Role of Microglial Cells in Selective Replication of Simian Immunodeficiency Virus Genotypes in the Brain

Abstract

An accelerated, consistent macaque simian immunodeficiency virus (SIV) model in which over 90% of pigtailed macaques (Macaca nemestrina) coinoculated with SIV/17E-Fr and SIV/DeltaB670 developed encephalitis was used to determine whether central nervous system (CNS) lesions are associated with the replication of specific genotypes in the brain and, more specifically, in the microglia. Ten of 11 inoculated macaques had severe (n ‫؍‬ 3), moderate (n ‫؍‬ 5), or mild (n ‫؍‬ 2) encephalitis at 3 months postinoculation. To compare actively replicating viral genotypes in the CNS and in microglia with those in the periphery, the V1 region of the SIV envelope gene was amplified and sequenced from RNA extracted from basal ganglia, from microglial cells isolated from the brain, and from peripheral blood mononuclear cells (PBMC) isolated from blood at the time of death. To distinguish between actively replicating with latent viral genotypes in the CNS, viral genotypes in RNA and DNA from basal ganglia were compared. Two macrophage-tropic, neurovirulent viruses, SIV/17E-Fr and SIV/DeltaB670 Cl-2, predominated in the brain RNA of macaques with encephalitis, comprising 95% of the genotypes detected. The same two viral genotypes were present at the same frequencies in microglial cell RNA, suggesting that microglia are pivotal in the selective replication of neurovirulent viruses. There was a significantly greater number of viral genotypes in DNA than there were in RNA in the brain (P ‫؍‬ 0.004), including those of both the macrophage-and lymphocyte-tropic viral strains. Furthermore, significantly fewer viral genotypes were detected in brain RNA than in PBMC RNA at the time of death (P ‫؍‬ 0.004) and the viral strain that predominated in the brain frequently was different from that which predominated in the PBMC of the same animal. These data suggest that many viral genotypes enter the brain, but only a limited subset of macrophage-tropic, neurovirulent viruses replicate terminally in the brains of macaques with encephalitis. They further suggest that the selection of macrophage-tropic, neurovirulent viruses occurs not at the level of the blood-brain barrier but at a stage after virus entry and that microglial cells may play an important role in that selection process.

Macrophage-Mediated Dorsal Root Ganglion Damage Precedes Altered Nerve Conduction in SIV-Infected Macaques

“…Rather, neurotoxic products produced by activated macrophages and viral proteins may contribute synergistically to neuronal damage. 41,42 Because replication of SIV in DRG macrophages may be the initiating, primary cause of DRG damage, therapeutic strategies aimed at tightly controlling viral replication and associated inflammatory responses may aid HIV-infected individuals suffering from HIV-induced peripheral neuropathy.…”

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis

“…Microglial identity was determined by incubation with DiI-Ac-LDL (Invitrogen Corp.). This marker identifies phagocytosing cells and has been reported to accurately identify microglial cells in the nervous system (44).…”

Emergence of CD4 Independence Envelopes and Astrocyte Infection in R5 Simian-Human Immunodeficiency Virus Model of Encephalitis

“…In this regard, HIV neurotropism is primarily determined by the viral envelope gene (13)(14)(15)(16), and compartmentalization of a genetically distinct envelope (Env) population in the CNS from that in the systemic circulation (17)(18)(19)(20), as a result of either a founder effect or independent viral adaptive evolution in the brain with long-term HIV infection, has been described (21,22). More-over, different env genotypes have been reported in different CNS regions of HIV-1-infected individuals and simian immunodeficiency virus (SIV)-infected macaques (23)(24)(25)(26), despite the use of a "clonal" inoculum in the latter (23,24), suggesting discordant regional virus evolution in this anatomical compartment, as well.…”