Abstract
Despite HAART, a significant number of HIV-1-infected patients develop neurological complications. However, the presence of specific neurotropic HIV-1 strains, the extent of viral replication in the brain, and the type of cells infected remain controversial issues. To address this controversy we have analyzed different V3 loop sequences of viral isolates from four vertically HIV-1-infected children who developed HIV-1-related encephalopathy. Moreover, we have determined that some biological and molecular properties of HIV-1 might contribute to AIDS neurological dysfunctions. We detected very different HIV-1 isolates (X4 and R5) in the brain despite no great differences in clinical, pathological, or immunological parameters. In vitro, no differences in replicative competence in glial or neuroblastoma cells were observed between virus isolated from the blood of children with or without clinical neurological symptoms. The expression of both CXCR4 and CCR5 RNAs was observed in the brain independently of HIV-1 infection and viral strain predominant in this location. Our results failed to show a particular phenotypic property of the HIV-1 virus that might explain its neurovirulence and/or neurotropism.
Similar content being viewed by others
References
Ait-Khaled M., McLaughlin J. E., Johnson M. A., and Emery V. C. (1995) Distinct HIV-1 long terminal repeat quasi-species present in nervous tissues compared to that in lung, blood and lymphoid tissues of an AIDS patient. AIDS 9, 675–683.
Albright A. V., Shieh J. T., Itoh T., Lee B., Pleasure D., O'Connor M. J., et al. (1990) Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. J. Virol. 73, 205–213.
Alvarez Losada S., Canto-Nogues C., and Muñoz-Fernández M. A. (2002) A new possible mechanism of human immunodeficiency virus type 1 infection of neural cells. Neurobiol. Dis. 11, 469–478.
An S. F., Groves M., Gray F., and Scaravilli F. (1999) Early entry and widespread cellular involvement of HIV-1 DNA in brain of HIV-1 positive asymptomatic individuals. J. Neuropathol. Exp. Neurol. 58, 1156–1162.
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 andimmuno histochemistry. AIDS 10, 573–585.
Bajetto A., Bonavia R., Barbero S., Florio T., Costa A., and Schettini G. (1999) Expression of chemokine receptors in the rat brain. Ann. N.Y. Acad. Sci. 876, 201–209.
Balluz I. M., Farrell M. A., Kay E., Staunton M. J., Keating J. N., Sheils O., Cosby S., et al. (1996) Colocalisation of human immunodeficiency virus and human cytomegalovirus infection in brain autopsy tissue from AIDS patients. Jr. J. Med. Sci. 165, 133–138.
Bouwman F. H., Skolasky R. L., Hes D., Selnes O. A., Glass J. D., Nance-Sproson T. E., et al. (1998) Variable progression of HIV-associated dementia. Neurology 50, 1814–1820.
Budka H. (1989) Human immunodeficiency virus (HIV)-induced disease of the central nervous system: pathology and implications for pathogenesis. Acta Neuropathol. 77, 225–236.
Canto-Nogues C., Hockley D., Grief C., Ranjbar S., Bootman J., Almond N., and Herrera I. (2001a) Ultrastructural localization of the RNA of immunodeficiency viruses using electron microscopy in situ hybridization and in vitroinfected lymphocytes. Micron, 32, 579–589.
Canto-Nogues C., Sanchez-Ramon S., Alvarez S., Lacruz C. and Muñoz-Fernández M. A. (2005) HIV-1 infection of neurons might account for progressive HIV-1-associated encephalopathy in children. J. Mol. Neurosci. 27, 79–89.
Chang J., Jozwiak R., Wang B., Ng T., Ge Y. C., Bolton W., et al. (1998) Unique HIV type 1 V3 region sequences derived from six different regions of brain: region-specific evolution within host-determined quasi-species. AIDS Res. Hum. Retroviruses 14, 25–30.
Connor R. I., Sheridan K. E., Ceradini D., Choe S., and Landau N. R. (1997) Change in coreceptor use coreceptor use correlates with disease progression in HIV-1-infected individuals. J. Exp. Med. 185, 621–628.
Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., et al. (1996) Identification of a major coreceptor for primary isolates of HIV-1. Nature 381, 661–666.
Di Stefano M., Monno L., Fiore J.R., Buccoliero G., Appice A., Perulli L. M. et al. (1998) Neurological disorders during HIV-1 infection correlate with viral load in cerebrospinal fluid but not with virus phenotype. AIDS 12, 737–743.
Di Stefano M., Wilt S., Gray F., Dubois-Dalcq M., and Choidi F. (1996) HIV type 1 V3 sequences and the development of dementia during AIDS. AIDS Res. Hum. Retroviruses 12, 471–476.
