Human immunodeficiency virus type 1 (HIV-1) penetrates the brain early in the course of disease, and frequently causes dementia and other neurologic manifestations in adults and children. Prominent viral infection has been documented in microglia and macrophages within brain parenchyma, and less widespread infection of astrocytes, endothelial cells and even neurons has also been noted. Pathogenesis is likely to involve both direct cytopathic effects on target cells via infection and indirect pathways driven by secreted cellular factors that alter neuronal viability andor excitability. Existing animal models, including rhesus macaques and a xenotransplant system, have provided important insights into these processes. A new rodent model would likely be a valuable additional tool for testing the contributions of specific pathways to pathogenesis, particularly if it can be manipulated genetically to vary selected host parameters. We have conducted extensive analyses of cells derived from several rodents, and have obtained evidence that rat cells have no insurmountable, species-specific blocks to the HIV-1 replication cycle. These experiments, using both rat-derived cell lines and primary cell cultures, have revealed relatively high levels of early and late HIV-1 gene expression as well as the production of infectious virions. Based on these findings, we have invested extensively in the development of a transgenic rat system for HIV-1 pathogenesis studies. Human molecules that are known entry cofactors for HIV-including human CD4, CCR5 and CXCR4-were expressed in rats via transgenesis. Substantial preliminary evidence has been obtained indicating that these transgenes are expressed in monocyte/macrophages, CD4 T-cells, and microglia. We have also found that these receptor/coreceptors are sufficient to permit productive infection of primary monocyte/macrophages and microglia by HIV-1. The present proposal seeks to use these novel transgenic animal lines to: (A) measure the effects of infection by HIV-1 on several biologic parameters relating to brain structure and function in vivo (Aim 1); (B) test the hypothesis that HIV-1 gp120 itself is a pathogenic factor acting through CD4 and a coreceptor (Aim 2); and (C) examine the trafficking of HIV-1-infected cells from the periphery into the CNS (Aim 3). This work should both define the utility of this new experimental system for studying neuropathogenesis and provide new information about the pathologic events that may contribute to impairment of neurologic function in HIV disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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AIDS and Related Research 8 (AARR)
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Joseph, Jeymohan
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J. David Gladstone Institutes
San Francisco
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Chan, Jonathan K; Bhattacharyya, Darshana; Lassen, Kara G et al. (2013) Calcium/calcineurin synergizes with prostratin to promote NF-?B dependent activation of latent HIV. PLoS One 8:e77749
Chan, Jonathan K L; Greene, Warner C (2011) NF-ýýB/Rel: agonist and antagonist roles in HIV-1 latency. Curr Opin HIV AIDS 6:12-8
Michel, Nico; Goffinet, Christine; Ganter, Kerstin et al. (2009) Human cyclin T1 expression ameliorates a T-cell-specific transcriptional limitation for HIV in transgenic rats, but is not sufficient for a spreading infection of prototypic R5 HIV-1 strains ex vivo. Retrovirology 6:2
Goffinet, Christine; Allespach, Ina; Keppler, Oliver T (2007) HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription. Proc Natl Acad Sci U S A 104:1015-20
Goffinet, Christine; Keppler, Oliver T (2006) Efficient nonviral gene delivery into primary lymphocytes from rats and mice. FASEB J 20:500-2
Keppler, Oliver T; Allespach, Ina; Schuller, Lismarie et al. (2005) Rodent cells support key functions of the human immunodeficiency virus type 1 pathogenicity factor Nef. J Virol 79:1655-65
Jones, Gareth; Zhu, Yu; Silva, Claudia et al. (2005) Peripheral nerve-derived HIV-1 is predominantly CCR5-dependent and causes neuronal degeneration and neuroinflammation. Virology 334:178-93