Joseph Mankowski of Molecular and Comparative Pathobiology on investigating HIV and the journey from veterinarian to researcher:
How did you get involved in research?
MANKOWSKI: I’m a veterinarian as well as a Ph.D. I was a neurobiology undergraduate, but my ultimate goal was to practice veterinary medicine. I wanted to be an equine veterinarian because I grew up with horses on our family farm. After vet school at Cornell, I did a clinical internship at the University of Pennsylvania and then spent four years in private practice. My practice included a hospital setting instead of just going to farms to treat horses. We performed surgery and managed medical cases in our clinic.
One day I got a call from Penn asking whether I would consider a residency in equine internal medicine. I thought about it quite a bit, but realized I was looking for something that had a broader horizon. I was intrigued by infectious diseases and was eventually drawn into doing a Ph.D. at Hopkins as well as a residency in pathology. Those were trying times doing both at the same time, but ultimately I was able to make it work. I was investigating virus entry across the blood-brain barrier for my Ph.D., and performing both human and animal post-mortem exams. The background in comparative pathology set me up for a career studying viral infections in the brain.
How does HIV affect the nervous system?
MANKOWSKI: Human immunodeficiency virus, HIV, is well known to infect and cause loss of immune cells, but it can also cause disease in other organ systems including the nervous system. I study the impact of HIV on the peripheral nervous system—the nerves outside of the brain and spinal cord. Damage to the peripheral nervous system can create a syndrome called sensory neuropathy, which manifests itself as persistent very painful burning on the soles of the feet—one patient described it as living years of his life walking on sharp glass.
HIV also damages the brain. It used to be that HIV would commonly cause overt dementia, but now treatment makes that much less common. However, today’s AIDS treatment cannot fully clear the virus because HIV is able to hide out indefinitely by incorporating itself into the genome of a patient’s cells. This means HIV-infected individuals must be treated for a lifetime, and neurological symptoms can still develop. I study why these HIV associated neurocognitive disorders develop.
How do you study the effects of HIV?
MANKOWSKI: We’ve been collaborating with members of the Departments of Neurology and Neurosurgery to explore how HIV causes sensory neuropathy in macaques. We’ve investigated how HIV affects the sensory neurons of dorsal root ganglia—incredibly amazing, long cells that track from the spinal cord all the way from the bottom of the feet. We’ve correlated the amount of virus and inflammation in the ganglia with a reduction in the nerve’s effectiveness in transmitting signals and seen that the virus mostly affects the longest nerves in the body.
Not all macaques develop the disease. We’re also trying to figure out why, genetically speaking, some develop the disease and others don’t. We’ve found a class of genes that appears to be neuroprotective— animals are six times less likely to develop nervous system changes if they have this gene. We’d like to know if eventually we can manipulate similar genes in humans to prevent the neurological effects of HIV.
Do you study any other aspects of HIV?
MANKOWSKI: We also study how HIV damages the heart—we’ve seen a decline in the heart’s ability to pump blood, especially the phase when the heart fills with blood. This mirrors what has been shown in many HIV studies, that HIV can cause dysfunction and heart failure even while patients are being treated.
It turns out that the decline isn’t entirely due to inflammation; it’s actually directly related to the amount of virus replicating within the heart. We’ve been interested in finding why this is the case, since other tissues in the body, like the brain, may be damaged primarily by inflammation. Our hypothesis is that the virus is actually binding to receptors on the muscle cells, which impairs contracting and relaxing. Because of this, we’ve done some pilot studies by treating animals with a compound that blocks that receptor. We’ve found that the compound reduces the disease’s growth in the heart, improving cardiac function.
--Interviewed by Vanessa McMains, edited by Sarah Lewin
Joseph Mankowski on how HIV damages organs: