Human immunodeficiency viruses can survive in reservoirs for years in the human body. They are the biggest obstacle to the cure of HIV but still need extensive research. In the world's largest longitudinal observational study of HIV reservoirs, a team of researchers from the University Hospital of Zurich (German acronym USZ) has gained new insights into these reservoirs.
The reservoirs form rapidly after HIV infection and survive decades of treatment with antiretroviral therapy (ART). Experts agree that the cure of an HIV infection must start with these viral reservoirs and either significantly reduce or - in the best case - eliminate the latently infected cells in them. However, the reservoirs have not yet been extensively investigated. It is known that their size decreases after the start of ART, and smaller studies have shown that the size of the reservoirs can change considerably individually and over time, even during ART.
However, due to the relatively small number of study participants, the relatively short duration of the study and the limited number of co-factors studied, these studies have not yet provided a comprehensive picture of the factors that influence the size and changes over time under ART.
Nadine Bachmann and her colleagues from a multidisciplinary national research team headed by HIV specialists Prof. Dr. Huldrych Günthard, Prof. Dr. Roger Kouyos and Prof. Dr. Karin Metzner from the Department of Infectious Diseases and Hospital Hygiene at the USZ, have now investigated in the largest longitudinal observational study to date how the size of the reservoir changes over the long term and which factors influence the changes or the size of the reservoirs.
For this purpose, the research team evaluated blood samples and the corresponding data from 1,057 persons who had been successfully treated with ART for many years in extensive test series. They were able to draw on the Swiss HIV Cohort Study (SHCS) with its comprehensive biobank. This prospective cohort study, which has been running since 1988, covers about 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, at least three samples from each of the 1,057 persons were available for measuring the HIV reservoirs, which had been taken on average 1.5, 3.5 and 5.4 years after the onset of ART. Data were available from 412 individuals that allowed the course of the HIV reservoirs to be traced back to ten years.
Thanks to this comprehensive clinical, virus genetic, demographic, behavioral and therapy-specific data, a large number of potentially reservoir-influencing factors could for the first time be investigated simultaneously in multivariable statistical models. "Our study covers ten times as many subjects as the largest comparative study to date and allows more reliable statements to be made," says Huldrych Günthard, explaining the large volume of data evaluated.
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 reservoir waste flattened significantly and appeared to conform to a plateau. Contrary to expectations, however, despite successful antiretroviral therapy in 281 persons (26.6 percent) there was no decrease but an increase in the size of the reservoirs. "This is a surprising and important finding. We do not yet know what leads to this increase," says Günthard. "It is possible that latently infected cells divide, or in some patients, the HI viruses still multiply at a low level despite ART. Both could lead to an increase in reservoirs in the longer term."
Targeted studies are being planned. The fact that patients' lack of adherence to therapy could lead to this effect can be largely ruled out: "SHCS has excellent, validated data which also document adherence to therapy and therapy interruptions.
If the therapy had started within the first year after HIV infection and the viral load was low at that time, the reservoirs were also low 1.5 years after the start of therapy. This observation confirms the results of earlier studies of other groups. What was new, however, was that viral "blips" were associated with larger reservoirs and with a smaller decrease in them over time. Previously, these blips were considered clinically irrelevant or hardly relevant at all. The study shows, however, that they are of biological importance. Furthermore, deeper HIV reservoirs were found in people of non-white ethnicity.
"For HIV research, studies that lead to a better understanding of the reservoirs and studies that test strategies to eliminate all HI viruses from infected patients have top priority in order to come closer to our goal of curing HIV," explains Huldrych Günthard. "The results of our study show that the behavior of reservoirs is still insufficiently understood. And our findings on the role of the blips have shown that proof of concept elimination studies should be conducted with carefully selected patients, otherwise we may miss out on important research effects.”
Nadine Bachmann, 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