Skip to main content
SpringerLink
Log in

HIV-1 infected and immune competent mononuclear phagocytes induce quantitative alterations in neuronal dendritic arbor: Relevance for HIV-1-associated dementia

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Neuronal loss, alterations in dendritic arbor, and decreased synaptic density, in infected brain tissue, are neuropathological signatures of HIV-1-associated dementia (HAD). Brain mononuclear phagocyte (MP) (macrophage and microglia) secretory products can effect neuronal compromise, although the underlying mechanism(s) remain incompletely defined. To these ends, we quantitatively assessed the effects of virus-infected and/or immune activated MP secretory products on multiple aspects of neuronal morphology. Rat cortical and hippocampal neurons were exposed to secretory products from HIV-1-infected and lipopolysaccharide (LPS)-activated human monocyte-derived macrophage (MDM). Our assays for alterations in neuronal dendritic arbor and cell loss included the quantification of neurofilament (NF), neuron-specific enolase (NSE), and MAP-2 by ELISA and cellular morphology. MDM conditioned media (MCM) enhanced neuronal survival. HIV-1 infection or activation by LPS had modest neurotoxic effects. In contrast, the combination of HIV-1 infection and activation of MDM produced significant neurotoxicity. Such MDM products altered dendritic arbor, decreased synaptic density, and increased LDH release. Comparable neurotrophic/toxic responses were observed when neurons were exposed to MCM collected from 12 separate human donors. Similar responses were observed with MCM from human fetal microglia, further supporting the role of HIV-1-infected and immune-activated brain MP in the overall neurotoxic responses. This work provides quantitative measures of neuronal damage by which virus infected and activated MP can elicit neuronal injury in HAD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AIDS:

acquired immune deficiency syndrome

DAB:

diaminobenzidine

GFAP:

glial fibrillary acidic protein

HAD:

HIV-1-associated dementia

LDH:

lactate dehydrogenase

LPS:

lipopolysaccharide

MAP-2:

microtubule associated protein-2

MCM:

monocyte-derived macrophage conditioned media

MDM:

monocyte-derived macrophages

MCSF:

macrophage colony stimulating factor

MP:

mononuclear phagocytes

NAD+ :

nicotinamide adenine dinucleotide

NF:

neurofilament

NGS:

normal goat serum

NSE:

neuronal specific enolase

RT:

reverse transcriptase

TMB:

3,3′,5,5′-tetramethylbenzidine

References

  • Adamson, D. C, Wildemann, B., Sasaki, M., Glass, J. D., McArthur, J. C, Christov, V. I., Dawson, T. M. and Dawson, V. L. (1996). Immunologic No Synthase: Elevation in Severe AIDS Dementia and Induction by HIV-1 gp41, Science274, 1917–1926.

    Article  PubMed  CAS  Google Scholar 

  • Asare, E., Dunn, G., Glass, J., McArthur, J., Luthert, P., Lan-tos, P. and Everall, I. (1996). Neuronal Pattern Correlates with the Severity of Human Immunodeficiency Virus-associated Dementia Complex, Am J Pathol148, 31–38.

    PubMed  CAS  Google Scholar 

  • Brenneman, D. E., Westbrook, G. L., Fitzgerald, S. P., Ennist, D. L., Elkins, K. L., Ruff, M. R. and Pert, C. B. (1988). Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide, Nature335, 639–642.

    Article  PubMed  CAS  Google Scholar 

  • Choi, D. W., Koh, J.-y. and Peters, S. (1988). Pharmacology of Glutamate Neurotoxicity in Cortical Cell Culture: Attenuation by NMDAv Antagonists, Teh journal of Neuroscience8,185–196.

    CAS  Google Scholar 

  • Conant, K., Garzino-Demo, A., Nath, A., McArthur, J. C, Halliday, W., Power, C, Gallo, R. C and Major, E. O. (1998). Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia, Proc Natl Acad Sci USA95, 3117–3121.

    Article  PubMed  CAS  Google Scholar 

  • Decker, T. and Lohmann-Matthes, M. L. (1988). A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity, J Immunol Methods15, 61–69.

    Article  Google Scholar 

  • Dore, G. J., Correll, P. K., Li, Y., Kaldor, J. M., Cooper, D. A. and Brew, B. J. (1999). Changes to AIDS dementia complex in the era of highly active antiretroviral therapy, Aids13,1249–53.

