Elite controllers: A potential model for a functional HIV cure?

In 2014, about 36 million people were living with HIV/AIDS worldwide, and an estimated 2 million people were newly infected, according to WHO. Despite decades of intensive research, an HIV cure or vaccine remains elusive.

However, there is hope found in a tiny subset of patients who are able to control virus replication without medication. Dubbed long-term nonprogressors, they typically maintain CD4 T-cell counts of 500 copies/mL. Elite controllers are an even smaller subgroup, comprising less than 1% of all patients with HIV. They maintain HIV levels — typically less than 50 copies/mL — that are nearly undetectable by the commercial assays currently in use.

“Somehow, these patients are able to spontaneously inhibit and suppress HIV replication,” Mathias D. Lichterfeld, MD, an infectious disease physician at Brigham and Women’s Hospital in Boston, told Infectious Disease News. “In many cases, that’s apparently done by immune-based mechanisms.”

Photo courtesy of Elaine Yu

Researchers are scrambling to learn about the immune systems of this unique group of patients in the hope of finding a pathway to an HIV vaccine or a functional HIV cure.

Living model of HIV control

“These patients are really the best type of human model that we can use to understand how the immune system is able to control HIV,” Lichterfeld said. “In addition, these patients are important for understanding how it may be possible to induce some type of condition that comes close to a cure of HIV. These patients are providing living evidence that, at least in principle, the human immune system is able to control HIV, and provide an opportunity to figure out what exactly is contributing to it.”

Elite controllers have features that set them apart from other patients with HIV. They “tend to have specific genetic characteristics, powerful HIV-specific immune responses, and highly activated immune systems,” Trevor A. Crowell, MD, PhD, infectious disease specialist at Johns Hopkins Hospital and research physician with the U.S. Military HIV Research Program, told Infectious Disease News. “Some of these factors contribute to this group’s unique ability to control HIV without medications, but they may have negative side effects as well.”

For instance, because they have such low levels of HIV replicating in the blood, elite controllers can maintain stable CD4 and CD8 T-cell counts without medicine. They also have lower levels of AIDS-defining infections.

While some patients will lose this control over time and require ART, many patients maintain their status for long periods.

“I’d say in our group, most of them have retained their status over many years,” Christopher W. Woods, MD, MPH, Infectious Disease News Editorial Board member and professor of medicine and global health at the Duke Global Health Institute. Of the 400 to 500 patients with HIV at his VA facility, Woods and colleagues have been monitoring three to five elite controllers over the years.

Researchers are still learning how elite controllers are able to suppress virus replication. Many believe that the predominant reasons explaining why elite controllers can control HIV is their superior T-cell–mediated immunity, according to Lichterfeld.

Role of dendritic cells

Recent research has demonstrated that innate and cell-intrinsic immune activities also may be important. Specifically, dendritic cells — part of the innate human immune system — may help explain an elite controller’s immune response.

“It looks like the dendritic cells have increased abilities to recognize HIV and to build immune responses against HIV,” Lichterfeld said. “That could explain why there is better T-cell immunity in elite controllers.”

Perhaps the best evidence on immune control of HIV is focused on CD8 T cells, according to Jonathan Z. Li, MD, MMSc, assistant professor of medicine at Harvard Medical School. “Elite controllers have an ability to control HIV proliferation and inhibit HIV replication in the laboratory setting,” he said during an interview.

According to Li, host genetics may be an important factor in understanding why elite controllers have this ability. “It has been shown that certain HLA alleles, including protective HLA alleles like HLA-B57 and B27, are enriched in the HIV-controller population,” Li said.

Through a series of ex vivo experiments, Lichterfeld and colleagues recently found that paradoxically, HIV-1 reverse transcription in dendritic cells from elite controllers is more effective than in dendritic cells from patients with progressive disease, likely because of reduced expression of the host protein SAMHD1. However, this higher susceptibility of dendritic cells to HIV-1 infection in elite controllers may allow these patients to sense HIV-1 infection at an early stage and to stage a more effective antiviral immune response.

Still, much more study is needed. “The immune system is very complex,” Lichterfeld said. “It’s a systems-level interaction between multiple different components of the immune system that will likely be important. I believe looking at it from a comprehensive perspective and evaluating multiple different components of the immune system simultaneously in these patients might be helpful.”

The research so far has made it clear that these patients are not simply facing a weaker or mutated version of HIV; the difference is immunological. “Evidence has come out that it’s the individual, it’s their immune characteristics that dictate whether you’re an elite controller or not, as opposed to it being a function of the virus with which someone is infected,” Crowell said.

