Acquired Immunodeficiency Syndrome: Ono F

Xing HQ, Mori K, Sugimoto C, Ono F, Izumo K, Kuboda R, Izumo S. · Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. · J Neuropathol Exp Neurol. · Pubmed #18520778 No free full text.

Abstract: Various types of neuronal damage have been reported in acquired immunodeficiency syndrome (AIDS) dementia. We previously demonstrated that inflammation and cortical damage occur independently according to viral tropism in a simian immunodeficiency virus (SIV)-infected macaque model of AIDS dementia. To elucidate the pathogenesis of cortical degeneration, we examined the frontal cortex of SIV-infected macaques and found apoptosis and decreased expression of the excitatory amino acid transporter 2 in astrocytes and diffuse activation of microglia in association with limited neuronal damage. Some activated microglia also expressed excitatory amino acid transporter 2 but not proinflammatory cytokines. No inflammatory changes were seen in the cortex or the white matter, and SIV-infected cells were not detected in or around cortical lesions either by immunohistochemistry or by the polymerase chain reaction detection of SIV genomes of extracted DNA from microdissected tissue samples. These results indicate that an astrocytic abnormality and a compensatory activation of microglia might provide a protective effect against neuronal degeneration in the frontal cortex of SIV-infected macaques without SIV encephalitis.

Xing HQ, Moritoyo T, Mori K, Sugimoto C, Ono F, Izumo S. · Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. · Neuropathology. · Pubmed #18507770 No free full text.

Abstract: The pathogenesis of acquired immunodeficiency syndrome dementia complex (ADC) is still poorly understood. Many studies suggest that proinflammatory cytokines such as IL-1beta and TNF-alpha released by microglia/macrophages or astrocytes play a role in CNS injury. A microscopic finding of a microglial nodule with multinucleated giant cells (MNGCs) is a histopathologic hallmark of ADC and named HIV encephalitis. However, in vivo expression of these cytokines in this microenvironment of HIV encephalitis is not yet clarified. One of the main reasons is complexities of brain pathology in patients who have died from terminal AIDS. In this study, we infected two macaques with macrophage-tropic Simian immunodeficiency virus SIV239env/MERT and examined expression of TNF-alpha and IL-1beta in inflammatory lesions with MNGCs and its relation to virus-infected cells using immunohistochemistry. One macaque showed typical inflammatory lesions with MNGCs in the frontal white matter. Small microglial nodules were also detected in the basal ganglia and the spinal cord. SIVenv positive cells were detected mainly in inflammatory lesions, and seemed to be microglia/macrophages and MNGCs based on their morphology. Expression of IL-1beta and TNF-alpha were detected in the inflammatory lesions with MNGCs, and these positive cells were found to be negative for SIVenv by double-labeling immunohistochemistry or immunohistochemistry of serial sections. There were a few TNF-alpha positive cells and almost no IL-1beta positive cells in the area other than inflammatory lesions. Another macaque showed scattered CD3+ cells and CD68+ cells in the perivascular regions of the white matter. SIVenv and TNF-alpha was demonstrated in a few perivascular macrophages. These findings indicate that virus-infected microglia/macrophages do not always express IL-1beta and TNF-alpha, which suggests an indirect role of HIV-1-infected cells in cytokine-mediated pathogenesis of ADC. Our macaque model for human ADC may be useful for better understanding of its pathogenesis.

Iwata N, Yoshida H, Tobiume M, Ono F, Shimazaki T, Sata T, Nakajima N. · Department of Pathology, National Institute of Infectious Disease, Tokyo, Japan. · J Neurovirol. · Pubmed #17454444 No free full text.