    Article  PubMed  CAS  Google Scholar 

  • Elkabes, S., DiCicco-Bloom, E. M. and Black, I. B. (1996). Brain Microglia/Macrophages Express Neurotrophins that Selectively Regulate Microglial Proliferation and Function, J Neurosci16, 2508–2521.

    PubMed  CAS  Google Scholar 

  • Everall, I., Luthert, P. and Lantos, P. (1993). A review of neuronal damage in human immunodeficiency virus infection: its assessment, possible mechanism and relationship to dementia, J Neuropathol Exp Neurol 52, 561–6.

    Article  PubMed  CAS  Google Scholar 

  • Everall, I. P., Glass, J. D., McArthur, J., Spargo, E. and Lantos, L. (1994). Neuronal density in the superior frontal and temporal gyri does not correlate with the degree of human immunodeficiency virus-associated dementia., Acta Neuropathol88, 538–544.

    Article  PubMed  CAS  Google Scholar 

  • Gabuzda, D., He, J., Ohagen, A. and Vallat, A. (1998). Chem-okine receptors in HIV-1 infection of the central nervous system, Immunol10,203–213.

    CAS  Google Scholar 

  • Gelbard, H., Nottet, H., Dzenko, K., Jett, M., Genis, P., White, R., Wang, L., Choi, Y.-B., Zhang, D., Lipton, S.,et al. (1994). Platelet-activating factor: a candidate human immunodeficiency virus type-1 infection neurotoxin, J Virol68,4628–4635.

    PubMed  CAS  Google Scholar 

  • Gendelman, H. E. (1997). The Neuropathogenesis of HIV-1-Dementia: a panel discussion. In The neurology of AIDS, H. E. Gendelman, S. A. Lipton, L. G. Epstein and S. Swindells, eds. (New York, Chapman and Hall), pp. 1–10.

    Google Scholar 

  • Gendelman, H. E., Orenstein, J. M., Martin, M. A., Ferrua, C, Mitra, R., Phipps, T., Wahl, L. A., Lane, H. C, Fauci, A. S. and Burke, D. S. (1988). Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes, J Exp Med167,1428–41.

    Article  PubMed  CAS  Google Scholar 

  • Gendelman, H. E., Zheng, J., Coulter, C. L., Ghorpade, A., Che, M., Thylin, M., Rubocki, R., Persidsky, Y., Hahn, F., Reinhard, J., Jr. and Swindells, S. (1998). Suppression of inflammatory neurotoxins by highly active antiretroviral therapy in human immunodeficiency virus-associated dementia, J Infect Dis178,1000–7.

    Article  PubMed  CAS  Google Scholar 

  • Ghorpade, A., Nukuna, A., Che, M., Haggerty, S., Persidsky, Y., Carter, E., Carhart, L., Shafer, L. and Gendelman, H. E. (1998). Human immunodeficiency virus neurotropism: an analysis of viral replication and cytopathicity for divergent strains in monocytes and microglia, J Virol 72, 3340–3350.

    PubMed  CAS  Google Scholar 

  • Giulian, D., Yu, J., Xia, L., Tom, D., Li, J., Lin, S. N., Schwarz, R. and Noonan, C. (1996). Study of receptor-mediated neurotoxins released by HIV-1 infected mononuclear phagocytes found in human brain, J Neurosci16, 3139–3153.

    PubMed  CAS  Google Scholar 

  • Glass, J. D., Fedor, H., Wesselingh, S. L. and McArthur, J. C. (1995). Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlation with dementia, Ann Neurol38, 755–762.

    Article  PubMed  CAS  Google Scholar 

  • Glass, J. D., Wesselingh, S. L., Seines, O. A. and McArthur, J. C. (1993). Clinical neuropathology correlation in HIV-associated dementia., Neurology43, 2230–2237.

    PubMed  CAS  Google Scholar 

  • Heese, K., Hock, C and Otten, U. (1998). Inflammatory signals induce neurotrophin expression in human microglial cells, J Neurochem70,699–707.

    Article  PubMed  CAS  Google Scholar 

  • Johnson, M. D. and Gold, L. I. (1996). Distribution of transforming growth factor-b isoform in human immunodeficiency virus-1 encephalitis, Human pathology27, 643–649.