Protection at a significant price

Elite controllers have long been considered a very special patient population who are at low risk for clinical disease.

However, the protection against HIV progresion seems to come at a high price, according Li. For example, elite controllers have increased rates of inflammation.

“Despite the fact that elite controllers can suppress the virus to very low levels, they’ve been found to have higher levels of T-cell activation, soluble markers of inflammation,” Li said. Sustained high levels of inflammation can lead to non-AIDS–related complications, such as cardiovascular disease.

In their study, Li and colleagues compared 42 elite controllers from the International HIV Controllers Study with two other cohorts: 80 HIV-suppressed, nonelite controllers and 43 HIV-negative participants. The researchers identified significant differences between the cohorts in 15 soluble inflammatory markers. Furthermore, the elite controllers had the highest levels in all but one inflammatory marker. Their findings suggested that median levels of seven markers — sCD14, IP-10, IL-4, IL-10, sCD40L, IFN-gamma and GM-CSF — were double that seen in the other cohorts.

There are a few reasons why elite controllers may have increased inflammation. “I think that the presence of the virus [and] the interplay of their strong immune system ... together is also leading to some of these higher levels of inflammation,” Li said.

The inflammation may be attributable to elite controllers’ unique genetics, according to Crowell. Or it could be partially disease-related; HIV attacks the lining of the gastrointestinal system, which generates inflammation, he said.

It is important to consider these patients’ other cardiovascular risk factors as well, according to Infectious Disease News Chief Medical Editor Paul A. Volberding, MD, director of the AIDS Research Institute at the University of California, San Francisco.

“The number of elite controllers is small, so that the studies that show perhaps some increased cardiovascular disease need to be taken with a grain of salt. We want to be sure that their other cardiovascular risk factors are being appropriately managed,” Volberding said. “My own guess is that the low level of virus ... might increase their inflammation markers enough to give them some of these other complications.” However, it remains important to control for the other risk factors, including smoking, exercise and lipid management, he said.

Another problem linked to elite controller status is increased hospitalization risk. Crowell and colleagues compared hospitalization rates and causes for elite controllers and patients with ART-controlled HIV. Their study included 149 elite controllers, making it one of the largest studies of its kind, he said. They found that elite controllers were hospitalized more frequently, and the typical driver of hospitalization was cardiovascular disease.

ART may benefit elite controllers

There is some debate on whether to initiate ART in elite controllers. Should they start therapy immediately after diagnosis or wait until their counts dip below a certain threshold? Currently, no clinical guidelines have been established; treatment decisions are made by the physician and the patient.

Offering elite controllers ART, however, is growing more popular. “More and more commonly, people are recommending antiretroviral therapy to elite controllers even though they don’t have measurable virus because we have seen this progression of CD4 loss,” Volberding said.

Evidence demonstrates that ART may further reduce HIV replication and ease chronic inflammation in elite controllers.

In the first prospective study of ART in 16 asymptomatic controllers, Hatano and colleagues found that treatment yielded significant decreases in plasma HIV RNA, rectal HIV RNA and markers of T-cell activation/dysfunction. They saw similar results in a subset of elite controllers. The researchers discovered that viral load could be further decreased with ART.

Li and colleagues hope to confirm the results of this study in a prospective trial, which they intend to complete next year. This study, which enrolled 38 patients, will assess how ART influences T-cell activation, CD4 counts, inflammatory markers and viral reservoir in treatment-naive elite controllers. Their hope is that ART will suppress inflammation and immune activation while diffusing the viral reservoir, Li said.

“Research is also showing the benefits of starting antiretroviral therapy earlier after infection than was previously the norm,” Crowell continued. “Patients started on ART within the first few weeks of infection, such as those in the RV 254 cohort, have very small reservoirs of latent virus and may be particularly good candidates for interventions to achieve HIV remission.”

According to Lichterfeld, patients who develop HIV-associated comorbidities such as lymphoma or kidney disease should start ART. “In those cases, where there’s evidence that HIV is causing active disease despite undetectable levels of HIV replication in the blood, there’s a very strong rationale for treatment,” he said.

Like any medication, however, ART is not risk-free. “It is important to counsel elite controllers about the possible risks and benefits of antiretroviral therapy,” Crowell said. “Currently available medications are safer and better tolerated than prior generations of therapies, so there are fewer risks associated with ART, and research is demonstrating more and more potential benefits.

