when it re-emerges as shingles."