Thanks to the introduction of highly effective drugs, in the developed world an HIV or AIDS diagnosis is no longer the swift death sentence it once was. But although deaths rates have fallen drastically, there has been no corresponding decline in the rates of dementia associated with HIV.
Twenty-five to 30 percent of persons infected with HIV develop an aggressive Alzheimer’s-like dementia even if they are taking anti-HIV drugs. Those figures are about the same as they were in the mid-1990s when highly active antiretroviral therapy, also known as HAART, was introduced.
Although HIV-associated dementia doesn’t kill people, it can quickly impair those who have it. And with people with HIV living longer, the overall number with minor HIV-related cognitive impairment appears to be on the rise.
There is no effective therapy for HIV-associated dementia. But a University of Florida evolutionary biologist is exploring the problem by investigating what genetic changes happen during HIV infection of the brain.
Marco Salemi, Ph.D., an assistant professor in the department of pathology, immunology and laboratory medicine at the UF College of Medicine, has won a five-year, $3.5 million grant from the National Institutes of Health to probe the genetic origins of HIV-associated dementia, using animal models and computational studies.
“It will give us the unprecedented opportunity to study the interaction between HIV and the brain and what causes dementia in HIV-infected people,” Salemi said. “It definitely opens a new way of looking at HIV infection in the brain.”
The research findings could ultimately lead to the development of new tools for diagnosis and treatment of HIV-associated dementia and other AIDS-related neurological disorders. They will also give insights into brain processes involving Alzheimer’s disease.
“Marco has led the way in the genetic analysis of HIV-associated dementia, and I greatly look forward to hearing the results of his new research,” said Oliver Pybus, D. Phil., one of the world’s leading experts in computational analysis of DNA sequences, who is at University of Oxford.
The multidisciplinary effort is a collaboration between UF and Boston College researchers including co-principal investigator Ken Williams, a neurobiologist and expert in the use of animal models to study an HIV-like disease, called SIV, which affects monkeys. The team will include theoretical and experimental researchers in the fields of virology, neurobiology, computational biology and bioinformatics and computer-based analysis of DNA sequences.
The work is also a project of the Florida Center for AIDS Research, which, under the leadership of Maureen M. Goodenow, Ph.D., is working to gain designation from the National Institutes of Health as a center of excellence for HIV/AIDS research.
Salemi’s team will study the forms in which the virus shows up in various tissues involved in brain infection. To examine what happens in the body before and after the brain becomes infected, they will sequence the viral DNA in simian blood, bone marrow and gut and lung tissue infected with a genetically diverse population of viral particles.
After sequencing, the researchers will use computer modeling to track genetic changes in the virus as the disease progresses, and see which virus-infected immune cells travel to the brain.
Salemi’s group was the first, in 2005, to use computational studies to show how HIV affects different parts of the brain.
Previous research shows that HIV-associated cognitive impairment is associated with increased presence in the brain of activated forms of immune system cells called microglia and macrophages. Since nerve cells are not themselves infected by the virus, that suggests there are indirect mechanisms of loss and injury of neurons in the central nervous system.
The researchers aim to identify the different types of immune system cells involved in the entry of disease into the brain and the establishment of viral reservoirs.
In the end, they hope to have compiled the most comprehensive database of the monkey virus sequences from a variety of tissues and cell types. That will help in pinpointing evolutionary “signatures” that could be used to predict and monitor the disease, and form the basis for development of drugs targeted at specific infected cells.