New study describes molecular basis of NeuroAIDS

May 3 2006

Using multi-disciplinary analysis that included cognitive, neurophysiologic, virologic, and molecular techniques, the team found both a low-level viral infection in the brain and immune cells that had infiltrated the brain in order to protect against the virus.

"As in the rest of the body, in the brain immune cells achieve a level of control of the virus, but are unable to clear the infection," says Howard Fox, associate professor at Scripps Research and director of Scripps NeuroAIDS Preclinical Studies center, who led the study. "Over the long-term, this immune response may act as a double-edged sword, protecting against rampant viral replication in the brain but leading to brain dysfunction."

The paper was published in the Journal of Neuroscience, the official journal of the Society of Neuroscience.

The study addresses a significant health problem. About one quarter to one third of all AIDS patients suffer from some form of central nervous system disorder in the course of their infection, ranging from minor cognitive and motor disorders to severe dementia, collectively known as neuroAIDS. Even subtle neurocognitive disorders limit quality of life with symptoms such as fatigue, and are correlated with difficulties ranging from a higher rate of traffic tickets to increased mortality.

In recent years, access to potent antiretroviral drugs in the United States and other developed countries has significantly improved the health, survival, and functioning of HIV-infected individuals. But since people are living longer with the virus, the overall prevalence of neuroAIDS appears to be increasing.

"Now that we're better at treating the immune/viral aspect of HIV, in many ways [AIDS] has turned into a chronic disease," says Fox. "The fact that many of the antiretroviral drugs do not show good penetration of the blood-brain barrier further puts the brain at risk, since the brain is infected soon after HIV exposure and infection."

While previous studies had linked end-stage dementia due to HIV to the presence of infected and activated immune cells, the nature of neurological changes in earlier stages of the disease, the so-called "chronic phase," were unknown-until now.

Using simian immunodeficiency virus-infected models in the chronic phase, the research team found both virus and infiltrating lymphocytes (CD8+ T cells) in the brain. Molecular analysis revealed that the expression of several immune response genes was increased, including CCL5, which has multiple effects on neurons as well as immune cells. CCL5 was significantly upregulated throughout the course of infection, and was present in the infiltrating lymphocytes.

In addition to Fox, authors of the April 26, 2006 Journal of Neuroscience (Volume 26, Number 17) paper, titled "Host Response and Dysfunction in the CNS During Chronic SIV Infection," are: Eleanor Roberts, Salvador Huitron-Resendiz, Michael Taffe, Cecilia Marcondes, Claudia Flynn, Caroline Lanigan, Jennifer Hammond, Steven Head, and Steven Henriksen.