Human immunodeficiency virus type 1 envelope-mediated neuropathogenesis: targeted gene delivery by a Sindbis virus expression vector.
Sindbis virus (SIN) expression vectors offer the opportunity for studying neuropathogenesis because of their distinct neural cell tropism. Here, we demonstrate that a recombinant SIN vector expressing EGFP (SINrep5-EGFP) infected multiple cell types including neural cells from several species relevant to lentivirus pathogenesis with high levels of transgene expression. Infection of human neurons by a recombinant SIN (SINrep5-JRFL) expressing the full-length envelope from a neurovirulent human immunodeficiency virus type 1 (HIV-1) strain (JRFL) caused increased cytotoxicity compared to infection with SINrep5-EGFP (P < 0.001), while no cytotoxicity was observed among infected human astrocytes or monocytoid cells. Both human monocyte-derived macrophages (MDM) (P < 0.01) and astrocytes (P < 0.001) infected with SINrep5-JRFL released soluble neurotoxins in contrast to SINrep5-EGFP or mock-infected cells, although this was most prominent for the astrocytes. Implantation of SINrep5-JRFL into the brains of SCID/NOD mice induced neuroinflammation, neuronal loss, and neurobehavioral changes characteristic of HIV-1 infection, which were not present in SINrep5-EGFP or mock-infected animals. Thus SIN expression vectors represent novel tools for studying in vitro and in vivo HIV-1 neuropathogenesis because of their high levels of transgene expression in specific cell types within the brain.
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
Guido
G
van Marle
Julie
J
Ethier
Claudia
C
Silva
Brian A
BA
Mac Vicar
Christopher
C
Power
D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D015686:Gene Products, env / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity*; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D009474:Neurons / Q000473:pathology / Q000821:virology*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D012845:Sindbis Virus / Q000235:genetics*
D015686:Gene Products, env; D008164:Luminescent Proteins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins