Dr. Lishomwa “Lish” Ndhlovu Takes the Lead

Lishomwa “Lish” Ndhlovu, M.D., Ph.D., is a proponent and practitioner of translational medical research—a multi-step process that expedites the transformation of basic science and understanding about illness into health interventions. He also understands that translational research withers in isolation. As director of the Laboratory of HIV Immunopathogenesis and Emerging Pathogens at Weill Cornell Medicine’s Division of Infectious Diseases, where he is Professor of Immunology in Medicine, Dr. Ndhlovu has assembled a stellar translational research team.

Dr. Ndhlovu, who is also a Professor of Immunology in Neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, earned his medical degree at the University of Zambia, before pursuing his Ph.D. in immunology at Tohoku University School of Medicine in Japan and a post-doc to study HIV immunology at University of California, San Francisco. He understands the “bench-to-bedside” pipeline, as well as the challenges faced by biomedical researchers, physicians, and patients alike.

The holistic teamwork that translational research relies upon is something at which amfAR has excelled, so it’s no surprise that Dr. Ndhlovu was recently chosen to helm its Scientific Advisory Committee, a volunteer group of leading researchers who review grant applications and guide the foundation’s research program. (Dr. Ndhlovu also serves on the Board of Directors and has equity with CytoDyn, Inc., a company that is developing therapeutics to treat HIV.)

In a recent interview, amfAR asked Dr. Ndhlovu about his team’s priorities, HIV cure strategies, and what he hopes to contribute to the foundation’s Scientific Advisory Committee over the course of the three-year appointment.

HIV and brain health

HIV can impact the central nervous system and achieving optimal brain health is an important area of HIV research in the Ndhlovu Lab. Given that the burden on cognitive dysfunction still persists in people living with HIV (PLWH) even despite achieving viral suppression with anti-HIV drugs, we have few therapeutic approaches to manage these complications. “Brain injury ranges in severity—from severe forms such as dementia (which is more common in individuals who didn’t have access to antiretroviral therapy), to milder forms of impairment that prompt daily-living challenges“ notes Dr. Ndhlovu. A question that runs through this field of research is, why do some people develop central nervous system abnormalities and others don’t?

Brain injury is multifactorial, not “an isolated, single entity,” explains Dr. Ndhlovu. “It’s a single body that’s exposed to multiple, long-term and also legacy effects that might be driving these outcomes in the brain and how they intersect.” These drivers may include aging, substance use, and HIV persistence.

“Currently we have no interventions for individuals who are experiencing cognitive and behavioral challenges and we have been taking a number of interesting research avenues to study the neuroimmunology and virology that accompanies HIV, particularly in the setting of well-treated infection,” he notes, adding that it has been extremely rewarding to try to identify interventions that might lessen the “debilitating challenges” that some PLWH have in order to improve their quality of life.

Focusing on disadvantaged settings

Interventions for PLWH need to include all PLWH. That’s part of the reason why the Ndhlovu Lab, according to its website, also “strives to promote research methods in disadvantaged settings with ongoing studies in Myanmar, Thailand and across Africa.”

“The most vulnerable cases of HIV on a global level are in resource-limiting settings,” Dr. Ndhlovu says about the focus. “Working in Africa early on in the pandemic, it was very distressing to see that lack of access was the biggest challenge to antiretroviral therapies. That obviously changed over time.”

The burgeoning interest in HIV cure research is another reason for the focus, he explains. “Cure studies are mostly done in more resource-viable settings. I think the next generation of investigators and clinicians working in this space could benefit from having the resources to participate in this effort.”

From a research perspective, the “unique features of HIV pathogenesis” will allow the lab to conduct studies in certain regions, Dr. Ndhlovu says, offering examples. Unlike the U.S., Myanmar is still grappling with mother-to-child transmission, and children there are still impacted by HIV and co-infections. Across Africa, he continues, the virus has various clades, whose biology must be understood to develop potentially different cure strategies. He adds: “Thailand offers a unique opportunity to capture individuals very early during infection, which allows us to conduct studies to better understand HIV pathogenesis and also to consider cure strategies at a very early stage when we think we may have a much more robust immune response and the size of the reservoirs may be smaller.”

“I’m happy to add my personal ideas to other ideas … in terms of improving the lives of people with HIV. But obviously the primary goal is to focus on a cure, so we’ll all do our best to push that agenda.”

Targeting HIV reservoir towards a cure

Recently, Dr. Ndhlovu and co-principal investigators, Susana Valente, Ph.D., of University of Florida, and Melanie Ott, M.D., Ph.D., Director of the Gladstone Institute of Virology , were awarded a $26 million grant as a Martin Delaney Collaboratory, the premier National Institutes of Health program for HIV cure research. The funded program, the HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory, will test an innovative HIV cure strategy based on “block, lock, and excise.”

The strategy takes its cue from the fact that ancient viruses, as part of the evolutionary process over millions of years, have integrated themselves into the human genome, yet stay epigenetically silenced or just do not work. As HIV accomplishes the same integrative task, a question arises: Is it possible to intervene in this process, silence the virus and lock it into a “deep” or “super” latent state for good?

Researchers are focusing on the genetic elements that the ancient viruses do not have that HIV reservoir cells do have (and need to reactivate in order to start to replicate): a sequence of DNA at the start of HIV’s genetic code and a protein called Tat. The HOPE collaboratory team has made progress in blocking Tat with certain drug-like small molecules. The team is also looking at altering the three-dimensional structure of the HIV genetic material, which makes it more difficult for other proteins to access the HIV genes and turn them on.

This dual strategy, the HOPE team thinks, could lock HIV into a silent state for good, without continuous treatment.

The “excise” component of the HOPE Collaboratory’s approach takes advantage of recent advances in genome editing. But, says Dr. Ndhlovu, the researchers are in the early stages of putting together advancing these approaches preclinically and in PLWH “to see which ones might be the most effective to target the virus in all of its stages—we think there are three stages of HIV—active, latent, and silenced that need to be targeted.” He also notes that different cure strategies may be needed at different stages of any intervention and likely in combination. “It’s a timing issue—when, where should we deploy these assets, if they work.”

Promoting the power of collaboration

Dr. Ndhlovu says he is very excited to join yet another team—the team at amfAR.

“First of all, I’m honored to help any funding agency that’s going to help us achieve the goal of a cure,” says Dr. Ndhlovu. “I’m happy to add my personal ideas to other ideas … in terms of improving the lives of people with HIV. But obviously the primary goal is to focus on a cure, so we’ll all do our best to push that agenda.”

amfAR has long heralded the practice of collaboration when it comes to HIV research and Dr. Ndhlovu provides his take on what it will take to realize cure goals—looking outside the field and pulling in resources and technologies, creating the space for “unexpected breakthroughs,” and embracing approaches that might entail “a bit more high risk.”

“We have to think outside the box with this virus and teamwork is key. I think it’s going to be exciting to see if we can put our heads together and address this complex issue together.”

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