Elite Suppressor (ELITE CONTROLLERS, 2009) (ELITE SUPPRESSORS, 2009)
Jan 31, 2009
Dear Dr. Bob. Last year when I was incredulous at my HIV test, and believed it must be an error, I wrote you and you were so kind. Of course, it was true...my partner had lied. My numbers were good: 220 VL and 440 cell count, but I was still devastated. I waited several months not wanting to go for my next round of lab tests. When I finally did, 7 months later, I found I was undetectable, with a much better cell count. Two subsequent lab rounds, at 3 months later, and then 5 months after that, have confirmed this condition. My wonderful doctor at the Madison Clinic in Seattle is amazed, as am I. Life seems not as bleak as it did. My question is, is this likely to continue? And, what should I do...is there some study I should join or is there some other way to help? I am in financial straits, so monetary contribution to research is not possible at the moment. I thank you for your kindness last year, and for just being there, for people such as I, who never, ever thought to be in this situation. I cry over the difficulties in my relationships still, as he is fearful over contagion, but I have hope now, as I did not before. Bless you for your work.
Response from Dr. Frascino
It appears you may well be an elite suppressor (or "elite controller"). Is this likely to continue? No one knows. It's possible your immune system will continue to control your HIV infection for quite some time. However, some elite suppressors lose control (suppression) for reasons we do not totally understand. There are a number of research groups studying elite suppressors. Your HIV specialists should be able to advise you if anyone in the Seattle area is doing this type of work. If not, he may be able to link you up with researchers at a distant site (such as San Francisco or Boston) where cohorts of elite controllers are being studied. This would require periodic blood specimens be sent to the research group for analysis. I'll repost some information about elite controllers/suppressors below.
Insights From People Who Keep HIV in Check Naturally
By Laura Sivitz
David first learned he had HIV in 1986. "I of course assumed that I'd be dead in two or three years at most," he recalls. (This story uses a pseudonym to maintain his confidentiality.) His first sexual partner died of AIDS around 1993, and his second partner has been HIV-positive and on antiretroviral medications for many years. David used to refer to his regular 6-month medical check-up as his "lottery ticket," never knowing when the virus would trigger disease in him as it had in so many others.
Twenty-two years after his diagnosis, David has not developed HIV-related disease despite never having taken medications to fight the virus. Remarkably, his immune system has remained healthy on its own.
Elite Controllers: Who They Are and What They Might Teach Us
David is part of a small group of HIV-infected individuals -- about 1 in every 3,000 -- whose immune systems naturally and durably control the virus. There is no standard definition for people like him, who are known variously as long-term nonprogressors, elite controllers, elite suppressors, or HIV controllers. Scientists generally define them as people who maintain no more than 50 copies of HIV per milliliter (mL) of blood over a period of at least 1 to 2 years despite never having taken antiviral medications. Some elite controllers have contained HIV at that low level for decades. In contrast, most HIV-infected individuals have between 10,000 and 1 million copies of HIV/mL before they start treatment. The higher the level of HIV, the more likely the person will develop disease and progress toward AIDS.
Elite controllers are of great medical interest. Their immune systems may inform the design of an HIV vaccine that suppresses virus replication and may reveal which cellular activities should be measured as markers of success in participants of HIV vaccine clinical trials.
Mark Connors, M.D., head of the HIV-Specific Immunity Section of NIAID's Laboratory of Immunoregulation, has studied elite controllers for 15 years to unveil the clues their immune systems possess. He first identified these remarkable individuals during his work on virus-specific immunity in the early 1990s. Among participants in his study at that time, "there were a few people who had this inexplicable level of control of HIV," he recalls. "We suspected that they were somehow different." In experiments with specialized mice containing transplanted human cells where HIV replicates, Dr. Connors and his colleagues demonstrated that certain immune-system cells from the HIV controllers mediated control of the virus in the mice. That finding led him to focus on determining how controllers' immune cells were keeping the virus at bay.
