NIH Awards $53M for HIV Cure Research for Adults, Children
By Allison Proffitt
August 23, 2021 | The National Institutes of Health has awarded approximately $53 million in annual funding over the next five years to 10 research organizations in a continued effort to find a cure for HIV. The new awards for the Martin Delaney Collaboratories for HIV Cure Research program further expand the initiative’s 2016 renewal from six institutions to 10, and represent a funding increase of approximately 75%.
Developing a vaccine has long been NIAID’s top HIV priority; it would be the most effective way to end the epidemic, explained Karl Salzwedel, PhD, Chief of the Pathogenesis & Basic Research Branch, Division of AIDS, NIAID. But as an effective vaccine remains elusive, more effort has dedicated to finding a curative treatment.
“We’ve been steadily increasing our investment in HIV cure research because as the therapies have gotten better, as we’ve continued to face challenges developing a vaccine, the prioritization of HIV cure research has increased over the years,” he told Bio-IT World. “The program is a collaboration among partners in academia and industry, in government, and in the community. It’s really bringing together all of the stakeholders in one grant program,” he said.
The evidence that a cure may be possible has been mounting. Two individuals who underwent bone marrow transplants for cancer treatment are still in HIV remission. For others, even without any intervention, their immune system seems able to control viral infection for many years.
“We do have more and more proof-of-concept examples from individuals who are able to control their infection or that have been cured through transplants. That gives us hope,” Salzwedel said. “We have more examples of that than when we started the program ten years ago. That gives us hope as we learn more and more about the reservoir and about the virus that we will be able to keep a cure strategy.”
The new awards will focus on three key areas: basic research on HIV reservoirs and/or post-treatment control; strategies for durable control of viral rebound; and approaches to reducing, eradicating, or inactivating the latent virus.
New concepts being introduced as a result of the program’s expansion include the first-time use of CRISPR gene-editing technology to inactivate or remove dormant HIV, enhance immune responses, and engineer immune cells to be resistant to HIV infection. Other new concepts include the exploration of epigenetic modifiers to either flush out dormant (latent) HIV or prevent its activation, known as a “block-and-lock” approach; inhibition of latency establishment upon starting antiretroviral therapy; exploration of correlates of control of HIV rebound; and the use of genetically engineered viruses to track viral reservoirs. New therapeutic technologies include engineering of B cells to express broadly neutralizing antibodies; CD4-mimetic compounds; mRNA vaccines; trispecific antibodies; and nanoparticle formulations.
The Pediatric Angle
Treatments for HIV are improving. Long-acting antiretroviral drugs that can be taken once a month or even once every few months are becoming available. People with well-managed HIV infections have similar life expectancies to those who are uninfected. But for most of the world’s approximately 38 million people living with HIV, the reality is still daily drugs—some with side effects—for the rest of their lives, or as long as they are connected to the health system.
This is particularly burdensome for pediatric HIV patients, and one of the new grants is focused specifically on HIV cure research in infants and children. The pediatric award will include work on developing assays, tools, and imaging modalities specifically for studies in infants and children.
Salzwedel believes seeking a curative treatment for children is especially important for a host of reasons. Children are the last to receive new treatments as trialing new drugs on pediatric populations is difficult. “It takes years for these advanced treatments to reach pediatric populations,” Salzwedel observes.
And the risk profile of drugs is different for developing bodies. “Because [the children] are going through years of development, there’s more potential for toxicities affecting things like their bone growth and bone density and things of that nature,” he said.
“If we had a curative treatment that we could give them once—just access the individual one time—you don’t have to worry about lifelong treatment.”
The HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory won the new grant for work in children. It will be led by researchers at Gladstone Institutes, Scripps Research Florida, and Weill Cornell Medicine. The HOPE Collaboratory approach, which aims to both silence and permanently remove HIV from the body, takes advantage of knowledge about how other viruses have become naturally inactivated over time.
The team calls their new, alternative tactic “block-lock-excise,” and it targets latent HIV in new ways, without reactivating it. The inspiration for the “block and lock” part of their strategy comes from ancient viruses that have integrated themselves into the human genome over millions of years of evolution. HIV also integrates into the genome of a person living with HIV. However, unlike HIV, the ancient viruses remain in a silenced state or are defective.
Researchers have found that these ancient inactive viruses are missing several genetic elements that HIV contains. Two particular elements—a sequence of DNA at the start of HIV’s genetic code and a protein called Tat—are needed for latent HIV to reactivate and begin replicating.
“We have shown that blocking Tat with certain drug-like small molecules can lock HIV in its dormant stage, and this block stays in place for some time, even if antiretroviral therapy is interrupted,” says Susana Valente, PhD, one of the principal investigators of the HOPE Collaboratory and associate professor of immunology and microbiology at Scripps Research in Florida in a press release. “With the ‘block and lock’ approach, we basically want to push HIV into becoming like a harmless, ancient virus.”
Salzwedel said there is reason to hope that a cure may be more possible for infants and pediatric patients. “Especially for perinatally infected children—infected around the time of birth—because the infection is at such an early stage and the immune system is quite different—what we call naïve—it basically hasn’t seen other pathogens before. It’s a very unique situation. The immune system is, perhaps, in a better situation to be able to clear, control the infection. Because it was caught early, there tends to be less HIV virus in the body.”
The following awardees will receive the noted amount of funds each year for five years:
Beth Israel Deaconess Medical Center, Boston Project Title: I4C 2.0: Immunotherapy for Cure Award: $4.9 million
Emory University, Atlanta Project Title: Enterprise for Research and Advocacy to Stop and Eradicate HIV (ERASE-HIV) Award: $5 million
Gladstone Institutes, San Francisco Project Title: HOPE (HIV Obstruction by Programmed Epigenetics) Award: $5.3 million
Johns Hopkins University, Baltimore Project Title: Pediatric Adolescent Virus Elimination (PAVE) Martin Delaney Collaboratory Award: $5.7 million
Sanford Burnham Prebys, La Jolla, California Project Title: RID-HIV (Reversing Immune Dysfunction) for HIV-1 Eradication Award: $5 million
Temple University, Philadelphia Project Title: CRISPR for Cure Award: $4.8 million
University of California, San Francisco Project Title: Delaney AIDS Research Enterprise to Cure HIV Award: $5.6 million
The University of North Carolina, Chapel Hill Project Title: Collaboratory of AIDS Researchers for Eradication (CARE) Award: $5.2 million
Weill Cornell Medicine, New York City Project Title: REACH: Research Enterprise to Advance a Cure for HIV Award: $5.7 million
The Wistar Institute, Philadelphia Project Title: BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy Award: $6.1 million