October 2016

In a Teenager’s Brain, HIV Infection Could Cause Unique Damage

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From the 1990s to today, a lot has changed. Babies born in that decade are now older adolescents and young adults. “Personal digital assistants” disappeared and were replaced with voice-activated intelligent helpers in our cell phones. Plaid went out of style and then came back again.

The face of the AIDS crisis has dramatically changed in the U.S., too. Then highly stigmatized from its 1980s emergence as a rapidly deadly infection highly transmitted among adult men who have sex with men, today HIV infection is often a manageable chronic disease that affects men and women of all ages. A major frontier now in HIV treatment is the need to handle complications for those already infected, including neurocognitive disorders.

And there is one more significant change: Many of those babies of the 1990s, from teenagers up through age 24, now make up about a quarter of new HIV infections each year, according to Centers for Disease Control and Prevention data. Among high-risk subsets of youth age 13 to 24, the annual incidence of new infections has increased by as much as 87 percent — even though, overall, new HIV infections in the U.S. declined 19 percent over the last decade.

“I would argue that this is really the face of the new epidemic in the United States,” said Jennifer McGuire, MD, a pediatric neurologist specializing in neurologic infections at Children’s Hospital of Philadelphia and assistant professor of Neurology and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Dr. McGuire is working to learn more about where two of those national HIV trends intersect with the study of how infection processes might cause age-specific brain changes and cognitive difficulties for young people through mechanisms involving inflammation in the brain. This area is understudied and ripe for new discoveries. No published studies to date focus specifically on neuroimaging data in adolescents with HIV, and published data about cognitive function in this population is also scarce.

“This is a really important question because when teenagers acquire HIV in their mid to late teens, it happens during a very active time of brain development,” Dr. McGuire said. “A lot of people may think that by the time you’re a teenager your brain is fully developed. But, in fact, brain maturation actively continues into the late third decade, particularly in refining areas of logic, abstract thought, planning, and risk assessment.”

Dr. McGuire recently completed a pilot study with 14 young adults with HIV at CHOP. These 18- to 22-year-old participants had measurable cognitive impairments at a rate about as high as that commonly seen in adult HIV populations more broadly, despite having been infected for relatively short periods of time and having healthier immune systems — both indicators that usually predict better cognitive performance among infected adults. MRI brain images from a subset of these youth also showed profoundly lower volumes in specific deep gray matter structures in the brain, compared to age- and sex-matched historical controls without HIV. Studies in adults with HIV had shown volume losses in these brain regions before, but not at such a high magnitude.

“This really prompts us to ask the question, is there some sort of age-specific HIV-mediated neuropathogenesis that’s happening here? And, if so, why?” Dr. McGuire said.

She is continuing to try to answer the first question with a new, five-year prospective study funded by the National Institute of Neurological Disorders and Stroke. The new brain-imaging study will enroll 40 youth from CHOP’s Adolescent HIV Initiative, from Penn, and from Philadelphia FIGHT, who have HIV and no history of cognitive impairment prior to their infection. A novel aspect of the study is its recruitment of a control population of 30 uninfected youth from Philadelphia FIGHT’s community center geared toward HIV prevention and support services for at-risk youth. Youth at the highest risk for acquiring HIV are more likely to be members of disadvantaged and stigmatized groups, including LGBT youth and youth of color, and they are more likely to be exposed to difficulties including poverty, trauma, and illicit drug use. By enrolling youth who share such risk factors and demographics, the researchers can control for the potential influences of these factors on cognitive function to identify whether there are indeed brain changes induced by HIV infection itself that are specific to youth.

While she continues to pursue this question, Dr. McGuire is also performing lab research in an effort to answer her second question: If so, why?

She and colleagues recently published a paper examining one of these possible mechanisms, a part of the innate immune system called the complement system that becomes activated in the body’s periphery when a person becomes infected with HIV. In the healthy brain, the complement system helps prune unneeded neural connections during normal brain maturation in adolescence and early adulthood, so Dr. McGuire and colleagues hypothesized that HIV infection could cause unique neurological damage in youth if it is ramped up in the brain at the time of HIV infection. Their small study, published in the Journal of Neurovirology, offered some preliminary evidence of associations between complement proteins and a biological marker of neurodegeneration in cerebrospinal fluid samples from youth. She is proceeding with a larger study examining expanded immune profiles in an effort to better identify and describe a potential mechanism.

Answering these questions is important to support youth because with antiretroviral medicines, people can live with HIV for decades. If the infection interferes with young people’s brain development, though, it could impede their success with finishing school, getting good jobs, and being functional members of society throughout their lives. In addition, there is a chance that HIV transmission itself might be affected by these neurological impacts if they involve parts of the brain involved in risk assessment and decision making, which are still developing during the teens and early-mid 20s. Knowing the mechanisms and clinical patterns of age-specific neurological damage could lead to new youth-targeted pharmaceutical treatments as well as approaches focused on cognitive rehabilitation.

While she pursues these research questions, Dr. McGuire also continues to help patients in the clinic. Working with infectious disease specialist Sanjeev Swami, MD, she co-leads a new clinical program in neurological infections at CHOP, which may be the first of its kind in the country. The clinic will care for youth with HIV and a variety of other infections affecting the brain and will ultimately integrate clinical care and research.

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