Elite controllers as model for potential HIV cure

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

However, writes Dr Elizabeth Connick, professor of infectious diseases at the University of Colorado, Denver, in an Infectious Diseases News report, there is hope found in a tiny subset of patients who are able to control virus replication without medication. Dubbed long-term non-progressors, 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,” Connick quotes Dr Mathias D Lichterfeld, an infectious disease physician at Brigham and Women’s Hospital in Boston, as saying. “In many cases, that’s apparently done by immune-based mechanisms.”

Connick writes that 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. “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,” says Dr Trevor A Crowell, infectious disease specialist at Johns Hopkins Hospital and research physician with the US Military HIV Research Programme in the report. “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,” Dr Christopher W Woods, professor of medicine and global health at the Duke Global Health Institute said in the report. 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.

Connick notes that according to Lichterfeld, 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. HIV-infected elite controllers (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, says Connick, there are perils in extrapolating from observational data, and even after controlling for many factors, it is possible to get the wrong answer. Unfortunately, she writes, given the small number of elite controllers, it is unlikely that a randomised 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.

She says as physicians, “we make decisions daily that are not based on randomised 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.”

Full Infectious Disease News report

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