HIV dementia has only rarely been reported from countries infected with clade C virus. Opportunistic infections of the nervous system, however, are a major cause of morbidity and mortality in these developing countries. For example, in India where there are nearly 5 million patients are infected with the virus, it was estimated that nearly 25% of patients have CNS manifestations, most of which are opportunistic infections. Since these infections are treatable, it is imperative to determine the long-term impact of these infections on the brain. Preliminary data shows that the inflammatory infiltrates associated with these infections have a large number of HIV infected macrophages. It remains unknown, however, if inflammatory infiltrates associated with the opportunistic infection may serve as a portal of entry for HIV and if the virus may then establish residence in the brain and then continue to evolve within the brain. The degree to which these strains may cause neuro-glial cell dysfunction remains unknown. Further it remains unknown if patients with meningeal infiltrates would be at similar risks as those with parenchymal infiltrates. A major limitation to studying these neuropathological consequences of HIV clade C virus infection is the lack of autopsy tissues from these countries. NIMHANS is a unique institution that has conducted autopsies on patients that have died of AIDS since 1990. To the best of our knowledge, this is the only source of well characterized brain tissue specimens from HIV infected patients in Asia and Africa. This represents an excellent opportunity to address questions about disease pathogenesis that could not have been done otherwise. We thus propose to, 1. To determine the extent of glial cell activation and neuronal injury in HIV infected patients with CNS toxoplasmosis or tuberculosis. 2. To identify and compare viral sequences from HIV infected cells in inflammatory infiltrates associated with CNS toxoplasmosis or tuberculosis. 3. To determine if brain derived sequences of env and tat in inflammatory infiltrates cause glial cell activation or neuronal injury in vitro. These goals will be accomplished through collaborative efforts between Johns Hopkins University and NIMHANS. An excellent working relationship has already been established between the two institutions over the last several years. We have also devised a plan for training and technology transfer for the NIMHANS investigators.

Public Health Relevance

CNS opportunistic infections are the major cause of morbidity and mortality in HIV infected populations in the developing world, however, the long-term impact of these diseases on the brain of patients successfully treated for these infections remains unknown. Using a unique resource of human brain autopsy tissue from India and a combined histopathological, molecular and cellular approach we will determine the mechanism of viral entry into the brain in the setting of the opportunistic infection and will also determine the impact of these infections on uninfected brain cells. This information will be critical in developing guidelines for long-term management of HIV-infected patients with opportunistic infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055628-05
Application #
8304304
Study Section
Special Emphasis Panel (ZRG1-BDA-K (51))
Program Officer
Wong, May
Project Start
2008-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$321,457
Indirect Cost
$102,779
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Pardo, Carlos A; Nabbout, Rima; Galanopoulou, Aristea S (2014) Mechanisms of epileptogenesis in pediatric epileptic syndromes: Rasmussen encephalitis, infantile spasms, and febrile infection-related epilepsy syndrome (FIRES). Neurotherapeutics 11:297-310
Netravathi, M; Mahadevan, Anita; Satishchandra, Parthasarathy et al. (2013) Progressive multifocal leukoencephalopathy (PML) associated with HIV Clade C--is not uncommon. J Neurovirol 19:198-208
Joseph, Jeymohan; Achim, Cristian L; Boivin, Michael J et al. (2013) Global NeuroAIDS roundtable. J Neurovirol 19:1-9
Nath, Avindra; Clements, Janice E (2011) Eradication of HIV from the brain: reasons for pause. AIDS 25:577-80
Johnson, Tory; Nath, Avindra (2011) Immune reconstitution inflammatory syndrome and the central nervous system. Curr Opin Neurol 24:284-90
Kumar, G G Sharath; Mahadevan, A; Guruprasad, A S et al. (2010) Eccentric target sign in cerebral toxoplasmosis: neuropathological correlate to the imaging feature. J Magn Reson Imaging 31:1469-72
Clifford, David B; De Luca, Andrea; DeLuca, Andrea et al. (2010) Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 9:438-46
Wang, Tongguang; Lee, Myoung-Hwa; Johnson, Tory et al. (2010) Activated T-cells inhibit neurogenesis by releasing granzyme B: rescue by Kv1.3 blockers. J Neurosci 30:5020-7
Rumbaugh, Jeffrey A; Steiner, Joseph; Sacktor, Ned et al. (2008) Developing neuroprotective strategies for treatment of HIV-associated neurocognitive dysfunction. Futur HIV Ther 2:271-280