Recovery.gov - Track the Money

UNIVERSITY OF MIAMI

The project R21 NS 062669, entitled, “HIV-1 infection: Central Serotonergic Activity and its Health Implications”, investigates the hypothesis that HIV-1 infection impacts the central serotonergic system in different brain regions and that the HIV-1 induced changes in the CNS serotonin activity is related with depression in HIV-1 infected individuals. HIV-1 infection has affected estimated 35 million people world-wide and more than a million people in the US. Introduction of highly active antiretroviral therapy (HAART) is effective in controlling the viral replication in the peripheral systems, however, the virus continues to thrive in the central nervous system (CNS), because some of the antiretroviral drugs do not penetrate the CNS, and progressive dysfunctions of various CNS systems continues in the brain, including those of biogenic amine systems. HIV-1 enters the CNS shortly after the initial infection and gets localized in different brain regions, causing a number of neurological, neuropsychological and mental health complications, including depression. This study hypothesizes that HIV-1 in the brain induces dysfunctions and loss of neurons in the regions of high serotonergic activity leading to depression. The objective of this study is to investigate the 1) the status of serotonin (5-hydroytryptamine, 5-HT) and its metabolite (5-hydroxyindoleacetic acid, 5-HIAA) in different regions of post mortem brains of individuals infected with HIV-1; and 2) to quantify HIV-1 RNA load in different brain regions of HI V-1 cases, and 3) to evaluate the relationship between changes in serotonergic status and HIV-1 mRNA levela in different brain regions and depression assessed during life of HIV-1 infected individuals. The brain regions for investigations include: the brain stem raphe nuclei, the main site of serotonergic neurons where serotonin is synthesized, as well as other brain regions (hippocampus, hypothalamus, basal ganglia, substantia nigra, amygdala, and frontocortical regions (cingulated and subgenual cortical areas) which receive serotonergic projections from the raphe nuclei and are involved in a number of physiological and behavioral functions. The brain regions of HIV-1 (N=25), and HIV-negative cases (N=15) proposed for investigations were obtained from the NIH sponsored National NeuroAIDS Tissue Consortium (NNTC) brain banks. The brain tissues were analyzed for measurement of 5-HT and 5-HIAA using the highly sensitive CoulArray HPLC-ECD system. For measurement of HIV-1 mRNA load in the same brain tissues, the real time reverse transcriptase TaqMan polymerase chain reaction (RT-PCR) technology was used. Specific primers and probes were used as proposed in the project. The methods used for measurement of 5-HT, 5-HIAA and HIV-1 viral RNA in the brain regions were standardized and evaluated rigorously for quality control in the PI’s Laboratory before analysis of tissues. Having completed analysis of all samples by the last quarterly period, we have collected data for 304 assays of 5-HT and 5-HIAA in different brain regions of HIV-1 , N=21 and HIV-negative (N-13) cases, and 152 samples for HIV-1 mRNA load in the same brain regions Our results show variable concentrations of 5-HT and 5-HIAA as well as HIV-1 mRNA is in different brain regions of HIV-1 cases, and also variable changes in 5-HT and 5-HIAA in some brain regions of HIV-1 cases compared to those in HIV-negative brain regions. HIV-1 mRNA concentration ranged from not detectable (ND) to log4.7 copies/g tissue in HIV-1 brain regions. All HIV-negative brain regions had no detectable HIV-1 RNA. Statistical analysis of the data is being evaluated for the relationship between 5-HT and 5-HIAA as well as HIV-1 mRNA and depression. We have submitted one manuscript for publication, and the other two manuscripts are in preparation.

Clarification of Codes