Dick A. D., Pell M., Brew B. J., Foulcher E., and Sedgwick J. D. (1997) Direct ex vivo flow cytometric analysis of human microglial cell CD4 expression: examination of central nervous system biopsy specimens from HIV-seropositive patients and patients with other neurological disease. AIDS 11, 1699–1708.
Ditmar M. T., Simmons G., Donaldson Y., Simmonds P., Clapham P. R., Schulz T. F., and Weiss R. A (1997) Biological characterization of human immunodeficiency virus type 1 clones derived from different organs of an AIDS patient by long-range PCR. J. Virol. 71, 5140–5147.
Donaldson Y. K., Bell J. E., Holmes E. C., Hughes E. S., Brown H. K., and Simmonds P. (1994) In vivo distribution and cytopathology of variants of human immuno-deficiency virus type 1 showing restricted sequence variability in the V3 loop. J. Virol. 68, 5991–6005.
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.
Epstein L. G., Sharer L. R., Oleske J. M., Connor E. M., Goudsmit J., Bagdon L., et al. (1986) Neurologic manifestations of human immunodeficiency virus infection in children. Pediatrics 78, 678–687.
Fauci A. S. (1996) Resistance to HIV-1 infection: it's in the genes. Nat. Med. 2, 966–967.
Galan I., Jimenez J. L., Gonzalez-Rivera M., De Jose M. I., Navarro M. L., Ramos J. T., et al. (2004) Virological phenotype switches under salvage therapy with lopinavirritonavir in heavly pretreated HIV-1 vertically infected children. AIDS 18, 247–255.
Glass J. D., and Johnson R. T. (1996) Human immunode-ficiency virus and the brain. Proc. Assoc. Am. Physicians 108, 47–54.
Gorry P. R., Bristol G., Zack J. A., Ritola K., Swanstrom R., Birch C. J., et al. (2001) Macrophage tropism of human immuodeficiency virus type 1 isolates from brain and lymphoid tissues predicts neurotropism independent of coreceptor specificity. J. Virol. 75, 10,073–10,089.
Gorry P. R., Taylor J., Holm G. H., Mehle A., Morgan T., Cayabyab M., et al. (2002) Increased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate. J. Virol. 76, 6277–6292.
Hesselgesser J., and Horuk R. (1999) Chemokine and chemokine receptor expression in the central nervous system. J. Neurovirol. 5, 13–26.
Keys B., Karis J., Fadeel B., Valentin A., Norkrans G., Hagberg L., and Chiodi F. (1993) V3 sequences of paired HIV-1 isolates from blood and cerebrospinal fluid cluster according to host and show variation related to the clinical stage of disease. Virology 196, 475–483.
Koot M., Vos A. H., Keet R. P., de Goede R. E., Dercksen M. W., Terpstra F. G. et al. (1992) HIV-1 biological phenotype in long-term infected individuals evaluated with an MT-2 cocultivation assay. AIDS 6, 49–54.
Korber B. T., Kunstman K. J., Patterson B. K., Furtado M., McEvilly M. M., Levy R., and Wolinsky S. M. (1994) Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences. J. Virol. 68, 7467–7481.
Lavi E., Kolson D. L., Ulrich A. M., Fu L., and Gonzalez-Scarano F. (1998) Chemokine receptors in the human brain and their relationship to HIV infection. J. Neurovirol. 4, 301–311.
Lawrence D. M., Durham L. C., Schwartz L., Seth P., Maric D., and Major E. O. (2004) Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells. J. Virol. 78, 7319–7328.
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.
Martin J., LaBranche C. C., and Gonzalez-Scarano F. (2001) Differential CD4/CCR5 utilization, gp120 conformation, and neutralization sensitivity between envelopes from a microglia-adapted human immunodeficiency virus type 1 and its parental isolate. J. Virol. 75, 3568–3580.
Mashke M., Kastrup O., Esser S., Ross B., Hengge U., and Hufnagel A. (2000) Incidence and prevalence of neurological disorders associated with HIV since the intro-duction of highly active antiretroviral therapy (HAART). J. Neurol. Neurosurg. Psychiatry 69, 376–380.
McArthur J. C., Haughey N., Gartner S., Conant K., Pardo C., Nath A., and Sacktor N. (2003) Human immuno-deficiency virus-associated dementia: an evolving disease. J. Neurovirol. 9, 205–221.
Mueller C., Gershenfeld H. K., Lobe C. G., Okada C. Y., Bleackley R. C., and Weissman I. L. (1988) A high proportion of T lymphocytes that infiltrate H-2-incompatible heart allografts in vivo express genes encoding cytotoxic cell-specific serine proteases, but do not express the MEL-14-defined lymph node homing receptor. J. Exp. Med. 167, 1124–1136.
Muñoz-Fernández M. A., Obregon E., Navarro J., Borner C., Gurbindo M. D., Sampelayo T. H., and Fernandez-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.
