With regard to viruses, the human immunodeficiency virus (HIV) is quite simple. The virus is about 100,000 times smaller than a red blood cell and expresses only dozens of proteins, yet it can create a lifelong infection that, if left untreated, causes acquired immunodeficiency syndrome (AIDS) and death. At Feinberg, HIV science ranges from examining the microscopic mechanisms of primary infection to trials of treatments, all pointing toward the goal of ending one of the world’s largest epidemics.
It was amazing to see science and medicine at work to bring about these improvements. We are seeing a new generation of scientists entering this field, and new perspectives will help us solve this problem.”
Thomas Hope, Ph.D., Professor of Cell Biology and Growth and Obstetrics and Gynecology
Identification of microscopic mechanisms
Many viruses exploit microtubule filaments in host cells, and travel along these “highways” to reach the virus’s preferred reproductive site within the cell. Mojgan Naghavi, PhD, professor of microbiology and immunology, has shown that HIV uses some unusual strategies to do so. The HIV capsid mimics a central regulator of microtubules to control their translocation and disassembly (commonly called uncoating), according to recent studies published in EMBO . magazine And Proceedings of the National Academy of Sciences (PNAS). This allows the virus to coordinate transport, uncoating, and convert its RNA genome into a form of DNA on its way to the nucleus, where it is then integrated into the host cell’s genome.
“More refined drugs that target highly specialized microtubule regulators could be an attractive approach to developing new, non-toxic therapeutic strategies for treating HIV,” Nagavi said.
This mechanism is one example of how HIV “hijacks” original processes in cells and uses them to replicate and spread. HIV is remarkably resourceful, according to Judd Holtquist, PhD, assistant professor of medicine in the Division of Infectious Diseases, who studies how the virus deals with the host cell’s machinery of reproduction.
In a recent study published in Nature CommunicationsHultquist and his collaborators used the CRISPR-Cas9 gene-editing method to eradicate more than 400 different genes in CD4+ T cells isolated from human blood donors. By challenging these cells with HIV in the lab, they were able to identify 86 host factors that the virus uses to reproduce. While nearly half of it has been studied previously, Holtquist said, the other half represent new targets for mechanistic study.
Studying the myriad ways in which HIV infects cells and alters their normal functioning is critical to developing better treatments and a definitive cure, according to Holtquist.
“If we’re going to build a drug with therapeutic potential, it has to be able to eliminate or inactivate the virus in all the places it might be lurking throughout the body,” Holtquist said.
According to Hope, the persistence of the virus is the main reason HIV treatment efforts have failed so far. Even with antiretroviral therapy (ART) that can reduce virus levels to undetectable levels, once someone stops taking these medications, the virus can bounce back. Hope has spent the past two years looking for HIV “depots”, the sites in the body where the virus remains even after treatment.
“Everyone looks in the blood, but the virus is detected in the blood about a week or so after infection,” Hope said. “To find a cure, we need to find these reservoirs where the infection occurs first and where the virus is hiding.”
Develop a better treatment
The past three decades have seen significant improvements in HIV treatment options, but the life expectancy of people with HIV is still shorter than that of other people. Due to the phenomenon of premature aging, people with HIV experience high rates of cardiovascular disease, dementia, and bone loss.
Frank Balilla, MD, Potocsnak Family – Professor of Medicine at CSC in the Division of Infectious Diseases, was recently appointed as associate director of the new Potocsnak Longevity Institute at Northwestern and director of the institute’s Potocsnak Center on Aging and HIV. According to Balila, the institute will address the special needs of elderly people living with HIV through research, education and patient care.
Northwestern is also involved in improving treatments. The three-drug regimen of antiretroviral therapy has worked well, but advances in the drugs themselves now allow for a two-drug regimen. Papafemi Taiwo, MD, Jane Stollerman Professor of Medicine and Chair of Infectious Diseases in the Department of Medicine, led the AIDS Clinical Trials Group (ACTG) study published in the journal.Clinical Infectious Diseases which demonstrated for the first time the effectiveness of this new treatment strategy.
“This portends a shift in the three-drug paradigm as a way to reduce lifelong exposure to these drugs,” Taiwo said. “We know this can be done successfully without compromising suppression.”
Increasing the duration of these treatments is another priority, as most cohorts require daily treatment that can complicate adherence or serve as a constant reminder of HIV infection. Current efforts include long-acting pre-exposure prophylaxis or antiretroviral therapy that can alleviate these problems and increase adherence to treatment.
The future of HIV
The COVID-19 pandemic has forced science and medicine to mobilize collective resources against an emerging threat, which could benefit infectious diseases beyond COVID-19. Of particular interest are developments such as mRNA vaccines, which have been shown to be effective against SARS-CoV-2, but have not yet been tested against a virus that mutates and mutates as rapidly as HIV, according to Hultquist.
“The pandemic has loosened the urgency in terms of testing and trying these big ideas,” Holtquist said. “It also precipitated a historic investment in virus research, and this has enabled us to bring together scientists across disciplines who may have never thought about viruses before, and here we are all working toward one common goal.”
Moreover, many patients with HIV have received stem cell transplants to treat cancer and have been cured of the virus. While this treatment is not possible on a larger scale, it does provide a blueprint for how scientists might one day design a treatment for HIV, according to Taiwo.
“We learn a lot from these patients,” Taiwo said. “We now know the biomarkers of the treatment, and we have a general strategy. But most importantly, we know it’s possible.”
Hope, Nagavi and Tayo are members of the Robert H. Laurie Comprehensive Cancer Center at Northwestern University.