40 years after the discovery of the AIDS virus, why have we still not found a vaccine?

It took less than six months to develop a vaccine against SARS-CoV-2, a previously unknown virus. But for HIV, discovered in June 1981, there is still no effective vaccine. Monsef Benkirane, research director at the Institute of Human Genetics at the CNRS, explains why all the attempts have so far failed.

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On June 5, 1981, a new type of pneumonia affecting immunocompromised individuals is reported in the United States. The start of a epidemic which will kill 33 million people worldwide in 40 years. However, the researchers were initially rather optimistic. ” The Page is about to be defeated. The Americans have spent $ 75 million on research and you might think that a vaccine will be developed within the next two years », Affirmed the diary ofAntenna 2 in 1984. Since then, disillusions have followed one another and the virus foiled all vaccine attempts. Monsef Benkirane, research director at the Institut de genetic human at the CNRS in Montpellier, explains why HIV still resists.

Futura: It is nevertheless striking to note that we were able to develop several vaccines against SARS-CoV-2 in less than six months while 40 years were not enough for AIDS?

Monsef Benkirane: First, vaccines against SARS-CoV-2 did not come out of nowhere ! We forget all the fundamental research that began several decades ago on MRNA and how to deliver them. In addition, the fact that the infected individuals were resistant to reinfection predicted that the development of a vaccine would be possible, which is unfortunately not the case for the VIH. An individual infected with HIV can become superinfected with another HIV. So, in this case, we will have to do better than the virus by matter immune response. It is also important to note that the development of the SARS-CoV-2 vaccine in six months was made possible thanks to the financial resources made available and the acceleration of administrative procedures.

Futura: SARS-CoV-2 and HIV are two RNA viruses. How are they so different?

Monsef Benkirane: The two viruses actually don’t have much in common. HIV is a retrovirus that transcribes its ARN in DNA, thanks to a enzyme named transcriptase inverse, and integrates it into genome of the cell, thanks to another viral enzyme named integrated. In addition, HIV precisely targets TCD4 cells, who are the “conductor” of the immune response. Infection with the virus therefore completely disrupts the immune response. The other problem is that HIV will lodge in the lymphocytes and remain “dormant”, thus constituting a stable viral reservoir ready to reactivate.

Next to HIV mutations, the few variants of SARS-CoV-2, it’s a joke!

Futura: Why don’t the antibodies destroy the virus?

Monsef Benkirane: As with any virus, the body does trigger a strong immune response against HIV. This is effective at the onset of infection. The problem is, reverse transcriptase produces an incredibly high number of errors during the replication : about one error every 1,000 bases when synthesizing DNA from viral RNA. On a virus genome of 10 kilobases, you can imagine the number of variants this produces! In the same person, we can thus have thousands or even millions of variants which coexist. Next to it, the few variants of SARS-CoV-2, it’s a joke! Suffice to say that HIV will always win the war that engages with the host’s immune response.

Futura: Why can’t we inject a surface protein “Spike” to produce antibodies like with SARS-CoV-2?

Monsef Benkirane: It is of course a track that has been tested. To induce antibody neutralizers, it is necessary to target the parts of the virus which allow it to block the site of binding with the cell or to prevent its fusion with the membrane. Unfortunately, these regions are not very immunogenic (they do not generate much antibody) and not easily accessible on the casing of the VIH-1 unlike the “Spike” envelope of SARS-CoV-2.

Futura: What other approaches have been tried for the vaccine?

Monsef Benkirane: Almost all classic and intuitive strategies have been tested without success: proteins or peptides of the viral envelope in recombinant form, vaccines based on viral vector (such asadenovirus used in vaccine AstraZeneca for SARS-CoV-2) or DNA vaccines. We even wondered if it was possible to induce a cellular response, by activating TDC4 cells. L’clinical test had to be quickly stopped, because we realized that by activating these cells, we “nourished” the HIV at the same time since it specifically targets TDC4.

Futura: So the development of an AIDS vaccine is impossible?

Monsef Benkirane: Not at all ! On the contrary, I am rather optimistic. We will achieve this thanks to ambitious fundamental and clinical research combined with very innovative approaches. For example, in France, researchers from the VRI (Institute for Vaccine Research) in Paris have started a clinical trial with a completely new approach: it is about target dendritic cells, who serve as “sentries” to the immune system. These cells will recognize the antigens and activate the “naive” cells of theimmunity. Other ongoing clinical trials aim to induce the production of broadly neutralizing antibodies. spectre (bNAbs), which target several strains of the virus at the same time.

Futura: Have all these failures been totally in vain?

Monsef Benkirane: No, it’s the opposite ! Research on AIDS first made it possible to develop triple therapies extremely effective. Before that, the virus had a 99% mortality. Today, 37.6 million people worldwide are living with HIV, and mortality has fallen 61% since 2004. AIDS research has also made significant progress in the development of treatments for HIV.Hepatitis C and theHepatitis B or for the genetical therapy. The day we find a vaccine against le Sida and once we have solved the problem of antibiotic resistance, we will have made a major breakthrough in our understanding of immunity and vaccinology.

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