Since then, hundreds of scientists -- many in collaboration with Dr. Connors -- have attempted to uncover the mechanism or mechanisms behind HIV control. Most have concluded that biological characteristics of elite controllers, not a quirk of the virus, are responsible. But identifying the factors at work is an extremely complex task because the bodies of elite controllers appear to employ different combinations of tactics to suppress HIV.
Pursuing the Keys to HIV Control Dr. Connors' group focuses on immune-system cells known as CD8+ T cells, also called "killer" T cells. As their name implies, killer T cells hunt down infected cells and destroy them. Our bodies have billions of killer T cells, but only a relatively small number can identify any one particular disease-causing microbe.
To understand the unique characteristics of HIV-specific killer T cells in elite controllers, Dr. Connors, staff clinician Stephen Migueles, M.D., and their coworkers are comparing the immune functions of controllers with the immune functions of two groups of chronically HIV-infected people who cannot control the virus naturally -- people known as "progressors" or "non-controllers." One group of progressors has not started antiretroviral treatment, while the members of the other group take antiretroviral drugs that have reduced their viral loads to levels similar to those of controllers. All these study participants, including David and 49 other elite controllers, come to NIAID from around the country once every 6 months for medical checkups and to donate white blood cells and plasma, the liquid part of blood.
"It's really gratifying to find a research study and people who [are trying] to figure out the mechanism of what's going on that allows me to be different," says David, who learned about the study through an online chat on an AIDS-focused Web site. (Volunteers continue to be recruited.)
Controllers and untreated progressors initially have comparable proportions of HIV-specific killer T cells relative to the total number of T cells in their blood. Yet in the controllers Drs. Connors and Migueles have studied, HIV-specific killer T cells have unique qualities that enable them to destroy HIV-infected cells.
For instance, in controllers, once an HIV-specific killer T cell detects an HIV-infected cell, the killer T cells quickly multiply. In progressors, however, they don't. In fact, controllers have 20 times more HIV-specific killer T cells than treated progressors.
Also, in the presence of HIV, controllers' HIV-specific killer T cells boost production of a molecule called perforin that pokes holes in HIV-infected cells, creating entryways for other molecules that program the infected cells to die. This boost in perforin production doesn't happen in progressors.
Furthermore, when molecules on the surface of HIV-infected CD4+ T cells -- the chief immune-system cells that HIV uses to replicate itself -- present pieces of chopped-up viral proteins to the immune system, the HIV-specific killer T cells of most controllers home in on a limited number of protein fragments presented by just one molecule. In contrast, progressors' HIV-specific killer T cells respond to 15 to 20 different protein fragments presented by a range of molecules on CD4+ cells, yet more is not better.
In addition, the killer T cells of controllers tend to be better "multitaskers" than those of progressors because they send out a greater variety of chemical messengers in larger quantities. This characteristic is called polyfunctionality.
In collaboration with Dr. Connors' group, Richard Koup, M.D., of the immunology laboratory in NIAID's Vaccine Research Center, identified polyfunctionality in both killer T cells and CD4+ T cells. Interestingly, Dr. Koup has found polyfunctionality to be a common thread across multiple viral infections controlled by the human immune system. "The more polyfunctional your T cells, the better the virus is controlled," he says, "or the better the virus is controlled, the more polyfunctional your T cells." More research is needed to determine whether polyfunctionality is a cause or an effect of low viral levels.
Dr. Connors is also investigating cause and effect of the proliferation of killer T cells and their accelerated production of perforin -- normal biological activities of healthy immune systems in response to a pathogen. Dr. Connors' group has demonstrated that using HIV medications to lower progressors' virus levels to the same point as that of elite controllers does not stimulate HIV-specific killer T cells to proliferate or to make more perforin. This indicates that progressors' HIV-specific killer T cells have a defect that persists even in the presence of low levels of HIV. But proving that the proliferation of HIV-specific killer T cells and their ramped-up production of perforin are actually driving forces behind HIV control will require more research. Dr. Connors says his group is gradually beginning to develop animal models to test this hypothesis. If he can prove causation in an animal, his work will suggest that stimulating killer T cells to proliferate and boost production of perforin may be part of the recipe for a vaccine or therapeutic that would help some people maintain low levels of HIV.