Nukuna A., Gendelman H. E., Limoges J., Rasmussen J., Poluektova L., Ghorpade A., and Persidsky Y. (2004) Levels of human immunodeficiency virus type 1 (HIV-1) replication in macrophages determines the severity of murine HIV-1 encephalitis. J. Neurovirol. 10 (Suppl. 1), 82–90.
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., Fernandez-Cruz E., Fresno M., and Muñoz-Fernández-Fernandez 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.
Pierson T., McArthur J., and Siliciano R. F. (2000) Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu. Rev. Immunol. 18, 665–708.
Power C., and Johnson R. T. (2001) Neuroimmune and neurovirological aspects of human immunodeficiency virus infection. Adv. Virus Res. 56, 389–433.
Power C., Gill M. J., and Johnson R. T. (2002) Progress in clinical neurosciences. The neuropathogenesis of HIV infection: host-virus interaction and the impact of therapy. Can. J. Neurol. Sci. 29, 19–32.
Power C., McArthur J. C., Johnson R. T., Griffin D. E., Glass J. D., Perryman S., and Chesebro B. (1994) Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences. J. Virol. 68, 4643–4649.
Power C., McArthur J. C., Nath A., Wehrly K., Mayne M., Nishio J., et al. (1998) Neuronal death induced by brain-derived human immunodeficiency virus type 1 envelope genes differes between demented and nondemented AIDS patients. J. Virol 72, 9045–9053.
Reddy R. T., Achim C. L., Sirko D. A., Tehranchi S., Kraus F. G., Wong-Staal F., and Wiley C. A. (1996) Sequence analysis of the V3 loop in brain and spleen of patients with HIV encephalitis. AIDS Res. Hum. Retroviruses 12, 477–482.
Sabri F., Tresoldi E., Di Stefano M., Polo S., Monaco M. C., Verani A., et al. (1999) Nonproductive human immuno-deficiency virus type 1 infection of human fetal astrocytes: independence from CD4 and major chemokine receptors. Virology 264, 370–384.
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.
Sanders V. J., Pittman C. A., White M. G., Wang G, Wiley C. A., and Achim C. L. (1998) Chemokines and receptors in HIV encephalitis. AIDS 12, 1021–1026.
Simmons G., Clapham P. R., Picard L., Offord R. E., Rosenkilde M. M., Schwartz T. W., et al. (1997) Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 276, 276–279.
Simpson D. M. (1999) Human immunodeficiency virus-associated dementia: review of pathogenesis, prophylaxis, and treatment studies of zidovudine therapy. Clin. Infect. Dis. 29, 19–34.
Smit T. K., Wang B., Ng T., Osborme R., Brew B., and Saksena N. K. (2001) Varied tropism of HIV-1 isolates derived from different regions of a dult brain cortex discriminate between patients with and without AIDS dementia complex (ADC): evidence for neurotropic HIV variants. Virology 279, 509–526.
Takahashi K., Wesselingh S. L., Griffin D. E., Mc Arthur 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.
Trujillo J. R., Wang W. K., Lee T. H., and Essex M. (1996) Identification of the envelope V3 loop as a determinant of a CD4-negative neuronal cell tropism for HIV-1. Virology 217, 613–617.
van der Meer P., Ulrich A. M., Gonzalez-Scarano F., and Lavi E. (2000) Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. Exp. Mol. Pathol. 69, 192–201.
Wesselingh S. L., and Thompson K. A. (2001) Immuno-pathogenesis of HIV-associated dementia. Curr. Opin. Neurol. 14, 375–379.
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.
Williams K. C., and Hickey W. F. (2002) Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS. Annu. Rev. Neurosci. 25, 537–562.
Yi Y., Chen W., Frank I., Cutilli J., Singh A., Starr-Spires L., Sulcove J., et al. (2003) An unusual syncytia-inducting human immunodeficiency virus type 1 primary isolate from the central nervous system that is restricted to CXCR4, replicates efficiently in macrophages, and induces neuronal apoptosis. J. Neurovirol. 9, 432–441.
Yi Y., Lee C., Liu Q. H., Freedman B. D., and Collman R. G. (2004) Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: Implications for neuropathogenesis. J. Neurovirol. 10 (Suppl. 1) 91–96.
Zheng J., Ghorpade A., Niemann D., Cotter R. L., Thylin M. R., Epstein L, et al. (1999) Lymphotropic virons affect chemokine receptor-mediated neural signaling and apoptosis: implications for human immunodeficiency virus type 1-associated dementia. J. Vitrol. 73, 8256–8267.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Álvarez, S., Jiménez, J.L., Serramía, M.J. et al. Lack of association of HIV-1 biological or molecular properties with neurotropism for brain cells. J Mol Neurosci 29, 131–144 (2006). https://doi.org/10.1385/JMN:29:2:131
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:29:2:131