Abstract
Direct and productive infection of neurons in vivo is still a matter of debate, although in vitro experiments have demonstrated that immature neuronal cells can be productively infected by various human immunodeficiency virus (HIV) strains. To address this controversy we have analyzed, using light microscopy and in situ hybridization (ISH), HIV-1 infected cells in brain tissue from four pediatric cases of HIV-1-associated encephalopathy (EP). HIV-1 RNA-expressing cells—therefore, actively infected cells—were detected by ISH in different amounts in all brain specimens from the four children. They mainly correspond to glial cells. However, in two of the four children, who had severe progressive EP, but not in the other two, who had the static form, HIV-1-infected neurons were clearly observed in the cortical brain samples. These results provide initial evidence that HIV-1 can actively infect neurons in vivo in children and show a cortical involvement of HIV brain infection in clear correlation with the clinical EP symptoms.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Álvarez Losada S., Cantó-Nogués C., and Muñóz-Fernández M. A. (2002) A new possible mechanism of human immunodeficiency virus type 1 infection of neural cells. Neurobiol. Dis. 11, 469–478.
American Academy of Neurology (1991) Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology 41, 778–785.
An S. F., Groves M., Gray F., and Scaravilli F. (1999) Early entry and widespread cellular involvement of HIV-1 DNA in brains of HIV-1 positive asymptomatic individuals. J. Neuropathol. Exp. Neurol. 58, 1156–1162.
Bagasra O., Hauptman S. P., Lischner H. W., Sachs M., and Pomerantz R. J. (1992) Detection of human immunodeficiency virus type 1 provirus in mononuclear cells by in situ polymerase chain reaction. N. Engl. J. Med. 326, 1385–1391.
Bagasra O., Lavi E., Bobroski L., Khalili K., Pestaner J. P., Tawadros R., and Pomerantz R. J. (1996) Cellular reservoirs of HIV-1 in the central nervous system of infected individuals: identification by the combination of in situ polymerase chain reaction and immunohistochemistry. Aids 10, 573–585.
Balluz I. M., Farrell M. A., Kay E., Staunton M. J., Keating J. N., Sheils O., et al. (1996) Colocalisation of human immunodeficiency virus and human cytomeg-alovirus infection in brain autopsy tissue from AIDS patients. Ir. J. Med. Sci. 165, 133–138.
Belman A. L., Muenz L. R., Marcus J. C., Goedert J. J., Landesman S., Rubinstein A., et al. (1996) Neurologic status of human immunodeficiency virus 1-infected infants and their controls: a prospective study from birth to 2 years. Mothers and Infants Cohort Study. Pediatrics 98, 1109–1118.
Brack-Werner R. (1999) Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. Aids 13, 1–22.
Brouwers P., Civitello L., DeCarli C., Wolters P., and Sei S. (2000) Cerebrospinal fluid viral load is related to cortical atrophy and not to intracerebral calcifications in children with symptomatic HIV disease. J. Neurovirol. 6, 390–397.
Calvelli T. A. and Rubinstein A. (1990) Pediatric HIV infection: a review. Immunodeficiency Rev. 2, 83–127.
Cantó-Nogués C., Hockley D., Grief C., Ranjbar S., Bootman J., Almond N., and Herrera I. (2001a) Ultrastructural localization of the RNA of immuno-deficiency viruses using electron microscopy in situ hybridization and in vitro infected lymphocytes. Micron 32, 579–589.
Cantó-Nogués C., Jones S., Sangster R., Silvera P., Hull R., Cook R., et al. (2001b) In situ hybridization and immunolabelling study of the early replication of simian immunodeficiency virus (SIVmacJ5) in vivo. J. Gen. Virol. 82, 2225–2234.
Delabie J., Tierens A., Gavrii T., Wu G., Weisenburger D. D., and Chan W. C. (1996) Phenotype, genotype and clonality of Reed-Sternberg cells in nodular sclerosis Hodgkin’s disease: results of a single-cell study. Br. J. Haematol. 94, 198–205.
Dickson D. W., Lee S. C., Hatch W., Mattiace L. A., Brosnan C. F., and Lyman W. D. (1994) Macrophages and microglia in HIV-related CNS neuropathology. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 72, 99–118.
Embretson J., Zupancic M., Beneke J., Till M., Wolinsky S., Ribas J. L., et al. (1993) Analysis of human immunodeficiency virus-infected tissues by amplification and in situ hybridization reveals latent and permissive infections at single-cell resolution. Proc. Natl. Acad. Sci. U. S. A. 90, 357–361.
Ensoli F., Cafaro A., Fiorelli V., Vannelli B., Ensoli B., and Thiele C. J. (1995) HIV-1 infection of primary human neuroblasts. Virology 210, 221–225.
Ensoli F., Wang H., Fiorelli V., Zeichner S. L., De Cristofaro M. R., Luzi G., and Thiele C. J. (1997) HIV-1 infection and the developing nervous system: lineage-specific regulation of viral gene expression and replication in distinct neuronal precursors. J. Neurovirol. 3, 290–298.
Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., and Popovic M. (1986) The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233, 215–219.
Groothuis D. R. and Levy R. M. (1997) The entry of antiviral and antiretroviral drugs into the central nervous system. J. Neurovirol. 3, 387–400.
Gurbindo D., Resino S., Sánchez-Ramón S., Leon J. A., and Muñóz-Fernández M. A. (1999) Correlation of viral load and CD8 T-lymphocytes with development of neurological manifestations in vertically HIV-1-infected infants. A prospective longitudinal study. Neuropediatrics 30, 197–204.
Kaul M., Garden G. A., and Lipton S. A. (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410, 988–994.
