Neuroimmunology of HIV Infections of the CNS

Organizers: Cedric Raine, Albert Einstein College of Medicine and Susan Morgello, Mount Sinai School of Medicine

Speakers: Sunhee Lee, Albert Einstein College of Medicine; David Volsky, Columbia University; Ehud Lavi, Weill Medical College of Cornell University

Abstracts

Microglia, what roles do they play in the neuropathogenesis of HIV/AIDS? Lessons learned from studies of microglia in vivo and in vitro: Sunhee C. Lee

Studies during the past two decades have brought microglial cells to the very center of human nervous system diseases both as instigators of neuronal dysfunction and potential therapy targets. Human immunodeficiency virus type 1 (HIV-1) specifically infects this cell population in the brain and makes them resistant to apoptotic as well as growth factor-induced signals, prolonging the survival of the virus. Identification of a molecule that is abundant in "resting" microglia that can also be functionally manipulated to suppress cell activation would be a boon. We have identified CD45, the prototype transmembrane tyrosine phosphatase, as such a protein. An agonist antibody to CD45 has a profound inhibitory effect on HIV-1 replication and microglial cell growth. Furthermore, an isoform of CD45 (RB) is constitutively expressed in normal microglia, making it an ideal tool for the study of microglial biology. Antibody-mediated targeting of microglial CD45 may provide a new therapeutic opportunity to suppress microglial activation and delay the progression of nervous system dysfunction in neurodegenerative and neuroinflammatory diseases.

A new model of HIV infection in mice and its application to the study of HIV neuropathogenesis:David J. Volsky

HIV-1 causes neuropathogenesis in a complex and protracted process involving productive infection of brain macrophages, interactions with of astrocytes, induction of neuroinflammation, and eventually neuronal damage. Most of these events are inaccessible to experimental validation in humans. We created a model of HIV-1 infection of conventional mice for investigation of viral replication and pathogenesis. The coding region of gp120 in HIV-1/NL4-3 or HIV-1/NDK was replaced with that of gp80 from ecotropic murine leukemia virus, creating chimeric retroviruses EcoHIV and EcoNDK with exclusive tropism for rodent cells. Adult mice were readily susceptible to infection by a single i.v. or i.p. inoculation of EcoHIV or EcoNDK as shown by detection of virus in splenic lymphocytes, peritoneal macrophages, and brain. At the peak of infection, an estimated 1%-3% of spleen cells and up to 10% of peritoneal macrophages carried HIV DNA; virus burden in brain was lower. The virus produced in animals was infectious and immunogenic. EcoNDK entered the brain within 3-4 weeks of infection, and it induced expression of infection response genes MCP-1, STAT1, IL-1beta, and complement component C3 in brain tissue. Long-term pathogenic and behavioral effects of EcoHIV infection in various strains of mice are under investigation.


The contribution of astrocytes to immune responses in CNS viral infections:Ehud Lavi

The brain has a unique local immune system that mainly consists of microglia and astrocytes, cells that provide the first line of defense against invading microorganisms. Our laboratory is exploring the reaction of astrocytes to viral infections under a variety of conditions. We analyze the proliferative aspects of astrocytes relative to that of microglia in human autopsy brains of individuals infected with HIV. In addition, we use an experimental model system of neurotropic and non-neurotropic coronavirus infection of the brain and brain cells in culture. We explore the pro-inflammatory cytokine, chemokine and signal transduction signaling mechanism during infection of the brain and brain cells. We compare the profile of cytokine signaling of different types of astrocytes in order to define which is the true immune cell among the astrocytes with different morphological and functional phenotypes.