Positive progress for the future of AIDS research anticipated

At the XVII International AIDS Conference, Anthony Fauci, MD, said biomedical research is key to future success in fighting HIV/AIDS.

Issue: September 2008

Biomedical research focusing on specific moments of opportunity in the development and transmission of HIV could lead to gains in the battle against the disease, according to Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases at the NIH.

Fauci addressed the future of HIV/AIDS research in a presentation at the XVII International AIDS Conference, held in Mexico City. According to Fauci, pathogenesis, diagnosis and monitoring, therapy, prevention and vaccines are the five areas where AIDS research should center in the immediate future.

Windows of opportunity

“The pathogenesis research of the future will be focused on areas such as the structural biological studies of the components of HIV and how they interact with host factors both intracellular, receptor-mediated, cellular and humoral,” Fauci said. “Host genetics has loomed large, particularly over the last year or two, in informing us about an individual’s propensity to progress or not.”

Early events shortly after the time of infection, including the activation of the immune system, are often referred to as the window of vulnerability. Fauci posed the idea that studying those moments could provide insight into why vaccines succeed or fail and how the disease might best be controlled. The formation of HIV reservoirs along with a dramatic increase in CD4+ T-cell deaths within days of infection results in a suppression of the immune system. Understanding the interactions that take place at those points in time may also make them a window of opportunity for researchers to explore.

Fauci discussed how rapid and accurate point-of-care diagnostics and then subsequent monitoring of the immune system and therapeutic regimens can be beneficial for a variety of reasons, including the identification of drug resistance.

Fauci praised the way biomedical research has been applied to therapy programs and how the resulting drugs have affected people with HIV. That effect has been “a major success story with a big caveat,” he said. “The big caveat is that there are so many people that need to be on therapy who do not have access to therapy.”

Further, he said, for every one person who begins receiving therapy, two to three people become infected.

Possible cures

Fauci discussed two types of cures: a sterilizing cure and a functional cure. He defined a sterilizing cure as one similar to that of other infections, whereby antiviral or antibacterial therapy combats the infection. The immune system then “cleans up afterward.” At that point, therapy can be eliminated. However, the aforementioned reservoir of HIV protects the virus from drug therapy and renders it virtually impossible to cease treatment altogether.

Though recent therapies have made it possible to attenuate the reservoir to almost undetectable levels, it persists, often in the gut. “I have hope that with either an intensification of therapy or a more aggressive therapy to begin with, particularly with integrase inhibitors that would block integration of the provirus into the genome of a cell leading to the establishment of a reservoir, we may be able to get the reservoir down to a very low level,” he said.

Fauci defined a functional cure as the suppression of replication of the virus and attenuation of the reservoir with antiretroviral therapy to the point that people with HIV are able to discontinue therapy while their immune system keeps the small amount of residual virus in check. He said that early diagnosis and intervention are key in bringing about a functional cure.

“You must treat the infection with aggressive ART early on. You preserve a substantial level of specific immune response. You get a prolonged suppression of viral load. You either add drugs or not, give HIV-specific immunotherapy or not, and have continual attrition of the HIV reservoir,” he said. “Ultimately, you can discontinue therapy in a carefully controlled manner to see if the prolonged suppression of viral rebound will occur by preserved and amplified anti-HIV immune responses.”

Prevention strategies

Fauci said that although prevention research is making progress, there is much to be done in the field. He discussed successful prevention strategies, including ones to combat sexual, bloodborne and mother-to-child transmission. He also indicated that ART has been successful in blocking mother-to-child transmission and as a postexposure prophylaxis.

He outlined the direction that he felt prevention research should move. The possibility of bringing down the viral load enough in people with chronic infection to have a preventive effect on transmission is one area that warrants further study. The other area is that of preexposure prophylaxis.

He also discussed promising prevention strategies that have yet to be clinically successful, including topical microbicides and the prevention and treatment of coinfections.

The topic of prevention strategies led Fauci toward a longer discussion of vaccines.

Vaccines

Fauci opened his comments on a potential HIV vaccine with an overview of why a traditional approach to vaccine development does not work. “We used outer viral proteins as a vaccine, thinking that hopefully we would induce a neutralizing antibody response,” he said. “What we learned as we were going along this pathway is that very few people naturally produce neutralizing antibodies. Also, the neutralizing epitope seems to hide itself from the immune system.” Vaccine trials using this approach failed as a result.

He also addressed T-cell–based vaccines. Encouraging results from animal studies in which viral loads were reduced gave way to disappointing results from trials of T-cell–based vaccines, including those from the NIAID-funded HIV Vaccine Trials Network that tested the Merck product.

In comments about the decision to cancel the large trial of the NIAID Vaccine Research Center product, Fauci said: “There are those who say that you do a large trial, and even if you do not get a positive efficacy signal, you can look at subsets of people and try to make immunological correlates. My feeling is that an immunological correlate in a failed trial is unlikely to give you enough information to validate the need for a very large trial.”

Despite the recent failures, Fauci said he looks forward to the pursuit of a vaccine, specifically one involving neutralizing antibodies, which he thinks will be key. He encouraged the development of animal models that examine vaccine-induced immune protection.

He then outlined specific strategies for the path of vaccine research in the coming years. “What we will be doing in the next few years is looking at how we can take those epitopes to which neutralizing antibodies bind and by proper scaffolding of the epitope turn them into immunogens that will actually induce a neutralizing antibody,” he said.

Final thoughts

Fauci said he is often asked about a cure and a vaccine. He said that he believes that it might be possible to eradicate HIV microbiologically in some patients but not very many. He reiterated the necessity of timely initiation of therapy and control of what he called the “recalcitrant reservoir.” A functional cure, short of eradication of the virus, would ultimately be possible in a somewhat larger number of patients, he said.

As for a vaccine, he is cautiously optimistic. He said that it may be possible to prevent infection in some patients and slow progress in others but that it will not be like a classic vaccine. A successful HIV vaccine will require the induction of broadly reactive neutralizing antibodies against HIV. “The history of AIDS research is one of, quite frankly, breathtaking accomplishments,” Fauci said. “And the future of AIDS research indeed looks bright and promising. However, we are gathered here ... in the middle of a raging epidemic. To be sure, there are multiple and daunting challenges ahead in how we confront HIV globally. Not all, but certainly some of these challenges, can only be addressed through biomedical research.” – by Rob Volansky

For more information:

Fauci A. The future of AIDS research. Presented at: the XVII International AIDS Conference; Aug. 3-8, 2008; Mexico City.