Unforeseen consequence

Starting elite controllers on ART may have an unintended consequence: It may limit researchers’ ability to study elite controllers’ unique immune systems. “Moving forward, that’s something that you’re going to have to consider when you consent people to participate in clinical trials,” Crowell said. “I think as an individual physician treating an individual patient, my recommendation is typically going to be that we start antiretroviral therapy, but as a researcher hoping to learn the most that I can about elite control, there may be situations where I don’t want to start antiretroviral therapy.”

According to Volberding, treatment may change the elite controller in some fundamental way. “Presumably, an elite controller on treatment is different than an elite controller not on treatment,” he said.

The good news is that stopping ART does not seem to impact elite controller status, according to Li. “In Hatano’s study, she saw that those who stopped therapy pretty much went back to being controllers,” he said. “They did not lose viral control after stopping therapy.”

The key to an HIV cure?

Woods thinks elite controllers may offer a trove of information for researchers. “We learn the most in science, [and] how I tend to push my students, in particular ... is to spend time looking at the outliers, to where there are discordant results from what you’re expecting,” he said. “That will often give you more information than just the standard analyses.”

Thus far, elite controllers have taught researchers a great deal about the biology of HIV and about the immune system and how it controls the disease. Research has yielded some tantalizing clues that may aid vaccine development.

“I think by studying people who are able to control the virus themselves, we’re finding some circulating antibodies that are giving us hints about vaccine development,” Volberding said. “There’s a lot of research going on looking at what are called broadly neutralizing antibodies. Those are being looked at both in vaccine development and as part of some of the cure research that’s going on.”

Research on elite controllers may help uncover ways to manipulate the immune system to develop new medications or immunologic interventions, such as antibody infusions or gene therapies, according to Crowell.

But for now, an HIV cure remains just out of reach. “This is a puzzle that still needs to be solved,” Li said. “The study of HIV controllers has helped guide vaccine research. It’s still too early to say whether they are potentially the key to an HIV cure, but I think they hold a lot of promise.”

Even if elite control research leads to a functional cure or functional remission, ART will still be paramount, according to Crowell. “Our study about hospitalizations and other studies looking at inflammation and cardiovascular disease in elite controllers suggest that if we were to come up with an intervention that induced elite control, that’s still not as good as what ART is accomplishing,” he said. “We’re seeing better clinical outcomes with people who are prescribed ART than we’re seeing with people who are naturally elite controllers. Inducing an elite control state is a step in the direction of a cure, but it’s still not as good as medications.”

Woods said research on elite controllers should have far-reaching results. “We are encouraging collaborative science to be performed across many different groups now in a way that has not been encouraged previously,” he said. This means that work on a small population like elite controllers can occur at many sites simultaneously. The ability to analyze immune system variables like the proteome, the metabolome, host gene expression and the antibodyome, and “developing concurrently statistical techniques that help us look at those data, may ultimately be able to really decipher what the secret sauce is that makes up an elite controller.”

This collaborative model will have applications to other noninfectious, noncommunicable diseases as well, according to Woods. “I think this is a model for how we will look at many of these types of problems,” he said. – by Colleen Owens

• References:
• Crowell TA, et al. J Infect Dis. 2015;doi:10.1093/infdis/jiu809.
• Hatano H, et al. PLoS Pathog. 2013;doi:10.1371/journal.ppat.1003691.
• Leng J, et al. Cell Host Microb. 2014;doi:10.1016/j.chom.2014.05.011.
• Li JZ, et al. Open Forum Infect Dis. 2015;doi:10.1093/ofid/ofu117.
• Martin-Gayo E, et al. PLoS Pathog. 2015;doi:10.1371/journal.ppat.1004930.
• WHO. HIV/AIDS. Fact sheet No. 360. http://www.who.int/mediacentre/factsheets/fs360/en/. Accessed September 11, 2015.

• For more information:
• Trevor A. Crowell, MD, PhD, can be reached at Johns Hopkins University School of Medicine, 5200 Eastern Ave., Baltimore, MD 21224; email: trevor.crowell@jhmi.edu.
• Jonathan Z. Li, MD, MMSc, can be reached at Partners Research Building, 65 Landsdowne St, Rm 421, Cambridge, MA 02139; email: jli@bwh.harvard.edu.
• Mathias D. Lichterfeld, MD, can be reached at Brigham and Women’s Hospital, 65 Landsdowne St, Cambridge, MA 02139; email: mlichterfeld@partners.org.
• Paul A. Volberding, MD, can be reached at UCSF School of Medicine, 550 16th St, San Francisco, CA 94158; email: paul.volberding@ucsf.edu.
• Christopher W. Woods, MD, MPH, can be reached at the Duke Global Health Institute, 310 Trent Drive, Durham, NC; email: chris.woods@duke.edu.

