Both HIV-1 and METH can cause behavioral changes and brain injury, but their interaction is poorly understood. In the current funding period, we observed that a one-time METH binge caused a reduction in hippocampal post-tetanic potentiation only in HlV/gp120-transgenic (tg) but not control mice. RNA expression studies indicated that both HIVgp120 and METH trigger significant changes of glutamatergic and GABAergic neurotransmission. In vitro studies showed that METH at 100 pM increased neurotoxicity of HIVgp120 and excitotoxic NMDA. METH also increased HIV infection of human macrophages in association with down-regulation of at least four interferon-inducible genes. Therefore, the overall hypothesis is that use of METH aggravates behavioral disturbances and neurotoxicity associated with HIV-1 infection.
Our Specific Aims are to: (1) identify affected neural networks by studying gene expression associated with long-term effects of METH in HlVgp120- and iTat-tg and non-tg control mice and to relate such gene expression changes to behavioral performance;(2) determine whether METH interferes with the efficacy of cART drugs to reduce viral replication and production of neurotoxic products by infected monocytes/macrophages.
For Aim 1, gp120- and iTat-tg and non-tg control mice will be treated with a novel chronic, low dose 12-week METH regimen. Following a 5-month abstinence period and behavioral testing, neuronal and glial injury and gene expression will be analyzed in brain tissue using deconvolution microscopy, microarray and qRT-PCR. Gene expression data will be analyzed separately for cortex, hippocampus, striatum and other brain regions, and correlated with behavioral outcomes and neuropathology. Follow-up studies to gene expression analyses will probe protein expression, localization and function using biochemical and microscopy approaches.
For Specific Aim. 2, macrophages infected with HIV will be treated with ARV combinations and varying METH concentrations. The neurotoxicity of supernatents from such macrophage experiments will be tested on rat microglia depleted mixed neuronal glial cerebrocortical cells. The long-term objective is to identify neurotoxic mechanisms that are potential targets for therapeutic intervention.

Public Health Relevance

Infection with HIV-1 is often associated with exposure to addictive drugs, such as Methamphetamine (METH), and both are major public health concerns. Our studies will improve the understanding of mechanism contributing to brain injury and behavioral alterations caused by the combination of METH exposure and HIV infection and thus will help to develop new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
2P50DA026306-06
Application #
8601379
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kamat, Rujvi; Doyle, Katie L; Iudicello, Jennifer E et al. (2016) Neurobehavioral Disturbances During Acute and Early HIV Infection. Cogn Behav Neurol 29:1-10
Noel, Richard J; Kaul, Marcus (2016) The 22nd Scientific Conference of the Society on Neuroimmune Pharmacology. J Neuroimmune Pharmacol 11 Suppl 1:S1-2
Soontornniyomkij, Virawudh; Umlauf, Anya; Soontornniyomkij, Benchawanna et al. (2016) Lifetime methamphetamine dependence is associated with cerebral microgliosis in HIV-1-infected adults. J Neurovirol 22:650-660
Gianella, Sara; Letendre, Scott (2016) Cytomegalovirus and HIV: A Dangerous Pas de Deux. J Infect Dis 214 Suppl 2:S67-74
Kesby, James P; Markou, Athina; Semenova, Svetlana (2016) The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice. Neuropharmacology 109:205-15
Hoenigl, Martin; Little, Susan J (2016) How can we detect HIV during the acute or primary stage of infection? Expert Rev Mol Diagn 16:1049-1051
Bischoff-Grethe, Amanda; Connolly, Colm G; Jordan, Stephan J et al. (2016) Altered reward expectancy in individuals with recent methamphetamine dependence. J Psychopharmacol :
Brown, Gregory G; Jacobus, Joanna; McKenna, Benjamin (2016) Structural imaging for addiction medicine: From neurostructure to neuroplasticity. Prog Brain Res 224:105-27
Hoenigl, Martin; Chaillon, Antoine; Moore, David J et al. (2016) Clear Links Between Starting Methamphetamine and Increasing Sexual Risk Behavior: A Cohort Study Among Men Who Have Sex With Men. J Acquir Immune Defic Syndr 71:551-7
Pérez-Santiago, Josué; Schrier, Rachel D; de Oliveira, Michelli F et al. (2016) Cell-free mitochondrial DNA in CSF is associated with early viral rebound, inflammation, and severity of neurocognitive deficits in HIV infection. J Neurovirol 22:191-200

Showing the most recent 10 out of 108 publications