HI viruses can survive for years in reservoirs inside the human body. They are the greatest obstacle to finding a cure to HIV and yet still inadequately understood. A team of researchers from University Hospital Zurich has made new discoveries about these reservoirs in what is largest longitudinal observational study in the world for researching HIV reservoirs.
An HIV infection is a heavy blow because only two people have ever been cured after receiving a stem cell transplantation. This, however, is out of the question as a standard method for curing people infected with HIV. Antiretroviral therapy (ART) has been available for many years and is a highly effective treatment that inhibits the virus from reproducing and prevents transmission to other people. Thanks to ART, people infected with HIV can now lead almost fully normal lives and have life expectancies close to that of non-infected individuals. ART must be taken for the rest of the person’s life, however, and ART medicines can place stress on the body due to their side effects. If treatment is stopped, the HI virus will return to detectable levels in the blood of nearly all HIV-infected individuals due to the reservoirs containing cells latently infected with HIV. These consist primarily of infected yet dormant CD4+ memory T cells.
An HIV cure must target viral reservoirs
These reservoirs form rapidly after a person becomes infected with HIV and even survive after decades of ART. To cure an HIV infection, experts agree that it is necessary to target these viral reservoirs and significantly reduce, or ideally eliminate, the latently infected cells. These reservoirs still have not been extensively researched. It is a known fact that their size initially declines after starting ART, and smaller studies have shown that the size of the reservoirs can greatly change depending on the individual case and over time – even during active ART. However, due to the relatively small numbers of study participants and the relative short duration of the studies, as well as the limited number of cofactors studied, these studies have yet to provide any comprehensive picture of the factors affecting the size and changes occurring over time with ART. Yet this knowledge is extremely important to gain a better understanding of latent reservoirs.
Highly differentiated and long-term observation of reservoirs
Nadine Bachmann and her colleagues from an interdisciplinary national research team headed by HIV specialists Prof. Huldrych Günthard, Prof. Roger Kouyos and Prof. Karin Metzner from the Department of Infectious Diseases and Hospital Hygiene at UHZ have now conducted the largest longitudinal observational study to date in order to examine how the size of the reservoirs changes in the long term and what factors affect the changes or size of the reservoir.
In the course of the study, the team of researchers carried out extensive test series on blood samples and the corresponding data from 1,057 people who have successfully been receiving ART for many years. For this purpose, the researchers had the Swiss HIV Cohort Study (SHCS) and its extensive biobank at their disposal. This prospective cohort study that has been ongoing since 1988 includes approximately 75% of all people living with HIV and receiving antiretroviral therapy in Switzerland and who have made their data and blood samples available for research. This means that the SHCS offers a unique data collection and basis for conducting HIV research. The collection provided at least three samples from each of the 1,057 people in order to measure the HIV reservoirs. On average, the samples were taken 1.5, 3.5, and 5.4 years after starting ART. For 412 individuals, data was available that enabled the status of the HIV reservoirs to be monitored over a period of ten years. This comprehensive clinical, virogenetic, demographic, behavioral and treatment-specific data has made it possible to study simultaneously a whole range of potential factors affecting reservoirs in multi-variable, statistical models for the first time. Huldrych Günthard explains the large scope of the data that was analyzed: “Our study includes ten times as many subjects as the largest comparable study to date and has therefore made it possible to draw sound conclusions.”
“Blips” practically ignored in the past now of relevance
On average, the size of the reservoir during the first 5.4 years after starting ART decreased, with an estimated half-life of 5.6 years. During the observation period, the shrinking of the reservoirs leveled off considerably and appeared to reach a plateau. Contrary to expectations, however, 281 people (26.6%) in the analysis exhibited no decline but rather an increase in the size of the reservoirs despite successful antiretroviral therapy. “This is a surprising and important discovery. We don’t know what is causing this increase,” says Günthard. “It’s possible that latently infected cells are dividing or that the HI virus is still multiplying at a low level in some patients, even while receiving ART. Both might lead to an increase in the reservoirs in the long term.” Studies focusing on this are being planned. The possibility that the effect may be due to treatment nonadherence in patients has been largely ruled out: “The SHCS has excellent, validated data that also documents therapy adherence and gaps in treatment.”
If the treatment was started during the first year after the HIV infection and the viral load was low at this point in time, the reservoirs also remained at a low level after 1.5 years. This observation backs up the results from past studies in other groups. What was new, however, was that viral “blips” – i.e. briefly detectable viral loads between two other undetectable plasma viral measurements in the blood – are related to larger reservoirs and a less pronounced reduction of them over time. These blips were previously considered clinically irrelevant or negligible, but the study shows that these are biologically significant. In addition, even smaller HIV reservoirs were detected among non-white ethnicities.
“For HIV research, studies that improve our understanding of the reservoirs and studies that test strategies for eliminating the HI virus entirely in patients have first priority on our path to curing HIV,” explains Huldrych Günthard. “The results from our study show that we still do not have an adequate understanding of how the reservoirs behave. Our findings related to the role of the blips also demonstrate that the “proof of concept” elimination studies should be conducted with carefully selected patients or we will probably miss out on important effects in research.”
Nadine Bachmannn, Chantal von Siebenthal, Valentina Vongrad et al.,