Microbiota, “natural killers”, gene therapy: new avenues of research against HIV-AIDS

Will it be possible to end HIV by 2030, as the UNAIDS association aims for? Forty years of research on HIV have made it possible to advance, notably on triple therapy treatments, which prevent the last phase of the infection called AIDS, then more recently on Prep, a preventive treatment which prevents infection in the event of exposure. But there is still a long way to go to truly overcome the disease. “We continue to be interested in the replication of the virus and in understanding how certain carriers escape HIV pathology. We hope that this work will make it possible to resolve certain aspects of the infection, particularly in the face of the failure of the vaccine in recent years,” declares Christophe d'Enfert, scientific director of the Pasteur Institute, which is hosting 3 days of conferences on the HIV from November 29 to December 1. Where is the basic, clinical and social research work? Le Figaro takes stock.

Faced with HIV, the body's cells defend themselves using proteins which "fight the virus by inhibiting its fusion with the host cell", explains Michaela Müller-Trutwin, head of the HIV, inflammation and persistence unit. the Pasteur Institute and president of the coordinated action on fundamental and translational HIV research for the ANRS MIE. “These proteins work against several viruses, such as Sars-CoV-2 and HIV.” Research on these proteins will perhaps make it possible to develop drugs to limit the ability of HIV to fuse with cells, therefore to release its genetic heritage and infect the entire body.

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HIV is a so-called “RNA” virus: its genetic heritage is carried by ribonucleic acid, a molecule very close chemically to DNA (deoxyribonucleic acid). When HIV target cells (TCD4 lymphocytes and macrophages) are infected, the virus's RNA is “reverse transcribed” into DNA, which allows the virus to use the cellular machinery to replicate. It has recently become known that this step takes place in the cell nucleus, an “RNA replication factory”, comments Michaela Müller-Trutwin. A field of research is therefore opening up on this very particular stage of a viral infection: preventing retrotranscription directly in the nuclei of infected cells would make it possible to block HIV replication.

A large number of infected cells lodge in the intestine. However, it contains a population of microorganisms, the intestinal microbiota, probably involved in HIV infection. “We suspect the microbiota of having a role but it is difficult to understand it,” recalls Asier Sáez-Cirión, director and head of the viral reservoirs and immune control unit at the Pasteur Institute and president of the scientific and medical committee. of Sidaction. “We know that there is clearly an impact of compounds produced by bacteria. We know that the person's metabolism will have an impact on the reservoirs, but the link is not clearly established. Experiments on mice with or without microbiota are underway to determine the role of the microbiota on virus acquisition and pathogenicity.”

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To defend itself, our body has two lines of cellular defense, innate immunity, rapid but not very specific, and adaptive immunity, slower because it requires the lymphocytes to mature, but more specific. Research focuses on rapid innate immunity cells, natural killer cells (or “NK”, for “natural killer”) which act quickly on infected cells and are capable of entering HIV reservoirs with difficulty. accessible through available treatments. The research aims to manufacture a vaccine capable of mobilizing these NK to prevent HIV infection and target the reservoirs. But Michaela Müller-Trutwin specifies that “the natural killer cells come into contact with these infected CD4 lymphocytes to kill them if they produce viruses, but they will not be able to recognize an infected cell that does not produce HIV”. The NK strategy will not be able to limit infections alone, but combined with triple therapy or future gene therapies, it could prove effective.

Only five cases of complete recovery have been recorded in the world. These are always patients who have benefited from a marrow transplant (for another pathology). Apart from these exceptions, we rather speak of remission of HIV infection, that is to say that there may still be some virus present in the body but the level is controlled, without any medication. . As for people treated with triple therapy, they now have undetectable levels of HIV in their blood and no longer transmit the virus, but they cannot completely get rid of it. HIV persists in host cells called “reservoirs”, macrophages and lymph nodes. Gene therapy trials are underway to try to make cells resistant to infection or prevent replication of the virus.

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A team from Rockefeller Hospital in New York uses broad-spectrum neutralizing antibodies naturally produced by a few rare patients. Today, “30 people are in remission from HIV with this neutralizing antibody technique,” ​​announces Asier Sáez-Cirión. However, Michaela Müller-Trutwin specifies that “we know how to make them in the laboratory but we do not know how to induce their production in a patient”. Another limitation: a high concentration must be injected to be effective.

The HIV virus mutates a lot, much more than the Covid virus, and many variants exist. The antigens present on its surface, which are targeted by the antibodies, therefore change a lot, which does not facilitate their identification. This variability currently prevents the manufacture of a vaccine that is effective on all existing viruses, testifies Michaela Müller-Trutwin. Many Phase I and II trials worked, but Phase III, which tests the true effectiveness of pharmaceuticals in large numbers of patients, failed. However, research into a messenger RNA vaccine against HIV has not been in vain: it has notably enabled the ultra-rapid development of the vaccine against Covid. Research for an AIDS vaccine is now turning to messenger RNA vaccines, capable of stimulating the production of neutralizing antibodies.