HIV Preclinical-Clinical Therapeutics Research: central nervous system approaches.

The prevalence of HIV-associated brain disorders is reportedly increasing due, in part, to the prolonged life span of individuals who are surviving well on highly active antiretroviral treatments (HAART). While clinicians report CNS-related deficits that are more subtle in presentation than the frank dementia evident in the pre-HAART era, the milder presentation continues to substantively reduce an individual's quality of life. The development of novel drugs or therapeutic strategies for treating HIV-related CNS disease is important as most investigators agree that the brain is a sanctuary for latent virus, local viral recrudescence, and associated brain inflammatory responses. The prolonged chronic and cumulative effects on the brain of living with HIV-related inflammatory processes, antiretroviral treatments, and their long-term side effects, toxicities, and brain-related aging processes collectively indicate that the burden of CNS and PNS complications will increase profoundly during the upcoming years. Considering the high expense for new drugs entering CNS-related clinical trials and their ultimately low success rate, the NIMH convened a meeting entitled, HIV Preclinical-Clinical Therapeutics Research Meeting, to discuss the current and proposed novel approaches for neuroAIDS drug development and clinical practices. The purposes of the meeting were twofold: to identify the most promising approaches for future neuroAIDS therapeutics development research and to discuss optimal structures and partnerships with industry that may facilitate the successful movement of compounds from the bench to the bedside. Several themes can be derived from the sessions and are highlighted below for preclinical, translational and clinical neuroAIDS therapeutics research.

Neurobiology of HIV, psychiatric and substance abuse comorbidity research: workshop report.

Viral infections can cause persistent and progressive changes in emotional and cognitive functions. The viral-induced imbalances in neuronal network functioning may precipitate or accentuate psychiatric conditions in vulnerable individuals, in part, as a function of the host response to proinflammatory cytokines resulting from infection or brain injury. Research indicates that the mediators of psychiatric illnesses and HIV-neuropathogenesis utilize similar brain structures, neurocircuitry and receptor systems. The genetic, cellular and molecular mechanisms contributing to HIV neuropathogenesis and its late stage clinical correlate, HIV-associated-dementia (HAD), are active areas of neuroAIDS research. The study of HIV in the context of psychiatric comorbidities and comorbid pathogenesis is in a fledgling stage despite epidemiological studies suggesting that >60% of HIV infected individuals will suffer from at least one major psychiatric disorder during the course of infection. Depression is the primary comorbid disorder but anxiety and substance abuse disorders are also considerable in certain HIV(+) populations. Certain substances of abuse and the biological mediators of psychiatric illnesses reportedly interact in the brain and presumptively worsen HIV-related neuropathogenesis and survival measures. A panel of experts discussed approaches for studying the neuroscience of HIV and psychiatric comorbidity at a basic, mechanistic level since they co-exist in high proportion in the human population. Recommended approaches ranged from improving human consent forms and maximizing the value of repository resources to novel research designs and identifying human and animal endophenotypes.

Workshop report: The effects of psychological variables on the progression of HIV-1 disease.

The reciprocal interactions between the neuroendocrine, immune, and autonomic nervous systems are complicated, yet worthy of examination. A body of literature suggests that psychological factors such as stress, or psychiatric conditions such as major depression, may influence the immune system thereby altering host susceptibility to viral, or other types of infection. Alternately, in an attempt to limit infection and replication, the anti-viral host response, via innate and acquired immunity and subsequent release of pro-inflammatory cytokines and additional anti-viral mediators, may affect mood, cognition emotion, and possibly precipitate a psychiatric disorder. In order to address what is known regarding neuroendocrine-immune interactions in the context of HIV infection, the Center for Mental Health Research on AIDS convened a panel of scientists from diverse areas of expertise. Their primary charge was to examine whether stress-induced activation of the neuroendocrine system affects the immune system in a manner that negatively influences HIV disease progression, and whether HIV infection influences the central nervous system and behavior. The ensuing report summarizes their deliberations as they discussed the current body of information and identified outstanding critical questions in the areas of research. The group consensus was that the biological mediators of psychological status can play an important role in mediating HIV disease progression, particularly in subgroups of vulnerable patients; furthermore, they identified candidate biological mediators and mechanisms of disease progression. The Workgroup outlined the inherent challenges and limitations of such research and provided recommendations as to the future directions of research utilizing human, animal, and in vitro models of HIV-1 infection and stress.

Levels of analysis in psychiatric research.

Most of the major psychiatric disorders have been analyzed at each of several different levels. For example, at the broadest level, epidemiological studies have served to establish the incidence of disorders like schizophrenia and major depression in a number of different populations. Family and twin studies have been important in determining the heritability of certain mental illnesses, and chromosomal and linkage analyses have identified a number of discrete loci that appear to be implicated in disease susceptibility or, even directly, in the pathogenesis of some disorders. In a few cases, specific genes have been found to be mutated or polymorphic and proteins they encode are currently being analyzed. This article reviews how these different levels contribute to our understanding of a number of psychiatric disorders, including drug addiction, which has been the focus of much of our own work.

The human genome project and its impact on psychiatry.

There has been substantial evidence for more than three decades that the major psychiatric illnesses such as schizophrenia, bipolar disorder, autism, and alcoholism have a strong genetic basis. During the past 15 years considerable effort has been expended in trying to establish the genetic loci associated with susceptibility to these and other mental disorders using principally linkage analysis. Despite this, only a handful of specific genes have been identified, and it is now generally recognized that further advances along these lines will require the analysis of literally hundreds of affected individuals and their families. Fortunately, the emergence in the past three years of a number of new approaches and more effective tools has given new hope to those engaged in the search for the underlying genetic and environmental factors involved in causing these illnesses, which collectively are among the most serious in all societies. Chief among these new tools is the availability of the entire human genome sequence and the prospect that within the next several years the entire complement of human genes will be known and the functions of most of their protein products elucidated. In the meantime the search for susceptibility loci is being facilitated by the availability of single nucleotide polymorphisms (SNPs) and by the beginning of haplotype mapping, which tracks the distribution of clusters of SNPs that segregate as a group. Together with high throughput DNA sequencing, microarrays for whole genome scanning, advances in proteomics, and the development of more sophisticated computer programs for analyzing sequence and association data, these advances hold promise of greatly accelerating the search for the genetic basis of most mental illnesses while, at the same time, providing molecular targets for the development of new and more effective therapies.