    Article  PubMed  CAS  Google Scholar 

  • Kalter, D. C, Nakamura, J. A., Turpin, J. A., Baca, L. M., Hoover, D. L., Dieffenbach, C, Ralph, P., Gendelman, H. E. and Meltzer, M. S. (1991). Enhanced HIV replication in macrophage colony-stimulating factor-treated monocytes, J Immunol146, 298–306.

    PubMed  CAS  Google Scholar 

  • Kim, W. G., Mohney, R. P., Wilson, B., Jeohn, G. H., Liu, B. and Hong, J. S. (2000). Regional Difference in Susceptibility to Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of Microglia, J Neurosci20, 6309–6316.

    PubMed  CAS  Google Scholar 

  • Koenig, S., Gendelman, H. E., Orenstein, J. M., Canto, M. C. D., Pezeshkpour, G. H., Yungbluth, M., Janotta, F., Aksamit, A., Martin, M. A. and Fauci, A. S. (1986). Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy, Science 233, 1089–93.

    Article  PubMed  CAS  Google Scholar 

  • Lipton, S. A. and Gendelman, H. E. (1995). Dementia associated with the acquired immunodeficiency syndrome, New Engl J Med16,934–940.

    Article  Google Scholar 

  • Marder, K., Albert, S., Dooneief, G., Stern, Y., Ramachan-dran, G. and Epstein, L. (1996). Clinical confirmation of the american academy of neurology algorithm for HIV-1-associated cognitive/motor disorder, Neurol47, 1247–1253.

    Google Scholar 

  • McGeer, P. L. and McGeer, E. G. (1995). The inflammatory response system of brain:implication for therapy of Alzheimer and other neurodegenerative diseases, Brain Res Review21,195–218.

    Article  CAS  Google Scholar 

  • Nath, A., Conant, K., Chen, P., Scott, C and Major, E. O. (1999). Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon, J Biol Chem 274, 17098–102.

    CAS  Google Scholar 

  • Nath, A. and Geiger, J. (1998). Neurobiological aspects of human immunodeficiency virus infection: neurotoxic mechanisms, Prog Neurobiol54,19–33.

    Article  PubMed  CAS  Google Scholar 

  • Nath, A., Psooy, K., Martin, C, Knudsen, B., Magnuson, D. S., Haughey, N. and Geiger, J. D. (1996). Identification of a human immunodeficiency virus type 1 Tat epitope that is neuroexcitatory and neurotoxic, J Virol70, 1475–80.

    PubMed  CAS  Google Scholar 

  • Nottet, H. S., Jett, M., Flanagan, C. R., Zhai, Q. H., Persidsky, Y., Rizzino, A., Bernton, E. W., Genis, P., Baldwin, T., Schwartz, J. H.,et al. (1995). A regulatory role for astrocytes in HIV-1 encephalitis. An overexpression of eicosa-noids, platelet-activating factor and tumor necrosis factor-alpha by activated HIV-1-infected monocytes is attenuated by primary human astrocytes, J Immunol154, 3567–81.

    PubMed  CAS  Google Scholar 

  • Nottet, H. S., Persidsky, Y., Sasseville, V.G., Nukuna, A. N., Bock, P., Zhai, Q. H., Sharer, L. R., McComb, R. D., Swindells, S., Soderland, C and Gendelman, H. E. (1996). Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain, J Immunol156, 1284–95.

    PubMed  CAS  Google Scholar 

  • Ohagen, A., Ghosh, S., He, J., Huang, K., Chen, Y., Yuan, M., Osathanondh, R., Gartner, S., Shi, B., Shaw, G. and Gabuzda, D. (1999). Apoptosis Induced by Infection of Primaty Brain Cultures with Diverse Human Immunodeficiency Virus Type 1 Isolates: Evidence for a Role of the Envelope, J Virol73, 897–906.

    PubMed  CAS  Google Scholar 

  • Oshima, K. H., Comans, T. W., Highsmith, A. K. and Ades, E. W. (1995). Removal of human immunodeficiency virus by an 0.04-um membrane filter, Journal of AIDS and Human Retrovirology8, 64–65.

    CAS  Google Scholar 

  • Persidsky, Y., Stins, M., Way, D., Witte, M. H., Weinand, M., Kim, K. S., Bock, P., Gendelman, H. E. and Fiala, M. (1997). A model for monocyte migration through the blood-brain barrier during HIV-1 encephalitis, J Immunol158,3499–510.

