Immune Response to HIV in the Brain a "Double-Edged Sword"

By Mika Ono

A team of researchers at The Scripps Research Institute has shed new light on the molecular basis of problems with brain function in models chronically infected with an immune deficiency virus similar to human immunodeficiency virus (HIV), the cause of acquired immune deficiency syndrome (AIDS). The findings may ultimately lead to new therapeutic interventions to prevent or reverse nervous system disorders in HIV-infected individuals.

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 April 26 issue of 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.

The recent research was supported by research grants from the National Institute of Mental Health (NIMH) of the National Institutes of Health, as well as an NIMH center grant, which provides support for research-associated infrastructure and training.

Moving Research Forward

The publication coincides with an $11.2 million award for a five-year renewal of the center called Scripps NeuroAIDS Preclinical Studies (a.k.a. SNAPS), which works with Scripps Research, local San Diego, national, and international investigators to understand, treat, and prevent neurological complications of HIV infection.

"The renewal of the center's grant will bring exciting new changes in the approaches and techniques used to further the mission of the NIMH and Scripps investigators," says Fox. "This work is an example of how the center is moving research forward."

The multi-disciplinary center is built around a number of core facilities.

• The Physiology Core, directed by Scripps Research Associate Professor Donna Gruol, provides in vivo, ex vivo, and in vitro studies essential to understanding how infection affects the central nervous system.

• The Phenomics Core, led by Gary Siuzdak, senior director of Scripps Research's Mass Spectroscopy facility, with the assistance of Steve Head, director of Scripps Research's DNA Microarray Facility, combines genomics, proteomics, and metabolomics.

• The Chemical Library Screening Core, led by Scripps Research Professor John Elder, is being instituted to provide the relevant biochemical and cell-based screening for preclinical therapeutics. The core uses chemical libraries provided by several members of the Scripps Research Department of Chemistry.

• A Systems Biology Core, led by Trey Ideker of the Bioengineering Department at the University of California, San Diego, is also being launched. This core enables the development of integrative models of HIV infection, particularly in macrophages and brain tissue, by combining expression data, transcription factor location data, protein-protein interaction data, and metabolomic data, helping scientists to study multiple aspects of the system as a single entity.

To support the existing neuroAIDS research at Scripps Research and to encourage other scientists to become interested in the area, the SNAPS center holds monthly meetings focusing on recent research on neuroAIDS and its basic scientific underpinnings.

For more information on the center, see the SNAPS web site at http://www.scripps.edu/services/snaps/. For more information on Fox, see his faculty web page.

Send comments to: mikaono[at]scripps.edu

The latest study by Associate Professor Howard Fox suggests that the same immune response that protects against rampant viral replication of HIV in the brain may also lead to brain dysfunction. Photo by Michael Balderas.