Guideline-compliant HIV therapies reduce the viral load, but do not lead to eradication. But the idea of curing HIV is not off the table. An overview of important approaches from basic research.
Today, physicians have effective antiretroviral therapies at their disposal to treat patients with HIV infection. The goal is to reconstitute the immune system and prevent the onset of AIDS. This considerably prolongs the life expectancy of HIV-infected people. Such drugs do not lead to a cure. However, since the reports about the "London patient" and the "Berlin patient", hope has been rising again that an eradication could be successful. In both cases, infected patients no longer needed drugs after the stem cell transplant. The current state of research was discussed by scientists at IAS 2021.
On the background: "We see dramatic progress in therapy and prevention," says Dr. Michaela Müller-Trutwin from the Institut Pasteur, Paris, France. "Nevertheless, it is and remains difficult to cure HIV." The speaker cites as reasons above all the rapid mutation of HI viruses, which leads to rapid resistance. And the persistence of the virus in very different tissues makes pharmacotherapies difficult. The incorporation of the HIV genome into host cells makes the infection virtually invisible to cells of the immune system. Tissue damage in turn leads to a microenvironment with immunosuppression, which further weakens the body's own viral defence.
With early antiretroviral therapies, some people succeed in controlling HIV themselves, said the speaker. This reduces the amount of virus in the body's own reservoirs. The danger of HIV mutating also decreases. Inflammatory processes are weaker and tissues are less damaged than when treatment is started later. The innate and adaptive immune response is preserved to a greater extent. "Nevertheless, minimal residual viraemia remains after early antiretroviral therapy," says Müller-Trutwin. "So what we need is a shock-and-kill strategy."
New molecular biology tools also offer great opportunities in HIV eradication. For example, the "gene scissors" CRISPR-Cas9 could be used to inactivate CCR5. This receptor protein is found on macrophages, T helper cells, cytotoxic T cells and NKT cells. CCR5 enables HI viruses to dock and infect cells. Researchers have shown that this concept generally works in the body in ATTR amyloidosis, a genetically caused disease. Transthyretin (TTR), a protein, accumulates in the body, causing symptoms. CRISPR-Cas9 made it possible to inactivate a gene and less TTR was produced.
Müller-Trutwin sees other possible uses for the "gene scissors". If HIV is integrated as a so-called provirus in the genetic material of cells, it could be removed by CRISPR-Cas9.
The "block-and-lock" strategy, on the other hand, envisages keeping HIV in its latency so that the virus does not infect healthy cells. Possible targets are lipoproteins, integrases, the serine/threonine kinase mTOR and many more. Alternatively, it remains to drive HIV-infected cells to their demise.
The "shock-and-kick" strategy involves releasing viruses from the body's own reservoirs and then eliminating them. Supramolecular adhesion complexes, Toll-like Receptor 7 (TLR7) and other structures might be suitable.
The immune system also plays a central role. Therapeutic vectors or immunomodulators can be mentioned as boosters for immune cells. Another approach is to repair damaged tissue.
Clinical applications are still a long way off. However, Müller-Trutwin mentioned in vitro studies and animal experiments for some of these strategies. It may be necessary to combine active substances, says the speaker. In macaques, a dual blockade of PD-1 and interleukin receptors has been successful in controlling simian immunodeficiency virus (SIV) without antiretroviral therapy. In the monkey model, interleukin-21 and interferon-alpha also proved to be suitable. Virus replication decreased and inflammatory processes were reduced. SIV is considered an experimental model for HIV. "There are some exciting developments at the moment," Müller-Trutwin summarises.
Reference:
International AIDS Society Conferences (IAS) 2021, Symposium "Why still invest in HIV cure research", 20 July 2021.