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Journal of Virology, July 2004, p. 7319-7328, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7319-7328.2004

Human Immunodeficiency Virus Type 1 Infection of Human Brain-Derived Progenitor Cells

Diane M. P. Lawrence,1 Linda C. Durham,1 Lynnae Schwartz,1 Pankaj Seth,1 Dragan Maric,2 and Eugene O. Major1*

Laboratory of Molecular Medicine and Neuroscience,1 Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 208922

Received 19 November 2003/ Accepted 10 March 2004

Although cells of monocytic lineage are the primary source of human immunodeficiency virus type 1 (HIV-1) in the brain, other cell types in the central nervous system, including astrocytes, can harbor a latent or persistent HIV-1 infection. In the present study, we examined whether immature, multipotential human brain-derived progenitor cells (nestin positive) are also permissive for infection. When exposed to IIIB and NL4-3 strains of HIV-1, progenitor cells and progenitor-derived astrocytes became infected, with peak p24 levels of 100 to 500 pg/ml at 3 to 6 days postinfection. After 10 days, virus production was undetectable but could be stimulated by the addition of tumor necrosis factor alpha (TNF-{alpha}). To bypass limitations to receptor entry, we compared the fate of infection in these cell populations by transfection with the infectious HIV-1 clone, pNL4-3. Again, transfected progenitors and astrocytes produced virus for 7 days but diminished to low levels beyond 8 days posttransfection. During the nonproductive phase, TNF-{alpha} stimulated virus production from progenitors as late as 5 weeks posttransfection. Astrocytes produced 5- to 20-fold more infectious virus (27 ng of p24/106 cells) than progenitors at the peak of 3 days posttransfection. Differentiation of infected progenitors toward an astrocyte phenotype increased virus production to levels consistent with infected astrocytes, suggesting a phenotypic difference in viral replication. Using this cell culture system of multipotential human brain-derived progenitor cells, we provide evidence that progenitor cells may be a reservoir for HIV-1 in the brains of AIDS patients.

* Corresponding author. Mailing address: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 36 Convent Dr., MSC 4164, Bldg. 36, Rm. 5W21, Bethesda, MD 20892. Phone: (301) 594-6270. Fax: (301) 594-5799. E-mail: MajorG{at}ninds.nih.gov.

Journal of Virology, July 2004, p. 7319-7328, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7319-7328.2004




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