Lentiviral Neuropathogenesis: Comparative Neuroinvasion, Neurotropism, Neurovirulence, and Host Neurosusceptibility

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Abstract
Despite extensive genetic diversity among lentiviruses, they share many biological properties, including similar structural and genomic organizations, Mg2-dependent reverse tran- scriptase activity, and broad cellular tropisms involving both proliferating and nonproliferating cells within and outside the nervous system (30). Lentiviruses can also be subdivided on the basis of pathogenesis into peripheral immune deficiency-in- ducing viruses, such as human (HIV), simian (SIV), feline (FIV), bovine (BIV), and chimeric simian-human (SHIV) im- munodeficiency viruses, and those that are immune activators, including caprine arthritis encephalitis virus (CAEV), maedi- visna virus (MVV), and equine infectious anemia virus (EIAV) (Table 1). Systemically, most lentiviruses exhibit a distinct dis- ease pattern in which primary infection induces acute disease and an intense immune response, followed by a lengthy period of subclinical infection (lenti slow) and a terminal phase resulting in death (22). Immunodeficiency-associated lentiviral infections usually trigger a robust host immune response that is diminished over time, permitting opportunistic infections. In contrast, infections by the immune-activating lentiviruses are characterized by a terminal phase of host immune activation. CAEV and MVV infections are manifested as systemic inflam- mation with chronic arthritis, pneumonia, and mastitis, while EIAV induces recurrent episodes of an autoimmune-mediated acute hemolytic disease (17, 57, 89). In contrast to the distinct differences in peripheral immune responses, both lentiviral groups exhibit immune dysregulation in the central nervous system (CNS), defined by inflammation and neuronal injury. Moreover, the ability to infect and replicate in cells of monocyte/macrophage lineage is common to all lentivi- ruses. Among the immunodeficiency viruses, which recapitulate many of the neurobehavioral and neuropathological features of HIV type 1 (HIV-1)-induced neurological disease, primary lenti- virus-induced neurological disease occurs more frequently with advancing immune suppression (84, 92, 102). The frequency of neuropathological changes induced in FIV- and SIV-infected cats and monkeys, respectively, varies depending on the viral strain and host-specific factors. FIV-induced brain disease occurs in 20 to 50% of infected animals, usually concurrent with depressed CD4 T-lymphocyte levels (98), and may manifest as psychomotor