People who are HIV positive can expect to live an average lifespan – a prospect that was unheard of only a generation ago. But while anti-retroviral drugs have tamed one aspect of this once-deadly condition, HIV has proven to be a stubborn adversary that continues to linger and haunt its victims.
Two EVMS faculty members hope to help ease this burden. Woong-Ki Kim, PhD, and Ming-Lei Guo, PhD, have received a combined $5.5 million in a pair of R01 grants from the National Institutes of Health to fund research to better understand the virus.
An estimated 27,000 people living with HIV reside in Virginia – including 8,000 in Hampton Roads. The hope is that new understanding of HIV will contribute to the development of more effective therapies.
Dr. Kim, Associate Dean for Research Faculty Development and Research Facilities and Professor of Microbiology and Molecular Cell Biology, is continuing his work to find and eliminate remnants of the virus that persist even after treatment.
“Despite effective anti-retroviral therapy (ART) that maintains HIV at non-detectable levels [in blood], HIV is not eradicated,” Dr. Kim says. “When individuals are off ART, or during ‘viral blips,’ viral reservoirs in the central nervous system can quickly rebound.”
Dr. Kim and others have found that a favorite hiding place is in perivascular macrophages (PVMs) — a type of protective white blood cell in the central nervous system. This HIV reservoir persists despite ART treatment, silently awaiting an opportunity to attack the body once again.
HIV targets these macrophages early during infection and throughout infection even with effective ART, Dr. Kim says.
In his research, funded by a $3.6 million grant, Dr. Kim will test the effectiveness of an experimental anti-cancer compound to prevent the virus from accumulating in the brain. They will test at multiple intervals – three and five months – to make sure the process works. If it works in animal models, it could eventually make its way into human research.
Dr. Guo, Assistant Professor of Pathology and Anatomy, is the first faculty recruit through the new Center for Integrative Neuroscience and Inflammatory Diseases (CINID). He is working with Dr. Kim, also a member of the CINID team, on a second HIV-related grant, this one valued at $1.9 million and studying the impact of HIV on neuropsychiatric disorders.
“People living with HIV have comparable life-expectancy as their HIV-negative peers but their life-quality is deeply compromised due to the high prevalence of neuropsychiatric disorders, including depression and anxiety,” he says. No effective treatment exists.
Among people with HIV, drug abuse is very common, particularly in developed countries, says Dr. Guo, who has had three previous NIH grants focused on HIV and drug abuse. Cocaine, in particular, can over-activate “microglia” — cells within the brain involved in the body’s immune response — injuring neurons and in the process exacerbating neurological disorders.
Evidence suggests that there are several potential contributing factors, including proteins expressed by the concealed virus, the long-term use of antiretrovirals to suppress the virus and the impact of cocaine and other drugs of abuse.
Drs. Guo and Kim will focus their research on a newly identified pathway known as “NLRP3 inflammasome signaling.” Tantalizing preliminary data points to NLRP3 as a key part of the intracellular communications behind the neurological damage, Dr. Guo says. They will test this hypothesis and study if by blocking these communications they can prevent neurological damages.
Their research findings could provide a foundation for the development of treatments to help ease the disorders and perhaps even reverse the neuronal damage. Potentially, a medication to block NLRP3 could be used to prevent the damage.