HIV reservoirs: New results on viral tracing

Modern HIV therapies cannot yet remove the viruses from the body. Treatments that attack viral reservoirs are of great hope to eliminate HIV in a patient.

When HIV becomes infectious again

Depending on the test used, the HIV detection limit is less than 20 to 50 viral copies per millilitre of blood. When the viral load is less than 200 viral copies per millilitre of blood, patients are no longer considered sexually infectious, according to the German AIDS Federation. Then the formula U=U applies, i.e. "undetectable equals untransmittable". This applies to blood, sperm and also breast milk - but not to the so-called reservoirs.

Even below the so-called detection limit, HIV viruses are still present in the bodies of people who have become infected with HIV. On the one hand, this is shown by the highly sensitive test procedures. But it also becomes clear when the ART drugs are discontinued or lose their effectiveness, for example because of drug resistance. Then the HI viruses multiply again: their number increases, they become detectable again, people with HIV can fall ill from the effects of infection, and pass on the viruses.

The HI viruses retreat into reservoirs

Experts assume that HI viruses are no longer detectable because they withdraw into so-called reservoirs, i.e. into certain cells and tissues, under the pressure of ART. At the International AIDS Conference IAS 2022 in Montreal, Canada, at the beginning of August, experts intensively discussed such reservoirs, in which the virus continues to be found even with effective therapy. Around the globe, experts are asking themselves which cells and tissues serve as reservoirs for the HI viruses. In addition, there are research questions aimed at eliminating the viruses. Modern detection methods and new research approaches give hope for new insights into HIV therapy.

HIV found in the brain

The central nervous system (CNS) is considered one of several reservoirs for HIV. However, it is not known exactly what significance the CNS has as a reservoir. To what extent does HIV damage the CNS when the viruses lie dormant there? Does the CNS possibly offer a replication-competent reservoir? A research group led by the Australian virologist Michael Roche asked themselves these and similar questions. In search of answers, they have examined the brains of deceased people with HIV. The autopsies of the organ donations with the help of PCR tests and in situ hybridisation (DNAscope) showed: both defective and intact proviral HIV DNA can be detected in the brain tissue. It made no difference whether the people received effective ART during their lifetime or not. The quantity and quality of the viral DNA found was surprisingly similar. "We were able to demonstrate for the first time that HIV remains capable of replication in the CNS even when viremia is successfully suppressed," the abstract states. What that means exactly, however, remains to be studied, Roche said.

The HIV genome in children: More frequently defective due to ART

A different approach to reservoir research is being pursued by the team led by Canadian data specialist Caroline Dufour from Montreal. She and her team analysed data from children in Thailand who were infected with HIV via their mothers. To do this, they looked for the HIV genome in the children's blood. This is because the genome often remains intact in latently infected cells in children for a long time, even if the children receive effective ART. Dufour was able to show clear differences depending on when and for how long the children received ART. The earlier ART started and the longer it worked, the less intact genome was found: while 48% of the genomes found were still intact before ART, their proportion was drastically reduced to eleven, six and one percent after two, three or more than three years of ART. From this, the researchers concluded that ART also has an effect in the reservoirs.

New microbiological tools help to clarify the connection between reservoirs and virus replication

The search for the HIV genome in the different reservoirs is facilitated by new analytical tools, so-called assays. Melissa Smith from Louisville (Kentucky, USA) described that research on HIV reservoirs can usually only examine those HIV genomes that can be represented in the cells of previous assays. That is why the biochemist and molecular geneticist has developed a new "single molecule" assay. With the HIV-SMRTcap, the proviral genome and its integration sites - the so-called HIV integron - can be detected simultaneously for all important HIV subtypes in cells and tissues. This is important in order to investigate at which sites an intact and thus reproducible genome becomes a defective one.

Do mRNA vaccinations against COVID-19 have an effect on HIV in the reservoirs?

The viral protein Nef plays an important role in the replication of HI viruses. The New York immunologist R. Brad Jones reported the hypothesis that the SARS-CoV-2 mRNA vaccination could activate the transcription of HIV proviruses. Therefore, he and his team compared the Nef activities in the relevant CD8 and T cells of people with HIV before and after a corresponding vaccination. As a result, it was indeed measurable that the vaccination apparently caused a decrease in HIV RNA. However, this did not apply to the intact or total HIV DNA. From this, Jones and his team conclude that only a small part of pro-viruses is responsible for transcription. Further research will show which part this is and how it can be influenced.

A cure for HIV?

The important role of research on reservoirs is also shown by the award given by the International AIDS Society (IAS) at the AIDS 2022 conference. Among others, the IAS awarded Marion Pardons, who conducts research at the HIV Cure Research Center in Ghent, Belgium. Pardons reported in Montreal on new ways of investigating the latency of HIV without causing a general reaction of T cells. Central to this are so-called latency reversing agents, or LRAs for short. Two LRAs described by Pardons could be combined both in vitro and in vivo and thus represent a step towards curing HIV.

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