Research

HNRC Scientific Themes

1. What attributes of the virus, host, and host-virus interaction determine presentation of HIV-associated neurobehavioral disorders?
2. What are the actual mechanisms by which the host-virus factors generate neural injury and neurobehavioral disorders?
3. What is the role of co-pathogens and comorbidities in neuroAIDS?
4. How can treatments be optimized to prevent or ameliorate neuroAIDS?
5. What is the effect of HIV neurocognitive complications on everyday functioning; do treatments that correct neurocognitive abnormalities restore productivity and quality of life?

1. What attributes of the virus, host, and host-virus interaction determine presentation of HIV-associated neurobehavioral disorders?

   From the aspect of the virus, what are the relationships of molecular diversity (e.g., of HIV-1 envelope sequences) and neurovirulence? What are the mechanisms for increased molecular diversity in brain or CSF derived virus versus plasma or lymph nodes? Are there clade-specific differences in neurotropism and neurovirulence, and what are the molecular mechanisms underlying these? Examples of questions from the host side may include questions such as the importance of polymorphisms in genes encoding various neuroinflammatory signaling molecules (e.g., MCP-1, STF-1) or their co-receptors in facilitating vulnerability to neuroAIDS. From an international perspective, if such host genotype vulnerabilities are found, are they distributed differently in various populations, such as those from North America/Europe, India, China, or Africa?

2. What are the actual mechanisms by which the host-virus factors generate neural injury and neurobehavioral disorders?
   
   We anticipate that there will be ongoing studies on toxic and inflammatory processes that lead to neurodegeneration and white matter disease. In particular, we anticipate further work on changes in protein function and metabolism under pressure from HIV, and in relation to co-factors such as aging, ARV treatment, multiple substance use, etc. We anticipate renewed focus also on neurovascular inflammatory pathology in HIV. Additional studies may involve research into dysregulation of genes involved in neuromaintenance, for example, does HIV in the CNS modify activity of genes involved in synaptic plasticity, neuronal signaling, control of neuronal cytoskeleton and cell cycling? This line of inquiry may also lead to consideration of how neurogenesis is affected by HIV, as well as the protective role of factors such as FGF, the immunophilins, etc.

3. What is the role of co-pathogens and comorbidities in neuroAIDS?
   
   For example, if drugs such as methamphetamine increase vulnerability to neuroAIDS, is it because methamphetamine up-regulates genes mediating inflammation in the central nervous system? Perhaps similar mechanisms obtain to explain the recent observation that persons co-infected with Hepatitis C and HIV are more likely to have neurocognitive impairment than either alone. On the international front, the role of additional pathogens such as HBV, GBV-C, T. pallidum, M. tuberculosis, and various protozoa need to be explored. Aging is another cofactor that will be increasingly important as persons with HIV survive longer. To the extent that HIV may trigger abnormalities in protein function and metabolism, is it possible that intercellular deposition of amyloid (observed in some older cases of HIV) reflect HIV-mediated inhibition of insulin degradation enzyme or disruption of transport of amyloid precursor protein, which are some of the putative mechanisms underlying age related brain changes?
   
   Preliminary work that we have undertaken at the HNRC indicates that there is specific gene dysregulation in HIV infected individuals with a recent episode of major depressive disorder (MDD). Some of the genes that we observed to be altered were similar in function to those perturbed in HIV encephalitis, while others such as the neuromodulatory gene somatostatin were specific to those suffering MDD. These intriguing results indicate that the gene dysregulation observed by HIV could produce a milieu where the affected individual is vulnerable to developing MDD which, when it manifests, is associated with further specific gene changes.

4. How can treatments be optimized to prevent or ameliorate neuroAIDS?
   
   With steady growth and diversity of ARVs that target multiple mechanisms of HIV pathogenesis, we anticipate that an important direction of future research will be to determine optimum strategies to prevent, reverse, or at least ameliorate CNS complications. Recognizing that reducing viral load is a critical endpoint (especially, according to HNRC-associated research, reducing CSF viral load), we anticipate studies into ARV kinetics and dynamics that improve action in the central nervous system. We anticipate studies that will aim to characterize CNS compartmentalization and intercompartmental trafficking through studies of HIV dynamics and genetics. We anticipate studies that employ ARV-resistance genotyping and phenotyping that may inform “compartment specific” targeting of treatments. Additionally, we envision further work into relevance of existing biomarkers, and promise of new ones in predicting and monitoring outcome of NCI.

5. What is the effect of HIV neurocognitive complications on everyday functioning; do treatments that correct neurocognitive abnormalities restore productivity and quality of life?
   
   In the post-HAART era in the developed world, as HIV disease becomes a chronic lifelong affliction, what are the continuing implications of subtle, persisting forms of neurocognitive deficit (or relapsing-remitting presentation) on ability to work, manage household, medication management, and other aspects of everyday functioning? How can novel laboratory measures of cognition and functional abilities be designed to improve upon standard neuropsychological tests in predicting performance of the HIV-infected person in the “real world”?
   
   From an international perspective, we foresee studies aimed both at method development (assessment of everyday functioning that is culturally relevant), as well as studies aimed at understanding effects of milder HIV neurocognitive disturbances on specific everyday functions.