Latency-absorbing substances for the shock-and-kill strategy

Many factors involved in virus latency

Latent HI viruses are a major source of renewed viremia after therapy discontinuation in HIV-infected individuals. They are the first target of the so-called shock-and-kill strategy. As part of this strategy, latency is eliminated by Latency Reversing Agents (LRAs). The current state of knowledge on LRA was presented by Carine M. van Lint, University of Libre of Brussels, Belgium, at CROI 2019 in Seattle, Washington, in March 2019.

"Combined antiretroviral therapy (CART) is not curative," van Lint states as an introduction. As soon as the therapy is stopped, there is a rapid increase in virus concentration. This is because HIV1 latent reservoirs are not eliminated by a cART. Infected CD4+-T lymphocytes, in particular, can form a reservoir for latent HIV1 as dormant cells. The reservoir can be activated, for example, by antigens, phorbol esters, mitogens or cytokines. This is a major source of renewed viremia after therapy discontinuation. In addition to CD4+ memory T cells, a number of other cell populations can serve as reservoirs for latent HI viruses, such as various lymphocyte populations, active CD4-positive T cells, or non-T cells such as monocytes, macrophages, dendritic cells or tissue macrophages.

Different therapeutic approaches aim at a sterilizing cure (all replicable viruses are eliminated) or functional cure (or remission with long-lasting control of HIV without cART, without clinical progression and HIV transmission). The remission is at least partly dependent on the size of the reservoir.

Among the treatment approaches, the shock-and-kill strategy has been the most widely researched. Latently infected cells are torn out of their latency by a "shock", so the cells are activated to produce viruses. The simultaneous continuation of cART prevents the spread of infection by the newly formed viruses. In the kill phase, the activated cells can then be killed by viral cytopathic effects or cytolytic effector mechanisms of the host.

Latency reversing agents reactivate latent HI viruses

Latency is a multifactorial phenomenon that is controlled and regulated by various aspects. Research into the molecular basis of the regulatory mechanisms of latency has led to the identification of latency-reversing agents (LRAs). These are small molecule substances that have often already been developed for other therapeutic areas and that are used in the shock-and-kill strategy to reactivate the latent HIV reservoir pharmacologically. Different substance classes act as LRAs:

Studies on different models

Most studies investigating the effect of LRA on HIV latency have used models, namely in-vitro models with specific cell lines or with cells and infectious virus, ex-vivo cultures of primarily infected T or non-T cells from the peripheral blood of cART-treated HIV-infected persons, or animal models with mice or monkeys. "It is uncertain to what extent regulatory mechanisms contribute to latency in vivo. But all these models together complement each other and can help to maintain a complete picture of the latency state in vivo," van Lint said.

Many factors involved in virus latency

Van Lint's group was able to show that it is probably not sufficient to initiate reactivation via just one mechanism. She believes that LRA combinations are necessary to stimulate viral transcription simultaneously at different levels via an effect on different latency mechanisms. It may also be possible to lower the dosage of individual LRAs in a combination, reducing their toxicity. In addition, the size of the virus reservoir and the integration site on the host DNA play a role. There are also gender-specific and tissue-specific factors.

In clinical pilot studies, different results were seen, some of which were encouraging with regard to the induction of HIV-1 transcription. However, no study showed that a significant and sustained reduction of the HIV reservoir could be achieved. "The reason for this ineffectiveness must be understood in order to improve the shock strategy so that clinical success can be achieved," says van Lint.

Source:
Van Lint CM. The current status of 
latency reversing agents. CROI 2019, Seattle, Washington, March 6, 209, Abstract 108. http://www.croiconference.org/sessions/current-status-latency-reversing-agents

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