Current and Future Priorities of the National Institute of Mental Health for NeuroAIDS Research Funding

J. Joseph¹ and D.M. Rausch<sup>1

1</sup>Center for Mental Health Research on AIDS, National Institute of Mental Health,
6001 Executive Boulevard, Rm 6209, MSC 9619, Bethesda, MD 20892-9619

E-mail: : jjeymoha@mail.nih.gov, dr89b@nih.gov

Keywords: NIH funding, research funding, NeuroAIDS funding, NIH contracts

Q: What areas of research in NeuroAIDS are currently supported by NIMH?
NIMH (http://www.nimh.nih.gov/) currently supports basic and applied research on the fundamental mechanisms of pathogenesis of HIV associated dementia (HAD) and minor cognitive/motor disorders. Its diverse portfolio ranges from virology and immunology to neuroscience. Studies include mechanisms of viral trafficking through the central nervous system (CNS), chemokine receptor utilization patterns for CNS-derived cells, apoptosis of neurons, and mechanisms of neuronal dysfunction in HAD. Other studies include those that focus on the role of cytokines, chemokines and other inflammatory mediators in CNS neuropathology and neurobehavioral manifestations, neuroimaging correlates of HIV associated CNS metabolic changes, and analyses of consequences of HIV infection of various CNS cell populations (perivascular macrophages, microglia, astrocytes, endothelial cells). Finally, studies focus on the virus, including viral determinants of neurovirulence, the role of viral proteins in inducing CNS pathology, and the relationship between CSF viral load and neurocognitive dysfunction. An emerging area of importance is the potential role of the CNS as a reservoir for virus, protected from efficient therapeutic penetration and subsequent viral eradication.

NIMH also supports research using animal models to study mechanisms of neuropathogenesis of HIV-1 and SIV in rhesus macaques, including transgenic and SCID mice.

Other research areas examine mental health and behavior, including the assessment of the effects of life events, stress, depression and HPA axis activity on immunity and disease progression. Functional assessments of HIV-1 induced neurobehavioral impairments with respect to the impact of HIV infection on daily living are being studied by NIMH-funded investigators. Another area of study is the impact of HIV infection and cytokine expression on fatigue and sleeplessness. SIV macaque models are being used to examine the relationships between social stress, and their behavioral, neuroendocrine, virological and immunological sequelae in the course of immunodeficiency diseases.

NIMH, along with NIDA and NINDS, supports the National NeuroAIDS Tissue Consortium which banks CNS tissue samples from HIV infected patients for whom comprehensive neuromedical and neuropsychiatric data were gathered antemortem. Tissue samples (brain, CSF, peripheral nerves and blood) are available to qualified investigators for research projects in NeuroAIDS and other areas (http://www.hivbrainbanks.org/).

Q: What are current and future funding priorities of NIMH in NeuroAIDS?
NIMH continues to support basic research efforts on the mechanisms of HAD, and it plans to expand its support for epidemiology, diagnosis, and treatment research.

One important new initiative to be funded in Fiscal 2001 was developed to better define the incidence and prevalence of neurologic disorders in the current era of potent anti-retroviral therapy (ART). Longitudinal and cross sectional studies will be conducted to assess the long-term effects of highly effective therapies on HIV-1-induced nervous system disease.

While current ART is very effective in reducing peripheral viral loads, these drugs do not efficiently penetrate the blood-brain barrier (BBB). Therefore, NIMH strongly encourages novel approaches to deliver anti-retroviral drugs across the BBB into the CNS. These studies are particularly important since latent brain reservoirs may not only affect nervous system disease, but also serve as a protected compartment for development of drug resistant strains. NIMH will also support future research on the mechanisms of establishment of latent cellular reservoirs in various cell populations of the CNS. Assessment of the potential pathways and mechanisms of reseeding of peripheral compartments from the CNS compartment is an important area of future support.

NIMH also encourages development and application of novel imaging technologies to track signatures linked to subtle changes in the CNS as a result of HIV induced cognitive disorders. These novel technologies are particularly important in monitoring improvements in cognition in patients receiving long-term potent ART.

Another area of interest is studies of the CNS-specific metabolic complications associated with potent ART. These may be related to mitochondrial dysfunction, lactic acidosis, lipodystrophy and other potential side effects. Studies of the interactions of potent ART therapy with psychoactive medications are also encouraged.

Q: What level of funding is NIMH providing for NeuroAIDS Research?
The NIMH budget for AIDS research in fiscal 2000 was $128,336,000, of which approximately 40% supported research targeted to the areas described above.

Q: Are there any special initiatives (RFAs, PAs, fellowships) planned by NIMH for stimulating NeuroAIDS research?
A major NIMH initiative for Fiscal 2001 is to assess the long-term effects of potent antiretroviral therapy (ART) on HIV-induced nervous system disease. A contract mechanism will be used to fund a multi-site cross sectional and longitudinal study that evaluates the incidence and prevalence of HIV associated dementia, minor cognitive motor disorders and neuropsychological impairments including depression and anxiety in all stages of infection and ART treatment history. Additional work to be performed under this contract will include neuroimaging assessments, evaluation of drug-drug interactions, and assessments of metabolic (lipodystrophy) and toxic effects (peripheral neuropathy) of potent ART. Details of this Request for Proposal (RFP) No. NIMH-01-AI-0005 can be found at http://www.nimh.nih.gov/grants/indexcon.cfm#RequestforProposal.

Several new Program Announcements relevant to NeuroAIDS have been issued recently in conjunction with other Institutes. These include: PAR-00-098 Novel HIV therapies: Integrated Preclinical/Clinical Programs, issued jointly with National Institute of Allergy and Infectious Diseases, http://grants.nih.gov/grants/guide/pa-files/PAR-00-098.html; PAS-00-123 HIV Infection of the Peripheral Nervous System, issued jointly with National Institute of Neurological Disorders and Stroke (NINDS), http://grants.nih.gov/grants/guide/pa-files/PAS-00-123.html ; PAS-00-065 (Mechanisms in HIV Dementia and other CNS Diseases, issued jointly with NINDS, National Institute on Drug Abuse (NIDA) and National Institute on Aging, http://grants.nih.gov/grants/guide/pa-files/PAS-00-065.html

NIMH uses a variety of research grant support mechanisms for NeuroAIDS funding, including research grants, career development awards, Small Business Technology Transfer and Small Business Innovation Research grants, as well as pre- and post-doctoral training and fellowship programs. Information can be obtained from the NIMH CMHRA web-site http://www.nimh.nih.gov/dmdba/index.htm#cmhr.

In summary, NIMH has made significant commitments to basic, epidemiology, diagnosis and treatment research in the area of NeuroAIDS. It is of note that NIMH has several joint initiatives with NINDS. NINDS (http://www.ninds.nih.gov/) also supports several research programs in NeuroAIDS.