Many elite controllers who volunteer in studies like those of Dr. Connors relish the opportunity to contribute to scientific understanding of HIV and AIDS. "It's one of the most amazing things I've ever been involved with," says David, who enrolled in the NIAID study in 2006. "I wish that I'd gotten involved earlier." Some elite controllers are willing to go so far as having a spinal tap or a gut-tissue biopsy to help HIV/AIDS researchers investigate unanswered questions. As far as David is concerned, "I'm just really glad there are peoplewho are willing to dedicate their lives to doing this research."
References MR Betts et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107(12):478189 (2006). SA Migueles and M Connors. The role of CD4(+) and CD8(+) T cells in controlling HIV infection. Current Infectious Disease Reports 4(5):46167 (2002). SA Migueles et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nature Immunology 3(11):106168 (2002). SA Migueles et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV infected long term nonprogressors. Proceedings of the National Academy of Sciences 97(6):270914 (2000). This article was featured in the spring 2008 issue of NIAID Discovery News.
Is it possible never to be on Meds (ELITE CONTROLLERS) Aug 19, 2007
Hello Dr Bob,
Is it poosible (or have u ever heard of someone) that is POZ and have never been on Meds or needed meds. I am POZ. I have been POZ for a year. My T-Cell is 860 with undectable Viral. I guess I am holding on to hope I will never need meds. Is it possible?
Response from Dr. Frascino
Is it "poosible?????" Considering Dubya and Voldemort (I mean Cheney) were reelected, I assume anything is "poosible!"
Seriously, yes, it is possible. A small number of poz-people have remained healthy and not shown the usual slow immunological decline associated with HIV/AIDS. We call these folks "elite controllers." See below. We also call them damn lucky! Will you be one of them? Time will tell. I certainly hope so!
No Meds (ELITE CONTROLLERS) Jul 27, 2007
I have been positive since 1992, and monitor my numbers religiously. I doubt that since this is a drug sponsored site this will ever be published, but it would be doing a service to note that NOT being on meds is what has kept me alive - as I watch others shrink, bloat and pop -- wishing they had never either. Also, what is the proposed co-factor along w/ HIV (as put forth by Montagnier - who believes HIV is not enough). BTW, my highest CD4 counts (non-blips) have occurred in the 14th year of infection and have remained range cound throughout.
Response from Dr. Frascino
As you can see, your doubts that your comments would be posted are unwarranted. Yes, the site does have some pharmaceutical company sponsorship (otherwise it wouldn't be able to function as a free service to all in need), but I can assure you I do not! The experts here present scientifically-sound information not product marketing!
Next, I'm delighted you are doing well never having taken medications. Although I have no idea what ". . . have remained range cound throughout" means, it appears that you may be one of the extremely small and very lucky HIVers who we call "elite controllers" or "non-progressors." We are actively studying such folks to gain additional information as to why HIV has not progressed in cases like yours. (See below.)
As for others who "shrink, bloat, and pop . . . ," I certainly will admit taking HIV meds is no picnic and the side effects can be challenging. However, please note that these medications are for many of us absolutely live saving. I have no doubt I would not be here today responding to your question without them! The miraculous decline in HIV/AIDS morbidity and mortality that occurred simultaneously with the introduction of HAART (highly active antiretroviral therapy) in mid-1996 cannot be denied. So even though you have done well not taking medications, please don't be so presumptuous as to assume those of us who did "wish we never had!" I can assure you that is not the case!
Finally, Montagnier's cofactor concept dates back to the early 1990s. That's ancient history in HIV/AIDS terms! We have learned much since then about HIV pathogenesis. I suggest you spend some time perusing the wealth of information on this site! You have much to learn!
Who Are the Elite Controllers?
By Bob Huff
Who are the elite controllers? No, they're not initiates of Yale's secretive Skull and Bones Society or members the Trilateral Commission. Elite controllers are people infected with HIV who have been able to suppress their virus without using antiretroviral medications. And Dr. Bruce Walker of Boston wants to meet them and find out how they do it. It's been appreciated for many years that some people with HIV do not progress to AIDS at the same pace as most. Typically, the immune damage of untreated HIV infection will lead to life threatening opportunistic infections within eight to 12 years. But some people have been infected for 20-25 years or more and have not yet experienced the severe loss of CD4 immune cells that signals AIDS.
