HIV Research: Advancements, Challenges, and Future Directions

In recent years, advances in HIV approach, the virus responsible for acquired immunodeficiency syndrome (AIDS), they have been huge. With the ever closer goal of 95% of people with HIV being diagnosed; that 95% of them are in treatment; and that 95% of them have an undetectable viral load and, therefore, non-transmissible, new challenges appear that are added to those that still exist.

Approaching patients with antiretroviral treatment, finding a cure or developing a preventive vaccine are some of the strategic lines on which work is currently being done. At points such as the development of a vaccine, professionals still encounter certain obstacles. “The problem with getting a preventive vaccine against HIV is that the immune system does not control the virus,” says the Dr. Jose Alcami, of the National Center for Microbiology. “Therefore, a vaccine against HIV that activates the immune system is insufficient, we need prototypes that ‘teach’ the immune system to do something that it does not do naturally, and we do not have such a prototype that has demonstrated efficacy,” he adds.

“Functional cure involves treating the patient with drugs that attack and eliminate viral reservoirs”

All these issues, challenges and advances will be addressed the next 9 and 10 June in the 8th edition of the meeting Milestones in Basic and Clinical Research on HIV/AIDS (HIBIC), organized by Gilead. This year, among other points, topics such as advances in genetics in HIV-1, the transmission of sexual diseases in these patients or the coinfections and comorbidities commonly associated with HIV infection will be discussed, as Dr. Alcamí told ConSalud. is

One of the points that you are going to present at HIBIC is transnational science. What challenges are presented in this field in terms of HIV?

The treatment of the infection is a success and, although there are new proposals such as long-acting drugs. Control of virus replication allows people with HIV to have an excellent life expectancy and quality of life. Given this, the two great challenges are getting a preventive vaccine and a cure.

Functional cure involves treating the patient with drugs other than those currently used. Drugs that attack and eliminate viral reservoirs through a direct action on infected cells or by enhancing the immune response so that our system destroys those cells that contain the virus.

In the HICV-1 virus reservoirs of patients who have been on antiviral therapy for twenty years, changes have been observed that you are going to highlight at the meeting. What are you finding in the samples?

What we have learned is that the reservoir is more dynamic than previously postulated. We can distinguish two functional compartments in these integrated viruses: viruses capable of replication and viruses incompetent for replication because they are defective or integrate into what we call “gene deserts”, areas of our genome where they are not expressed.

“We can define in each individual cell if it is infected or not, if the virus replicates or is defective”

Over the years in patients undergoing treatment, the “replicating” viruses, which are the dangerous ones, decrease because the infected cells die when the virus replicates or are destroyed by the immune system and the antiretroviral treatment prevents this “dangerous” virus from ” infect new cells and spread. Proportionally, defective viruses that do not replicate and are not seen by the immune system accumulate, and replicative viruses decrease.

However, it is difficult to define when a functional cure scenario could occur in which we reach such a low reservoir level that we could withdraw treatment. Unfortunately, it does not seem that we are in this scenario because the interruption of treatment causes a rebound in viral load levels in the vast majority of patients.

The truth is that we are talking about great advances in molecular and genomic research on the HIV virus. In this field, how have study techniques evolved?

In the last five years progress has been spectacular thanks to omics combined with single cell technology. With these techniques we can define in each individual cell if it is infected or not, if the virus replicates or is defective, the site where it is integrated, and the characteristics of the infected cells.

This allows us to draw a complete map of the state of the infection in the different cellular compartments. However, these techniques have limitations. In addition to its extremely high cost and great technical difficulty, we do not have access to infection in tissues (ganglion, digestive system, nervous system) and our map is reduced to understanding the situation in peripheral blood.

There are many results that have been obtained in these investigations to which you refer. What implications do they have, however, in the approach to infection?

So far, a great deal of theoretical knowledge has been generated, especially our paradigms on the viral reservoir have changed. However, in practice, there are no major changes in treatment for patients.

Speaking of treatment, what pharmacological strategic lines are currently under investigation? And at this point, what role can combined strategies have in the search for a cure for HIV?

On the one hand, treatment with “long-acting” or long-acting drugs, which allow treatment by intramuscular and subcutaneous injections every three months and in the future every six months, represent a new strategy that can already be applied.

“It is not possible, viable or ethical to perform a bone marrow transplant in a patient who does not require it due to hematological cancer”

On the other hand, there is very active research to boost the immune system or adopt new strategies combining antibodies, virus-reactivating or blocking drugs, and immunomodulation strategies that make it possible to reduce virus reservoirs, but the results are still modest and do not allow for interruption. treatment that maintains control of viral replication in the medium or long term.

In this sense, in recent years the results of four patients who have been freed from HIV through a stem cell transplant from donors carrying the CCR5-delta32 mutation have been published, a natural mutation that confers resistance to HIV by preventing for the virus to enter cells and infect them. What do these advances mean?

They are very spectacular cases and they always raise a great media frenzy that dies out in a few days. Its consequences in the management of patients with HIV are nil because it is not possible, viable or ethical to perform a bone marrow transplant in a person who does not require it due to hematological cancer. These are interesting cases from the conceptual point of view, but they cannot be extrapolated to the clinic.

The prospect of achieving a similar situation with gene therapy strategies that select for or edit the CCR5 gene is being studied, but the results are so far poor and it is technically difficult to apply it generally.

Taking all this into account, how do you assess the current HIV situation?

There are lights and shadows. Among the successes is the fact that we have extraordinarily effective treatments that allow infected subjects to have a normal life expectancy and an excellent quality of life. The fact that viral load control means that the treated subject does not transmit the disease – undetectable = untransmissible – is also a great achievement. The implementation of PrEP pre-exposure prophylaxis as a preventive measure in subjects at high risk of infection is also great news despite the difficulties that arise in its application.

As for the shadows, we have the increase in sexually transmitted infections that are not preventable by PrEP and the two great challenges previously mentioned: we have not been able to generate a preventive vaccine and we are still far from a functional cure. But personally I consider that the biggest failure is that in 2021 1.5 million people have been infected, of which 140,000 are children or adolescents. That 10 million patients do not have access to treatment and that 750,000 people have died of AIDS in 2021. HIV continues to kill in countries with fewer resources and this is a scourge for everyone.

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