    PubMed  CAS  Google Scholar 

  • Power, C, McArthur, J. C, Nath, A., Wehrly, K., Mayne, M., Nishio, J., Langelier, T., Johnson, R. T. and Chesebro, B. (1998). Neuronal Death Induced by Brain-Derived Human Immunodeficiency Virus Type 1 Envelope Genes Differs between Demented and Nondemented AIDS Patients, J Virol 72, 9045–9053.

    PubMed  CAS  Google Scholar 

  • Strizki, J. M., Albright, A. V., Sheng, H., O’Connor, M., Per-rin, L. and Gonzalez-Scarano, F. (1996). Infection of primary human microglia and monocyte-derived macrophages with human immunodeficiency virus type 1 isolates: evidence of differential tropism, J Virol70, 7654–7662.

    PubMed  CAS  Google Scholar 

  • Weis, S., Haug, H. and Budka, H. (1993). Neuronal damage in the cerebral cortex of AIDS brains: a morphometric study, Acta Neuropathology85,185–189.

    Article  CAS  Google Scholar 

  • Wiley, C. A. and Achim, C. (1994). Human Immunodeficiency Virus Encephalitis Is the pathological Correlate of Dementia in Acquired Immunodeficiency Syndrome, Ann Neurol36, 673–676.

    Article  PubMed  CAS  Google Scholar 

  • Wiley, C. A., Masliah, E., Morey, M., Lemere, C, Teresa, R., Grafe, M., Hansen, L. and Terry, R. (1991). Neocortical damage during HIV infection, Ann Neurol 29, 651–657.

    Article  PubMed  CAS  Google Scholar 

  • Yoshioka, M., Shapshak, P., Srivastava, A. K., Stewart, R. V., Nelson, S. J., Bradley, W. G. and Berger, J. R. (1994). Expression of HIV-1 and interleukin-6 in lumbosacral dorsal root gangalia of patients with AIDS, Neurology44,1120–1130.

    PubMed  CAS  Google Scholar 

  • Zheng, J., Thylin, M., Ghorpade, A., Xiong, H., Persidsky, Y., Cotter, R., Niemann, D., Che, M., Zeng, Y., Gelbard, H.,et al. (1999). Intracellular CXCR4 signaling, neuronal apoptosis and neuropafhogenic mechanisms of HIV-1-associated dementia, J Neuroimmunol98, 185–200.

    Article  PubMed  CAS  Google Scholar 

  • Zheng, J., Thylin, M. R., Persidsky, Y., Williams, C. E., Cotter, R. L., Zink, W., Ryan, L., Ghorpade, A., Lewis, K. and Gendelman, H. E. (2001). HIV-1 infected immune competent mononuclear phagocytes influence the pathways to neuronal demise, Neurotoxi Res. vol, pages.

Download references

Author information

Authors and Affiliations

  1. The Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, 68198-5215, Omaha, NE

    Jialin Zheng, Michael R. Thylin, Robin L. Cotter, Alicia L. Lopez, Anuja Ghorpade, Yuri Persidsky, Huangui Xiong, Gary B. Leisman, My Hanh Che & Howard E. Gendelman

  2. The Departments of Pathology and Microbiology, University of Nebraska Medical Center, 68198-5215, Omaha, NE

    Jialin Zheng, Michael R. Thylin, Robin L. Cotter, Alicia L. Lopez, Anuja Ghorpade, Yuri Persidsky, Huangui Xiong, Gary B. Leisman, My Hanh Che & Howard E. Gendelman

  3. Departments of Medicine, University of Nebraska Medical Center, 68198-5215, Omaha, NE

    Howard E. Gendelman

  4. The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198-5215, Omaha, NE

    Howard E. Gendelman

Authors
  1. Jialin Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael R. Thylin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robin L. Cotter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alicia L. Lopez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anuja Ghorpade
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuri Persidsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huangui Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gary B. Leisman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. My Hanh Che
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Howard E. Gendelman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jialin Zheng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zheng, J., Thylin, M.R., Cotter, R.L. et al. HIV-1 infected and immune competent mononuclear phagocytes induce quantitative alterations in neuronal dendritic arbor: Relevance for HIV-1-associated dementia. neurotox res 3, 443–459 (2001). https://doi.org/10.1007/BF03033203

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033203

Keywords

Search

Navigation