These people have been termed long-term nonprogressors, and in the mid 1990s, researchers began studying them to try to understand why some people progressed to disease and others didn't. The ultimate hope was that whatever protective qualities these people carried naturally could be stimulated in everyone. There are also other long-term survivors of AIDS who have experienced immune damage but have managed to thwart the virus with treatments, although these people may also have had help from their immune system or a genetic resistance to HIV.
For Walker and colleagues at the Partners AIDS Research Center who are coordinating the study, duration of infection is not the main criterion; they are looking for anyone who can control their HIV without drugs. Elite controllers are defined as people with asymptomatic HIV infection not taking antiretroviral therapy (ART) who have experienced at least one year with HIV RNA below 50 copies/mL (undetectable). Participants must have at least three sets of test results documented within one year. Occasional viral load blips up to 1,000 copies/mL are allowable.
Walker estimates that there may be 1,500 or more elite controllers in the United States. The research group has already collected blood from over 100 people and has set a target of enrolling 1,000 elite controllers into the study. They are also interested in finding a similar group of people with asymptomatic HIV infection who, while not undetectable, do manage to keep their HIV RNA levels under 2,000 copies/mL without drugs. Walker calls these people, who may be much more common, viremic controllers. A long list of prominent HIV physicians have signed up to scout for elite controllers, but individuals who think they fit the criteria can contact Walker's group in Boston directly to submit a blood sample.
The study plans to use gene sequencing techniques of the Human Genome Project to construct a haplotype map for each participant, in hopes of identifying genetic factors that may be contributing to their ability to control HIV infection. A haplotype map allows scientists to look for variations in genes as they are commonly organized on the chromosomes. Advanced data analysis will evaluate if multiple gene variants are possibly associated with spontaneous control of HIV. Genetic sequencing and data analysis will be performed at the Broad Institute in Boston. Additionally, high resolution HLA typing will be conducted to look for genetic differences in these immune markers, and adaptive immune responses and antibody studies will also be performed. The entire genome of each person's virus will also be sequenced to see if some viruses are more controllable than others.
These new genetic tools allow researchers to take the closest look yet at what might make those lucky few who can control their HIV without drugs different from everyone else. If they can uncover some previously unrecognized protein or mechanism that is common to all elite controllers, then the next step will be to look for a drug than can safely produce the same effect in everybody else.
Researchers to Study HIV-Positive "Elite," "Viremic Controllers"
August 17, 2006
Researchers on Wednesday at the XVI International AIDS Conference in Toronto announced plans to conduct a collaborative study on HIV-positive "elite controllers" and "viremic controllers," the Washington Post reports (Brown, Washington Post, 8/17). Elite controllers are HIV-positive people whose immune systems for long periods of time have been able to keep the virus at undetectable levels without using antiretroviral drugs. Viremic controllers are HIV-positive people whose immune systems have kept the virus at barely detectable levels without antiretrovirals. Researchers believe it is unlikely that elite or viremic controllers can transmit the virus (Kaiser Daily HIV/AIDS Report, 7/6). Bruce Walker, director of Partners AIDS Research Center at Massachusetts General Hospital, and colleagues already have enrolled 200 elite controllers in a study, and the researchers in the next six months plan to enroll 1,000 more elite and 1,000 viremic controllers, Toronto's Globe and Mail reports (Abraham, Globe and Mail, 8/17). The researchers plan to compare genetic sequences of the elite participants with other HIV-positive people, as well as HIV-negative people, to determine whether there are genetic variations that can explain why elite and viremic controllers can suppress the virus (Fox, Reuters AlertNet, 8/16). Researchers need to enroll at least 1,000 elite controllers, so that their genetic findings can have significance, the San Francisco Chronicle reports (Russell, San Francisco Chronicle, 8/17). "We're looking at people whose bodies durably live with HIV without it causing a problem," Walker said (Chase, Wall Street Journal, 8/17). "If we could discover how these individuals can coexist with this virus without damage to their immune system and could find a way to replicate that ability in others, we would have a recipe for halting the HIV epidemic," Walker said, adding, "There is a reasonable chance we will come up with something very important with this" (Globe and Mail, 8/17). He also said that while researchers are "excited about the possibilities," they "realize this might not lead to any breakthroughs" (Wall Street Journal, 8/17). Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, on Wednesday said that it is too early for optimism but that the research could be promising. "I believe we should get out and study elite controllers, but we should be conservative in what we expect from this research," Fauci said, adding, "This is still a very problematic and enigmatic virus." The study was funded by a $2.5 million grant from the Mark and Lisa Schwartz Foundation (San Francisco Chronicle, 8/17).
