Morphological correlates of neurological dysfunction in macaques infected with neurovirulent simian immunodeficiency virus

Abstract

The pattern of neurological disease caused by human immunodeficiency virus (HIV) infection of the central nervous system (CNS) was investigated using a macaque model of acquired immune defiency syndrome (AIDS). Seven of nine macaques inoculated with neurovirulent simian imunodeficiency virus (SIVmac ) developed AIDS within 3 months. Four of these had clinically obvious neurological disease and extensive conduction defects in the form of latency increases in evoked potential (EP) responses. Neuropathologically, all four animals had disseminated white matter disease in the form of multifocal, perivascular and nodular parenchymal mononuclear cell infiltrates, along with extensive involvement of the cortical grey matter, leptomeninges and intracranial portions of cranial nerves. A brisk multinucleated giant cell (MGC) response was a frequent accompaniment in the affected areas. Three of the animals in this group also showed spongiform vacuolation in the occipital grey matter, a lesion described only rarely in HIV encephalitis. In the remaining three animals, there was only minimal evidence of overt neurological impairment or conduction defects. These animals had only mild to moderate neuropathological changes and lesions were virtually confined to the white matter regions of the brain. MGC responses were rare or absent in the CNS of these animals. Neuropathological findings in this SIVmac model have therefore shown good correlation with the severity of clinical and neurophysiological changes, and are reminiscent of HIV-1 encephalitis. More importantly, white matter involvement was a consistent finding in the affected macaques, regardless of the duration and severity of disease, or type of virus inoculated, suggesting an unusual susceptibility for lentiviral infection in these regions of the macaque CNS.

Increased In Vivo Activation of Microglia and Astrocytes in the Brains of Mice Transgenic for an Infectious R5 Human Immunodeficiency Virus Type 1 Provirus and for CD4-Specific Expression of Human Cyclin T1 in Response to Stimulation by Lipopolysaccharides

“…Although animal models do not completely recapitulate all aspects of HIV infection in humans, studies using various animal model systems, including simian immunodeficiency virusinfected macaques and pigtail monkeys, feline immunodeficiency virus-infected cats, HIV-infected hu-SCID mouse models, and transgenic mouse models have provided insights into the pathophysiology of HIV-1-mediated neuronal dysfunction and permitted the evaluation of therapies directed toward improving mental function in HIV-infected subjects with cognitive and motor dysfunction (42,57,61,68,70). Mice, with their well-characterized immune systems, ease of genetic manipulations, and low cost, have been used extensively as an in vivo small-animal model for studying the pathogenesis of infectious diseases.…”

Morphine Potentiates Neuropathogenesis of SIV Infection in Rhesus Macaques

“…SIVmacR71/17E(Raghavan et al, 1999) was originally prepared from pooled brain homogenates from macaques infected with R17 and R71E both of which cause encephalitis. Virus stock was prepared in CD8+T cell depleted, ConA-activated macaque peripheral blood mononuclear cells (PBMC) and assayed for infectivity in CEMx174 cells and by plaque assay in GHOST Hi5 cells.…”

“…The rationale for using R71/17E (Raghavan et al, 1999) a SIVmac239 derivative, in the present study is that analogous to the human situation, this virus causes a highly productive infection in memory CD4+ T cells that are primarily located in the secondary and gut-associated lymphoid tissues (Veazey et al, 1998; Veazey et al, 2000a; Veazey et al, 2000b), leading to increased viremia. Various studies have explored the effect of opiate dependence on progression of SIV infection, but similar to epidemiological studies, the results have led to contrasting conclusions.…”

Rhesus Macaque Model of Chronic Opiate Dependence and Neuro-AIDS: Longitudinal Assessment of Auditory Brainstem Responses and Visual Evoked Potentials

“…The SIVmac239 (R71/E17) virus has been shown to cross the blood brain barrier shortly after inoculation (Sharma et al, 1992; Narayan et al, 1997) and productively replicates primarily in memory CD4+ T cells in the gut-associated lymphoid tissue (GALT) and spleen (Veazey et al, 1998; Veazey et al, 2000a, b). Our neuropathological and stereological studies, utilizing a cohort of SIV mac R71/17E inoculated Indian origin rhesus macaques have demonstrated many of the features of HIV-1 encephalopathy (Raghavan, et al, 1999; Marcario et al, 2004) as well as a significant loss of neurons in the lateral geniculate nucleus (Berman et al, 1998), the globus pallidus, and the substantia nigra (Marcario et al, 2004). Thus, our model not only closely mimics the natural disease course of HIV infection but also demonstrates many of the hallmarks associated with HIV-related neurological disease.…”