Depletion of CLIP170 or DCTN1 in human cells causes only modest decreases in microtubule dynamics, determined by measuring comet EB1 lengths (in green), which track the growth of microtubule ends. The nucleus of human cells is in blue.
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As far as viruses go, the human immunodeficiency virus (HIV) is pretty straightforward. About 100,000 times smaller than a red blood cell, the virus expresses only a dozen proteins, but it can establish a lifelong infection that, if left untreated, causes acquired immune deficiency syndrome ( AIDS) and death. At Feinberg, HIV science ranges from examining the microscopic mechanisms of initial infection to testing treatments, all directed toward the goal of ending one of the world’s greatest pandemics.
Thomas Hope, PhD, professor of cell and developmental biology, obstetrics and gynecology and member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.
“It’s amazing to see science and medicine working to produce these improvements,” said Thomas Hope, PhD, professor of cell and developmental biology and obstetrics and gynecology. “We are seeing a new generation of scientists entering the field, and these new insights will help us solve this problem.”
Identify microscopic mechanisms
Many viruses exploit microtubule filaments in host cells, traveling along these “highways” to reach the virus’ preferred site of replication within a cell. Mojgan Naghavi, PhD, professor of microbiology-immunology, showed that HIV uses unusual strategies to do this; According to recent studies published in The EMBO newspaper and Proceedings of the National Academy of Sciences (PNAS). This allows the virus to coordinate the transport, stripping and conversion of its RNA genome into a DNA form on its way to the nucleus, where it then integrates into the host cell’s genome.
“More refined drugs targeting highly specialized microtubule regulators could potentially be an attractive approach for the development of novel, non-toxic therapeutic strategies to treat HIV,” Naghavi said.
Judd Hultquist, PhD, assistant professor of medicine in the Division of Infectious Diseases, associate director of the Center for Pathogen Genomics and Microbial Evolution.
This mechanism is an example of how HIV “hijacks” native processes in cells and uses them to replicate and spread. HIV is remarkably resourceful, according to Judd Hultquist, PhD, an assistant professor of medicine in the Division of Infectious Diseases, who studies how the virus manipulates the host cell’s machinery to replicate itself.
In a recent study published in Nature Communication, Hultquist and co-workers used a CRISPR-Cas9 gene-editing approach to knock out 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 replicate. While nearly half of them have been previously studied, the other half represent new targets for mechanistic study, Hultquist said.
Studying the myriad ways that HIV infects cells and impairs their normal function is key to developing better treatments and a possible cure, Hultquist says.
“If we want to create a drug with curative potential, it must be able to eliminate or deactivate the virus in all places where it can hide in the body,” Hultquist said.
The persistence of the virus is the main reason that efforts to cure HIV have so far proven unsuccessful, according to Hope. Even with antiretroviral therapy (ART) that can reduce virus levels to undetectable levels, as soon as someone stops taking these drugs, the virus can rebound. Hope has spent the past two years looking for “reservoirs” of HIV, the places in the body where the virus remains even after treatment.
“Everyone looks in the blood, but the virus isn’t detected in the blood until about a week after infection,” Hope said. “To find a cure, we need to find those reservoirs where the infection first occurs and where the virus hides.”
Develop a better treatment
The last three decades have seen significant improvements in HIV treatment options, but the life expectancy of people living with HIV is still shorter than that of other people. Due to premature aging, people living with HIV experience high rates of cardiovascular disease, dementia and bone loss.
Frank Palella, MD, Potocsnak Family – CSC Professor of Medicine in the Division of Infectious Diseases, Associate Director of the Potocsnak Longevity Institute, and Director of the Potocsnak Center for Aging and HIV.
Frank Palella, MD, Potocsnak – CSC Professor of Family Medicine in the Division of Infectious Diseases, was recently named associate director of Northwestern’s new Potocsnak Longevity Institute and director of the institute’s Potocsnak Center for Aging and HIV. . The institute will address the special needs of people aging with HIV through research, education and patient care, according to Palella.
Northwestern is also involved in improving therapies. The classic three-drug ART regimen has worked well, but advances in the drugs themselves now allow for a two-drug regimen. Babafemi Taiwo, MBBS, Gene Stollerman Professor of Medicine and Chief of Infectious Diseases in the Department of Medicine, led the AIDS Clinical Trial Group (ACTG) study published in the journalClinical infectious disease who first showed the effectiveness of this new treatment strategy.
“This heralds a shift in the three-drug paradigm as a way to reduce lifetime 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 regiments require daily medications that can complicate adherence or serve as a constant reminder of HIV infection. Current efforts include long-acting pre-exposure prophylaxis, or ART, which may alleviate these problems and increase treatment adherence.
The future of HIV
The COVID-19 pandemic has forced science and medicine to mobilize collective resources against an emerging threat, which could pay dividends for infectious diseases beyond COVID-19. Of particular interest are advancements such as mRNA vaccines, which have been shown to be effective against SARS-CoV-2 but have yet to be tested against a virus that mutates and changes as rapidly as HIV, according to Hultquist.
“The pandemic has loosened the wheels in terms of testing and trying these big ideas,” Hultquist said. “It also precipitated a historic investment in virus research, and it allowed us to bring together scientists from various disciplines who may have never even thought about viruses before, and here we are all working towards one goal. commmon.”
Additionally, several HIV-positive patients have received stem cell transplants to treat cancer and have been cured of the virus. While this treatment may not be feasible on a larger scale, it provides a blueprint for how scientists might one day design a cure for HIV, according to Taiwo.
“We learn a lot from these patients,” Taiwo said. “We now know the biological markers of healing, and we have a general strategy. But the most important; we know it is possible.
Hope, Naghavi and Taiwo are members of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.