Disclosures: Crowell, Lichterfeld, Volberding and Woods report no relevant financial disclosures. Li reports being a consultant for Merck and SeraCare Life Sciences and has received research funding from Gilead Sciences.

Should elite controllers be offered ART?

Elite controllers should be offered ART.

Elite controllers are HIV-infected individuals with the remarkable ability to maintain undetectable plasma HIV RNA for prolonged periods in the absence of ART. However, HIV is readily detectable in these individuals using more sensitive plasma- and tissue-based assays, and there are substantial data to suggest that this immune control is not without a “cost” to the host.

Elite controllers have elevated levels of CD4+ and CD8+ T-cell activation, markers of coagulopathy and microbial translocation, and increased lymphoid tissue fibrosis compared with HIV-uninfected individuals and in some cases, higher levels than HIV-infected persons on suppressive ART. Many of these markers, which are elevated in elite controllers, have been associated with an increase in comorbid conditions, such as cardiovascular disease and increased mortality in the HIV-infected population. Small studies have found that elite controllers have a higher prevalence of subclinical atherosclerotic disease as measured by carotid intima media thickness and CT angiography. Importantly, there is now evidence to support the hypothesis that these increased levels of immune activation and inflammation in elite controllers have clinical consequences. A recent study by Crowell and colleagues found that even after adjusting for demographic and clinical factors, elite controllers had higher rates of hospitalization than HIV-infected individuals on ART. Cardiovascular hospitalizations were the most frequent cause of admission in elite controllers.

Whether ART by itself will reverse all of these effects is less clear. However, two very small, single-arm studies have shown that ART can reduce markers of immune activation in elite controllers. Furthermore, given the improved side effect profiles and ease of dosing of many ART regimens, there are less downsides to therapy now than ever before. Nonetheless, larger, controlled clinical trials should be done to more definitively answer this question, and an AIDS Clinical Trials Group study is currently underway (NCT01777997). However, we should not wait for those data to recommend what we think is best for our patients now, just in the same way that many of us treated our patients with higher CD4 counts prior to the recent START study results.

Leslie R. Cockerham, MD, MAS, is an assistant professor of infectious disease at the Medical College of Wisconsin. She can be reached at the Medical College of Wisconsin, 9200 W. Wisconsin Ave., Suite 5100, Milwaukee, WI 53226. Disclosure: Cockerham reports no relevant financial disclosures.

• References:
• Chun T-W, et al. J Infect Dis. 2013;doi:10.1093/infdis/jit306.
• Crowell TA, et al. J Infect Dis. 2015;doi:10.1093/infdis/jiu809.
• Hatano H, et al. PLoS Pathog. 2013;doi:10.1371/journal.ppat.1003691.
• Hunt PW, et al. AIDS. 2011;doi:10.1097/QAD.0b013e32834c4ac1.
• Hunt PW, et al. J Infect Dis. 2008;doi:10.1086/524143.
• Hunt PW, et al. PloS One. 2011;doi:10.1371/journal.pone.0015924.
• Hsue PY, et al. AIDS. 2009;doi:10.1097/QAD.0b013e32832b514b.
• Kelesidis T, et al. J Infect Dis. 2012;doi:10.1093/infdis/jis545.
• Krishnan S, et al. J Infect Dis. 2014;doi:10.1093/infdis/jit581.
• Kuller LH. PLoS Med. 2008;doi:10.1371/journal.pmed.0050203.
• Pereyra F, et al. AIDS. 2012;doi:10.1097/QAD.0b013e32835a9950.
• Sanchez JL, et al. J Infect Dis. 2015;doi:10.1093/infdis/jiu586.
• Sandler NG, et al. J Infect Dis. 2011;doi:10.1093/infdis/jiq118.

It is unknown if immediate ART initiation will reduce HIV-associated morbidity.

The primary goals of HIV therapy are to “reduce HIV-associated morbidity and prolong the duration and quality of survival, restore and preserve immunologic function, maximally and durably suppress plasma HIV viral load and prevent HIV transmission,” according to national guidelines. HIV elite controllers are by definition capable of preserving immunologic function and durably suppressing plasma HIV viral load without HIV therapy. It can be argued that elite controllers do suffer morbidity related to HIV with increased coronary atherosclerosis secondary to chronic inflammation and may also have higher levels of health care utilization compared with HIV-infected persons on ART. There may also be evidence that elite controllers contribute to the ongoing HIV pandemic with forward transmissions.

