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New results on HIV reservoirs

HI viruses can persist in reservoirs for years in the human body. They are the biggest obstacle to the cure of HIV but are still under-researched. In the world's largest longitudinal observational study on HIV reservoirs, a research team from the University Hospital Zurich has gained new insights into these reservoirs.

So far the largest study evaluates blood samples from 1,057 people

HI viruses can persist in reservoirs for years in the human body. They are the biggest obstacle to the cure of HIV but are still under-researched. In the world's largest longitudinal observational study on HIV reservoirs, a research team from the University Hospital of Zurich has gained new insights into these reservoirs.

The reservoirs develop rapidly after HIV infection and last for decades of ART treatment. Those skilled in the art agree that healing of HIV infection must target these viral reservoirs and either significantly reduce or, at best, eliminate the latent infected cells. However, the reservoirs are not yet fully explored. Although it is known that their size decreases after the start of ART, smaller studies have shown that the size of the reservoirs can change greatly, individually and over time, even under an ongoing ART.

However, due to the relatively small numbers of study participants and the relatively short duration of studies as well as the limited number of co-factors studied, these studies have not yielded a comprehensive picture of the factors influencing size and changes over time under ART.

Highly differentiated and long-term observation of the reservoirs

Nadine Bachmann and her colleagues from a multidisciplinary national research team led by HIV specialist Prof. Dr. med. Huldrych Günthard, Prof. Roger Kouyos and Prof. dr. Karin Metzner from the Department of Infectious Diseases and Hospital Hygiene at the USZ, have now examined in the largest longitudinal observational study so far, how the size of the reservoir changes in the long term and which factors influence the changes or the size of the reservoirs.

For this purpose, the research team used extensive series of tests to evaluate blood samples and the associated data from 1

,057 people who had been successfully treated with ART for many years. They were able to rely on the Swiss HIV Cohort Study (SHCS) with their comprehensive biobank. This prospective cohort study, which has been running since 1988, covers approximately 75 percent of all HIV-infected people in Switzerland who receive antiretroviral therapy and make their data and blood samples available for research. Thanks to this collection, each of the 1,057 people had at least three samples available for the measurement of HIV reservoirs taken on average 1.5, 3.5 and 5.4 years after the start of ART. Of 412 people, data were available that allowed the history of HIV reservoirs to be traced back to ten years.

Comprehensive clinical, viral-genetic, demographic, behavioral, and therapeutic data enabled a multitude of potential reservoir-influencing factors to be investigated simultaneously in multivariable statistical models. "Our study captures ten times more subjects than the largest comparable study to date and allows for more robust statements," explains Huldrych Günthard the large volume of data analyzed.

So far hardly noticed "Blips" prove to be relevant

On average, there was a decrease in reservoir size during the first 5.4 years after the onset of ART with an estimated half-life of 5.6 years. Over the observation period, the waste of the reservoirs flattened significantly and seemed to equalize to a plateau. Contrary to expectations, despite successful antiretroviral therapy, there was no decrease in 281 persons (26.6%) but an increase in the size of the reservoirs. "This is a surprising and important finding, but we do not yet know what will lead to this increase," says Günthard. "Possibly, latent infected cells divide, or in some patients the HI viruses still proliferate despite the ART, which could lead to increased reservoirs in the longer term."

Targeted studies are in the planning stage. The lack of patient adherence to this effect could be largely ruled out: "The SHCS has excellent, validated data that also document compliance and treatment interruptions."

If the therapy had started within the first year after the HIV infection and the viral load was low at this time, the reservoirs were also deep 1.5 years after the start of therapy. This observation confirms the results of previous studies of other groups. What was new, however, was that viral "blips" are associated with larger reservoirs and with a smaller drop in them over time. So far, these blips were considered clinically not or hardly relevant. The study shows, however, that these are of biological importance. Furthermore, deeper HIV reservoirs were found in people of non-white ethnicity.

"For HIV research, studies leading to a better understanding of reservoirs and studies that test strategies for elimination of all HI viruses from infected patients have been a top priority to get closer to our goal of curing HIV "explains Huldrych Günthard. "The results of our study show that reservoir behavior is still poorly understood, and our findings on the role of blips have demonstrated that proof of concept elimination studies should be done with carefully selected patients because we otherwise may miss important effects for research. "

Nadine Bachmannn, Chantal von Siebenthal, Valentina Vongrad et al., [Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART]. Nature Communications, https://doi.org/10.1038/s41467-019-10884-9

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