Kure K., Weidenheim K. M., Lyman W. D., and Dickson D. W. (1990) Morphology and distribution of HIV-1 gp41-positive microglia in subacute AIDS encephalitis. Pattern of involvement resembling a multisystem degeneration. Acta Neuropathol. 80, 393–400.
Lavi E., Strizki J. M., Ulrich A. M., Zhang W., Fu L., Wang Q., et al. (1997) CXCR-4 (Fusin), a co-receptor for the type 1 human immunodeficiency virus (HIV-1), is expressed in the human brain in a variety of cell types, including microglia and neurons. Am. J. Pathol. 151, 1035–1042.
Li X. L., Moudgil T., Vinters H. V., and Ho D. D. (1990) CD4-independent, productive infection of a neuronal cell line by human immunodeficiency virus type 1. J. Virol. 64, 1383–1387.
Lipton S. A. (1991) HIV-related neurotoxicity. Brain Pathol. 1, 193–199.
Lyman W. D., Kress Y., Kure K., Rashbaum W. K., Rubinstein A., and Soeiro R. (1990) Detection of HIV in fetal central nervous system tissue. Aids 4, 917–920.
McGuire D. and Marder K. (2000) Pharmacological frontiers in the treatment of AIDS dementia. J. Psychopharmacol. 14, 251–257.
Mintz M. (1994) Clinical comparison of adult and pediatric NeuroAIDS. Adv. Neuroimmunol. 4, 207–221.
Muñóz-Fernández M. A. and Fresno M. (1998) The role of tumour necrosis factor, interleukin 6, interferon-gamma and inducible nitric oxide synthase in the development and pathology of the nervous system. Prog. Neurobiol. 56, 307–340.
Muñóz-Fernández M. A., Obregon E., Navarro J., Borner C., Gurbindo M. D., Sampelayo T. H., and Fernández-Cruz E. (1996) Relationship of virologic, immunologic, and clinical parameters in infants with vertically acquired human immunodeficiency virus type 1 infection. Pediatr. Res. 40, 597–602.
Nath A. and Geiger J. (1998) Neurobiological aspects of human immunodeficiency virus infection: neurotoxic mechanisms. Prog. Neurobiol. 54, 19–33.
Nuovo G. J., Forde A., MacConnell P., and Fahrenwald R. (1993) In situ detection of PCR-amplified HIV-1 nucleic acids and tumor necrosis factor cDNA in cervical tissues. Am. J. Pathol. 143, 40–48.
Nuovo G. J., Gallery F., MacConnell P., and Braun A. (1994) In situ detection of polymerase chain reaction-amplified HIV-1 nucleic acids and tumor necrosis factor-alpha RNA in the central nervous system. Am. J. Pathol. 144, 659–666.
Obregon E., Punzon C., Fernández-Cruz E., Fresno M., and Muñóz-Fernández M. A. (1999) HIV-1 infection induces differentiation of immature neural cells through autocrine tumor necrosis factor and nitric oxide production. Virology 261, 193–204.
Price R. W., Brew B., Sidtis J., Rosenblum M., Scheck A. C., and Cleary P. (1988) The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science 239, 586–592.
Rottman J. B., Ganley K. P., Williams K., Wu L., Mackay C. R., and Ringler D. J. (1997) Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am. J. Pathol. 151, 1341–1351.
Saito Y., Sharer L. R., Epstein L. G., Michaels J., Mintz M., Louder M., et al. (1994) Overexpression of nef as a marker for restricted HIV-1 infection of astrocytes in postmortem pediatric central nervous tissues. Neurology 44, 474–481.
Sharer L. R., Saito Y., Da Cunha A., Ung P. C., Gellbard H. A., Epstein L. G., and Blumberg B. M. (1996) In situ amplification and detection of HIV-1 DNA in fixed pediatric AIDS brain tissue. Hum. Pathol. 27, 614–617.
Simpson D. M. (1999) Human immunodeficiency virusassociated dementia: review of pathogenesis, prophylaxis, and treatment studies of zidovudine therapy. Clin. Infect. Dis. 29, 19–34.
Takahashi K., Wesselingh S. L., Griffin D. E., McArthur J. C., Johnson R. T., and Glass J. D. (1996) Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann. Neurol. 39, 705–711.
Tardieu M., Le Chenadec J., Persoz A., Meyer L., Blanche S., and Mayaux M. J. (2000) HIV-1-related encephalopathy in infants compared with children and adults. French Pediatric HIV Infection Study and the SEROCO Group. Neurology 54, 1089–1095.
Torres-Muñóz J., Stockton P., Tacoronte N., Roberts B., Maronpot R. R., and Petito C. K. (2001) Detection of HIV-1 gene sequences in hippocampal neurons isolated from postmortem AIDS brains by laser capture microdissection. J. Neuropathol. Exp. Neurol. 60, 885–892.
Trillo-Pazos G., Diamanturos A., Rislove L., Menza T., Chao W., Belem P., et al. (2003) Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol. 13, 144–154.
Vazeux R., Brousse N., Jarry A., Henin D., Marche C., Vedrenne C., et al. (1987) AIDS subacute encephalitis. Identification of HIV-infected cells. Am. J. Pathol. 126, 403–410.
Wiley C. A., Schrier R. D., Nelson J. A., Lampert P. W., and Oldstone M. B. (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc. Natl. Acad. Sci. U. S. A. 83, 7089–7093.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cantó-Nogués, C., Sánchez-Ramón, S., Álvarez, S. et al. HIV-1 infection of neurons might account for progressive HIV-1-associated encephalopathy in children. J Mol Neurosci 27, 79–89 (2005). https://doi.org/10.1385/JMN:27:1:079
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:27:1:079