On the other hand, the literature reports that elite controllers have experienced spontaneous resolution of HIV-associated nephropathy, viremic control following superinfection and maintenance of viremic control even in the setting of HIV-1 dual infection, both states which are associated with rapid immunologic decline. It also remains unclear if elite controllers achieve any additional immunologic benefit from ART with several studies demonstrating conflicting data.

With the advent of simpler and less toxic ART regimens (specifically the integrase inhibitors and the soon-to-be-available tenofovir alafenamide [Gilead Sciences]), the argument for immediate treatment of elite controllers is compelling. In fact, current guidelines do recommend treating all HIV-infected individuals. However, it still remains unknown whether immediate antiretroviral treatment of elite controllers will reduce HIV-associated morbidity or prevent transmission of HIV. Thus, for each individual patient, clinicians should weigh the possible benefits of ART against the potential risks of treatment fatigue, medication off-target effects and drug interactions, and out-of-pocket costs.

Maile Ann Young Karris, MD, is an assistant professor of medicine at the University of California, San Diego. She can be reached at the University of California, San Diego, 200 W. Arbor Drive #8208, San Diego, CA 92103-8208; email: m1young@ucsd.edu. Disclosure: Karris reports no relevant financial disclosures.

• References:
• Blankson JN, et al. AIDS. 2011;doi:10.1097/QAD.0b013e3283458805.
• Boufassa F, et al. PloS One. 2014;doi:10.1371/journal.pone.0085516.
• Crowell TA, et al. J Infect Dis. 2015;doi:10.1093/infdis/jiu809.
• Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. https://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_9.pdf. Accessed September 11, 2015.
• Gottlieb GS, et al. Lancet. 2004;363:619-622.
• Grabar S, et al. AIDS. 2009;doi:10.1097/QAD.0b013e32832b44c8.
• Hatano H, et al. PLoS Pathog. 2013;doi:10.1371/journal.ppat.1003691.
• Hubert JB, et al. AIDS. 2000;14:123-131.
• Killian MS, et al. J Med Case Rep. 2012;doi:10.1186/1752-1947-6-291.
• Okulicz JF, et al. Clin Infect Dis. 2010;doi:10.1086/651421.
• Olson AD, et al. PLoS One. 2014;doi:10.1371/journal.pone.0086719.
• Pereyra F, et al. AIDS. 2012;doi:10.1097/QAD.0b013e32835a9950.
• Pernas M, et al. J Acquir Immune Defic Syndr. 2013;doi:10.1097/QAI.0b013e31829bdc85.
• Rachinger A, et al. Clin Infect Dis. 2008;doi:10.1086/592978.
• Streeck H, et al. J Exp Med. 2008;doi:10.1084/jem.20080281.

Not enough data to support major risks, benefits of ART in elite controllers

HIV-infected elite controllers, ie, untreated individuals with most viral loads undetectable and no viral loads above 1,000 copies/mL, constitute less than 0.5% of patients in care. Observational studies have suggested that untreated elite controllers have higher rates of atherosclerosis and hospitalization related to cardiovascular disease compared with individuals on ART. Evidence that elite controllers have elevated levels of monocyte activation and inflammatory markers compared with individuals treated with ART combined with the well-established association between immune activation and cardiovascular events seen in the SMART study suggest a mechanism by which such increased rates of events could be occurring in elite controllers. Nevertheless, there are perils in extrapolating from observational data, and even after controlling for many factors, it is possible to get the wrong answer.

Unfortunately, given the small number of elite controllers, it is unlikely that a randomized clinical trial with concrete clinical endpoints will ever be performed to definitively address this question. Smaller studies to look at the effects of ART on inflammatory markers in elite controllers are in progress, and should provide suggestive, although not conclusive, data.

As physicians, we make decisions daily that are not based on randomized controlled clinical trial data, since many of our patients differ from the populations in which drug trials were performed. Elite controllers are another patient population for which we need to make clinical decisions in the absence of concrete data.

In my practice, I offer ART to all HIV-infected patients, although in the case of an elite controller I would explain that we do not have strong evidence to support either a major benefit or a major risk of ART. In the case of elite controllers who have additional risk factors for CVD besides HIV-1 infection, and particularly those with overt CVD, I urge them to consider ART, with the caveat that we do not have definitive proof that it will help, but only circumstantial evidence. As more data become available, my approach could change.

Elizabeth Connick, MD, is an Infectious Disease News Editorial Board member and professor of infectious diseases at the University of Colorado Denver. She can be reached at the University of Colorado Denver, 12700 E 19th Ave, Aurora, CO 80045; (303) 724-4930; email: Liz.Connick@ucdenver.edu. Disclosure: