In June 1981 the Centers for Disease Control (CDC) and Prevention published a report about a mysterious illness affecting young homosexual men in Los Angeles. The cause of the unfamiliar disease, eventually dubbed AIDS, would come to light in 1984 with the discovery of the human immunodeficiency virus (HIV). Over a relatively short period of time, extraordinary advances in antiretroviral therapy (ART) transformed HIV/AIDS from a universally fatal disease into a chronic condition. Now some 1.2 million Americans are living with the virus, according to the latest statistics from the CDC.
At the dawn of the HIV epidemic, Northwestern University researchers were at the forefront of understanding the virus, developing therapies to combat AIDS and preventing new infections. Before HIV was even discovered, Northwestern became one of the founding sites in 1983 for the landmark Multicenter AIDS Cohort Study (MACS) — the first and longest running study of the natural history of AIDS. In 2008 the journal Science listed Northwestern among the top 10 institutions making the biggest impact on fighting the disease. Today the battle still rages on, with multidisciplinary experts on both campuses working to prevent and perhaps, even cure HIV, which infects some 40,000 new individuals each year and leads to the premature aging of those with long-term exposure to the virus and ART.
The depth and breadth of HIV/AIDS research at Northwestern Medicine continues to expand and evolve. Our basic, clinical and translational scientists routinely publish in the field’s top peer-reviewed journals and successfully compete for highly coveted National Institutes of Health (NIH) grants. Here’s just a sampling of how Northwestern investigators are working to defeat this still deadly and widespread global disease.
A United Front
With the largest HIV-infected population in the world, South Africa maintains a solid lead, but Chicago is unfortunately catching up in the ratings game—of recently diagnosed HIV infections, that is.
In the United States, young men who have sex with men (YMSM) have the highest rate of new cases reported each year. In Chicago, HIV infection in this demographic group (ages 16-29) is rising at a disturbing five percent annually, with most cases occurring in black gay men. Feinberg School of Medicine investigators hope to reverse this trend with the support of a recent $6.25 million NIH grant awarded to Northwestern Medicine and other Chicago-area academic, municipal and community partners in August. The federal funding will support the creation of the Third Coast Center for AIDS Research (CFAR) to quell the HIV epidemic among young men in the Windy City.
Richard D’Aquila, MD, CFAR director, head of the Northwestern HIV Translational Research Center and Howard Taylor Ricketts Professor of Medicine, has worked on a number of groundbreaking projects during his long career. This May, he and Harry Taylor, PhD, research assistant professor of Medicine in the Division of Infectious Diseases, detailed in PLOS Pathogens an exciting discovery: how to take advantage of HIV’s sugar fix as the virus can’t live without it. In laboratory in vitro studies, researchers found a small molecule that blocks the virus’ access to sugar and other nutrients in HIV-invaded immune cells. This sugar-free diet prevented the virus from replicating itself in human cells, without harming the cells in vitro.
Another significant research effort in the D’Aquila lab focuses on novel drug therapies to boost a defensive immune system protein called APOBEC3G (or A3 for short) to achieve sustained remission after ART stops or, optimistically speaking, a cure. He and his colleagues discovered that more ample stores of cellular A3 appear to enable one percent of HIV-infected individuals to control the virus naturally and without antiviral drugs. First published in 2013 in PLOS ONE, this finding has important implications for shortening ART, which, along with continuing chronic inflammation caused by the virus, may contribute to the premature onset of health problems such as heart disease and stroke in this patient population.
Cross-campus collaborations have proven fruitful. Chisu Song, PhD, research assistant professor of Medicine in the Division of Infectious Diseases, partnered with investigator Gary Schiltz, PhD, at the Center for Molecular Innovation and Drug Discovery on the Evanston campus and D’Aquila to discover small molecules that increase A3 in vitro. The hope is that this will keep A3 from being depleted after HIV infection, and enable more of those infected to control HIV off of antiretroviral therapy. Planning to launch testing of promising A3 boosters discovered at NU in mice and then monkey models in 2016, Dr. D’Aquila sees the new CFAR as a valuable asset in accelerating research toward helping the other 99 percent of those with HIV control their disease off drug therapy. “The center will reach out to a segment of the population now contracting the virus,” says the professor of Medicine in the Division of Infectious Diseases. “This effort will provide us with the very individuals who we think would benefit most from new strategies for cure or sustained remission: the young people who are now becoming infected.”
Romance Gone Viral
What does love have to do with HIV? Perhaps a great deal, according to Brian Mustanski, PhD, director of a recently launched Northwestern University-wide Institute for Sexual and Gender Minority Health and Wellbeing.
“It was often assumed that casual hookups put young gay men at the highest risk of HIV infection,” says the co-director of CFAR and associate professor of Medical Social Sciences, who studies mental and behavioral factors as they relate to HIV/AIDS in young gay and bisexual men. “Our research revealed that HIV transmission appears more likely to occur among individuals involved in serious romantic relationships. It’s hard to have love without trust, and it’s hard to self-protect when you have that trust. Understanding this tension allows us to develop and put into place interventions that address the compatibility of romance and HIV prevention.”
A translational behavioral scientist, Mustanski conducts research projects focused on HIV and LGBT health. The data he collects ultimately leads to novel HIV prevention tactics such as text messaging and social media to reach a younger generation of people at risk. He serves as the principal investigator of RADAR, a study aimed at identifying and understanding the connections among sexually transmitted diseases like HIV, alcohol and drug use and romantic or sexual patterns over time in YMSM. Supported by an $8.7 million five-year grant from the National Institute on Drug Abuse awarded in 2014, this major research endeavor employs a multilevel approach, from looking at the micro level of genetics of the virus to the macro level of sexual and social networks.
“Not only are we creating one of the largest longitudinal studies of young gay and bisexual men and their romantic partners,” says Mustanski, “but we are also creating new ways to integrate across different social science and biomedical pieces involved in driving new HIV infections.”
Tried and true methods to prevent the sexual transmission of HIV exist to keep the virus at bay. Condoms, abstinence or popping an oral antiviral pill once a day work well—when used. The problem? Not enough of those at most risk for contracting the virus take the necessary precautions to safeguard themselves and others.
Building another defense against HIV infection, Northwestern Medicine scientists have recently embarked on an extensive multidisciplinary endeavor to develop an innovative implantable drug system. They hope to design a subcutaneous implant that will automatically deliver a controlled dose of antiretroviral medication such as cabotegravir and last for up to a year. Supported by a recently awarded $17.5 million National Institute of Allergy and Infectious Diseases (NIAID) grant, biomedical engineer Patrick Kiser, PhD, and immunologist Thomas Hope, PhD, are co-PIs of the Sustained Long-Acting Protection Against HIV (SLAP HIV) program aimed at protecting individuals who need it most.
“The virus frequently targets the dispossessed, the uninformed or those who think they are invincible,” says Kiser, associate professor of Obstetrics and Gynecology and Biomedical Engineering at the McCormick School of Engineering. “We need more tools to decrease transmission rates. HIV is an insidious virus. You can’t take your eye off of it for a moment.”
A viable vaccine for HIV has remained elusive since its discovery more than three decades ago. The virus’ uncanny ability to thwart the immune system has stymied scientists the world over. Hope, professor of Cell and Molecular Biology, Obstetrics and Gynecology and Biomedical Engineering, has focused his work on mucus and its potential role in fighting invading pathogens such as HIV. Found in many areas of the human body, mucus contains antibodies produced by our immune system to create a protective barrier. The Hope laboratory has studied how HIV moves in this environment, searching for molecules that might offer the best defense against the virus. The investigators recently discovered tight binding sites in antibodies residing in mucin, the protein that makes up mucus, which tether pathogens and then allow the mucus to expel them. This finding has the potential to advance progress toward a vaccine. Says Hope, “By understanding how some antibodies interact with certain mucin, we might be able to identify approaches that will move us closer to developing an effective vaccination against HIV.”
Genomics of HIV
HIV thoroughly takes advantage of its infected host. It targets the very immune response that would normally kill it to replicate or lie dormant for years. Taking advantage of human proteins, HIV invades immune cells and convinces the host DNA to help it copy itself over and over again. But not every host or person is a willing participant based on their unique genetic makeup.
“In our lab, we seek host cell genetic variants that protect some people from HIV infection or disease progression,” says Steven Wolinsky, MD, ’82 GME, chief of Infectious Diseases and Samuel J. Sackett Professor of Medicine. “Natural variations in the expression levels of human proteins typically borrowed by the virus can hinder HIV replication and significantly impact how the immune system fights off the virus.”
The Wolinsky laboratory studies the extent of human genetic variations that influence HIV/AIDS susceptibility by analyzing the genomes of hundreds of HIV-infected patients. Better understanding how our DNA contributes to the evolution of the virus and development of AIDS and other diseases could lead to potential drug targets and improvements in patient care.
A renowned HIV researcher and principal investigator of the prestigious Multicenter AIDS Cohort Study since 2000, Wolinsky has witnessed the great strides made in fighting the disease, but more still needs to be accomplished.
“Although advancements have made it possible for people with HIV to live much longer lives, they are aging faster and developing health problems more often seen in uninfected people 10 or 20 years their senior,” he says. “Through MACS and the efforts of investigators at Northwestern and around the world, we hope to better manage the care and treatment of people living with HIV/AIDS and move closer to a functional cure.”