Los Angeles Times Examines HIV-Positive "Controllers," Studies, Research Difficulties
July 6, 2006
The Los Angeles Times on Thursday examined HIV-positive "elite controllers" -- people whose immune systems for long periods of time have been able to keep HIV at undetectable levels without using antiretroviral drugs -- and "viremic controllers" -- HIV-positive people whose immune systems have kept the virus at barely detectable levels without using antiretrovirals -- and the difficulties of conducting research on such individuals. According to the Times, elite controllers are "extremely rare" and account for about one-third of 1%, or about 2,000, known HIV-positive people. Researchers believe it is "unlikely" that elite or viremic controllers can infect others with HIV, the Times reports. "I would say we still don't have the faintest idea why these people are doing as well as they are," Bruce Walker, director of Partners AIDS Research Center at Massachusetts General Hospital, said, adding, "Achieving the state that these guys have reached in their bodies -- if we could do that through some intervention, we would solve the AIDS epidemic."
Studies To learn why and how HIV remains at extremely low levels in controllers, researchers are studying both the innate immune system -- which provides a "general response" that immediately activates to "dismantle" incoming pathogens -- and the adaptive immune system -- which is a longer-term response that relies heavily on antibodies, including CD4+ T-cells -- according to the Times. Steven Deeks of the University of California-San Francisco and colleagues assembled a group of 50 elite controllers to analyze their adaptive immune systems and found that half of the controllers fought the virus through a "powerful response by T-cells," and the other half showed no T-cell response, the Times reports. "The 25 people in our cohort who have no T-cell reaction can provide insight into whole new ways of thinking," Deeks said, adding, "There are 25 guys who have no reason for controlling the virus." In a related study, Jay Levy of the University of California-San Francisco and colleagues focused on the infection-fighting tools of the innate immune system to identify antiviral proteins found in controllers, the Times reports. Controllers show that the immune system is able to contain HIV naturally, Levy said, adding, "This has been a long time coming, but in my opinion we can look forward to long-term survival without toxic drugs."
Research Difficulties Some researchers believe that controllers are able to contain HIV because the strain of the virus with which they are infected is defective, the Times reports. To study every controller for defective HIV would be "prohibitively expensive," Deeks said, adding that if such a study were initiated, the idea would be "to see if the virus is there and if it is defective, because, in theory, that virus will give good insights into making an effective vaccine." Another problem with studying controllers is that there are not enough of them to assemble local cohorts large enough to study effectively, the Times reports. Walker and his research team at Massachusetts General Hospital have assembled 76 elite controllers and 100 viremic controllers from across the country to participate in a new study. "Basically, we want to recruit every single one of these people in the [U.S.]," Walker said, adding, "We have to have a large enough sample to begin to see patterns in this population" (Ricci, Los Angeles Times, 7/6).
elite controllers Jul 12, 2007
Hello Dr Bob you are one funny guy.. Re elite controllers . assuming low or undetectable viral load does antibody test always present positive? Thank you for your response and all the best.
Response from Dr. Frascino
Would that be "funny" as in funny Ha! Ha! or "funny" as in severely twisted individual??? Oh, all of the above!?! I see. Well OK then, I'll answer your question.
Even with undetectable viral loads, elite controllers would always test HIV-antibody positive. (If they didn't, we'd never know they were HIV infected or they were controlling anything, elite or not.)
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