Human immunodeficiency virus encephalitis in SCID mice

Yuri Persidsky, Jenae Limoges, Rodney D McComb, Paul Bock, Tonia Baldwin, William Tyor, Angelo Patil, Hans S L M Nottet, Leon Epstein, Harris Gelbard, Ellen Flanagan, John Reinhard, Samuel Jay Pirruccello, Howard Eliot Gendelman

Research output: Contribution to journalArticle

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Abstract

The human immunodeficiency virus (HIV) is neuroinvasive and commonly causes cognitive and motor deficits during the later stages of viral infection (referred to as HIV dementia). The mechanism(s) for disease revolves around secretory products produced from immune-activated brain macrophages/microglia. Recently, we developed an animal model system for HIV dementia that contains xenografts of HIV-1-infected cells inoculated into brains of mice with severe combined immunodeficiency (SCID). This animal system was used to quantitatively evaluate HIV-induced neuropathology. Xenografts of HIV-1-infected human monocytes (placed into the putamen and cortex of SCID mice) remained viable for 5 weeks. HIV-1 p24 antigen expression in mouse brain was persistent. Progressive inflammatory responses (including astrogliosis and cytokine production), which began at 3 days, peaked at day 12. The range of astrocyte proliferative reactions exceeded the inoculation site by >1000 μm. Brains with virus-infected monocytes showed a ≤1.6-fold increase in glial fibrillary acidic protein (staining distribution and intensity) as compared with similarly inoculated brains with uninfected control monocytes. These findings paralleled the accumulation and activation of murine microglia (increased branching of cell processes, formation of microglial nodules, interleukin (IL)-1β and IL-6 expression). An inflammatory reaction of human monocytes (as defined by HLA-DR, IL-1β, IL- 6, and tumor necrosis factor-α expression) and neuronal injury (apoptosis) also developed after virus-infected monocyte xenograft placement into mouse brain tissue. These data, taken together, demonstrate that this SCID mouse model of HIV-1 neuropathogenesis can reproduce key aspects of disease (virus- infected macrophages, astrocytosis, microglial activation, and neuronal damage). This model may serve as an important means for therapeutic development directed toward improving mental function in HIV-infected subjects with cognitive and motor dysfunction.

Original languageEnglish (US)
Pages (from-to)1027-1053
Number of pages27
JournalAmerican Journal of Pathology
Volume149
Issue number3
StatePublished - Sep 1 1996

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Severe Combined Immunodeficiency
Encephalitis
HIV
Monocytes
HIV-1
Brain
Heterografts
Microglia
Virus Diseases
Interleukin-1
Dementia
Interleukin-6
Macrophages
Viruses
Gliosis
Putamen
Glial Fibrillary Acidic Protein
HLA-DR Antigens
Astrocytes
Animal Models

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Persidsky, Y., Limoges, J., McComb, R. D., Bock, P., Baldwin, T., Tyor, W., ... Gendelman, H. E. (1996). Human immunodeficiency virus encephalitis in SCID mice. American Journal of Pathology, 149(3), 1027-1053.

Human immunodeficiency virus encephalitis in SCID mice. / Persidsky, Yuri; Limoges, Jenae; McComb, Rodney D; Bock, Paul; Baldwin, Tonia; Tyor, William; Patil, Angelo; Nottet, Hans S L M; Epstein, Leon; Gelbard, Harris; Flanagan, Ellen; Reinhard, John; Pirruccello, Samuel Jay; Gendelman, Howard Eliot.

In: American Journal of Pathology, Vol. 149, No. 3, 01.09.1996, p. 1027-1053.

Research output: Contribution to journalArticle

Persidsky, Y, Limoges, J, McComb, RD, Bock, P, Baldwin, T, Tyor, W, Patil, A, Nottet, HSLM, Epstein, L, Gelbard, H, Flanagan, E, Reinhard, J, Pirruccello, SJ & Gendelman, HE 1996, 'Human immunodeficiency virus encephalitis in SCID mice', American Journal of Pathology, vol. 149, no. 3, pp. 1027-1053.
Persidsky Y, Limoges J, McComb RD, Bock P, Baldwin T, Tyor W et al. Human immunodeficiency virus encephalitis in SCID mice. American Journal of Pathology. 1996 Sep 1;149(3):1027-1053.
Persidsky, Yuri ; Limoges, Jenae ; McComb, Rodney D ; Bock, Paul ; Baldwin, Tonia ; Tyor, William ; Patil, Angelo ; Nottet, Hans S L M ; Epstein, Leon ; Gelbard, Harris ; Flanagan, Ellen ; Reinhard, John ; Pirruccello, Samuel Jay ; Gendelman, Howard Eliot. / Human immunodeficiency virus encephalitis in SCID mice. In: American Journal of Pathology. 1996 ; Vol. 149, No. 3. pp. 1027-1053.
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