VIRAL SANCTUARY IN THE CENTRAL NERVOUS SYSTEM

  • Petito, Carol, (PI)

Project: Research project

Description

The central nervous system is often infected by HIV. Not only does this brain infection result in an encephalitis, an infection closely linked to AIDS dementia, but also this brain infection may provide a site that allows HIV to replicate in the setting of highly active anti-retroviral therapy. Our own studies suggest that the choroid plexus may be an important sanctuary for HIV since productive HIV infection develops in monocytes and dendritic cells in this structure even during the period of clinical latency, when brain infection is absent or nonproductive. We found CPx infection in 58% of AIDS cases in whom HIVE was present in only 20%. Similarly, we found Cpx infection in 2 of 7 asymptomatic HIV-infected cases, none of whom had productive brain infection. During the course of these investigations, we detected specific viral sequences from brain isolates that may identify neurotropism although we did not find evidence of sequences identifying neurovirulence in the small population of AIDS cases so studied (n=4). We also have examined in greater detail the biological significance of the AIDS-related breakdown of the blood-brain barrier (BBB), a finding first identified by us in post-mortem brains of AIDS patients several years ago. In this setting, the BBB leak significantly correlated with intramural and perivascular T cell infiltrates in end-stage patients. Although the causal relationship between these two events are not known, we hypothesize that the immune cell entry causes the barrier leak which may, in turn, enhance the immune cell entry. The present application will explore the hypotheses that l) the Cpx is initial hematogenous dissemination of HIV; 2) viral- infected immune cells infect brain after the onset of immunosuppression and AIDS and 3) specific sites provide CNS sanctuary for HIV. These hypotheses will be explored in human autopsy material from controls, asymptomatic HIV-infected and AIDS cases with and without HIVE as well as in animal models combining BBB break with immune cell activation. The hypotheses and their specific aims address the central goal and selective subaims of RFA #NS99-002, "Central Nervous System as the HIV Sanctuary".
StatusFinished
Effective start/end date8/1/9911/30/06

Funding

  • National Institutes of Health: $435,183.00
  • National Institutes of Health: $50,000.00
  • National Institutes of Health: $446,847.00
  • National Institutes of Health: $423,855.00
  • National Institutes of Health: $50,000.00
  • National Institutes of Health: $412,857.00
  • National Institutes of Health: $432,280.00

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Acquired Immunodeficiency Syndrome
Central Nervous System
HIV
Brain
Infection
Blood-Brain Barrier
HIV-2
Choroid Plexus
Immunosuppression
Dendritic Cells
HIV Infections
Dementia
Monocytes
Autopsy
Animal Models
T-Lymphocytes
Population

ASJC

  • Medicine(all)
  • Neuroscience(all)