Abstract: The pathogenesis of neurologic dysfunctions caused by human immunodeficiency virus type 1 (HIV-1) infection is not yet well understood. Simian immunodeficiency virus (SIV) infection of macaques is an important animal model for HIV-1 infection. This is the first report to characterize brain progenitor cells (BPCs) isolated from embryonic brain of cynomolgus monkeys (Macaca fascicularis) by neurosphere assay and utilize BPC-derived cell culture for studying SIV infection. The self-renewal and multilineage differentiation properties of BPCs are convenient for planning viral infection experiments. The BPC-derived culture does not contain macrophage/microglial cells, fibroblasts, or endothelial cells. Thus, this culture is appropriate for studying direct relation between SIV infection and neuronal and glial cells. First, the authors characterized undifferentiated and differentiated simian BPCs by immunocytochemistry, flow cytometry analysis, real-time polymerase chain reaction (PCR), and reverse transcriptase (RT)-PCR. The BPCs induced to differentiate by the addition of 1% fetal bovine serum (FBS) were composed of heterogeneous cells expressing nestin, glial fibrillary acidic protein (GFAP), and/or tubulin beta III isoform (Tuj). None of them expressed the monocyte/macrophage/microglial marker. mRNA expression of CD4, CXCR4, CCR5, GPR1, STRL33, and APJ in both undifferentiated and differentiated BPCs were shown by RT-PCR method, suggesting that SIV would infect and replicate in this culture system. Then, it was confirmed that the neurotropic SIV strain, SIV17/E-Fr, replicated productively in BPC-derived cells. The SIV/17E-FrDelta nefGFP was inoculated to identify the infected cells and immunocytochemistry analysis revealed that green fluorescent protein (GFP)-expressing cells were mostly GFAP positive and coexpressed with SIV p27 antigen. Thus, BPC-derived cell culture system is applicable for studying SIV infection in glial and neuronal cells.

Xing HQ, Moritoyo T, Mori K, Tadakuma K, Sugimoto C, Ono F, Hayakawa H, Izumo S. · Division of Molecular Pathology and Genetic Epidemiology, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, Japan. · J Neurovirol. · Pubmed #12907395 No free full text.

Abstract: Highly active antiretroviral therapy (HAART) has been successful to reduce progression of acquired immunodeficiency syndrome (AIDS). Nevertheless, recent autopsy analysis of the brain from patients with human immunodeficiency virus (HIV)-1 infection reported same or even increasing numbers of AIDS encephalopathy. This insufficient effect of HAART for central nervous system (CNS) complication might be explained by independent pathogenetic processes in lymph node and CNS. We inoculated macaques with three Simian immunodeficiency virus (SIV) strains and investigated relationship between degree of the lymph node pathology and that of AIDS-related brain pathology. Animals infected with T-cell-tropic viruses SIVmac239 and SHIV-RT developed typical AIDS pathology in the lymph node 46 to 156 weeks after infection. The cerebral cortex of these animals showed focal or diffuse gliosis, and electron microscopic analysis demonstrated degenerative changes, such as accumulation of dense lamellar bodies in the dendrites and swelling of astrocytic processes. However, there was no evidence of microglial nodules or multinucleated giant cells in the white mater. The animals infected with macrophage-tropic SIV239env/MERT did not develop lymph node pathology of AIDS in the same or longer period of infection. The white mater of the animal, however, showed microglial nodules with multinucleated giant cells, a pathological hallmark of AIDS encephalopathy. SIV immunoreactivity was demonstrated in these giant cells as well as macrophage/microglia cells. On the other hand, there was no abnormality in the cerebral cortex. These findings suggest that there are two independent pathogenetic processes in AIDS encephalopathy: immune response against virus infected macrophage/microglial cells in the white mater without immunodeficiency and cortical degeneration caused in the late stage of AIDS.

Sugimoto C, Tadakuma K, Otani I, Moritoyo T, Akari H, Ono F, Yoshikawa Y, Sata T, Izumo S, Mori K. · Tsukuba Primate Center for Medical Sciences, National Institute of Infectious Diseases, Tsukuba, Japan. · J Virol. · Pubmed #12634375 links to  free full text

Abstract: The pathogenesis of AIDS virus infection in a nonhuman primate AIDS model was studied by comparing plasma viral loads, CD4(+) T-cell subpopulations in peripheral blood mononuclear cells, and simian immunodeficiency virus (SIV) infection in lymph nodes for rhesus macaques infected with a pathogenic molecularly cloned SIVmac239 strain and those infected with its nef deletion mutant (Deltanef). In agreement with many reports, whereas SIVmac239 infection induced AIDS and depletion of memory CD4(+) T cells in 2 to 3 years postinfection (p.i.), Deltanef infection did not induce any manifestation associated with AIDS up to 6.5 years p.i. To explore the difference in SIV infection in lymphoid tissues, we biopsied lymph nodes at 2, 8, 72, and 82 weeks p.i. and analyzed them by pathological techniques. Maximal numbers of SIV-infected cells (SIV Gag(+), Env(+), and RNA(+)) were detected at 2 weeks p.i. in both the SIVmac239-infected animals and the Deltanef-infected animals. In the SIVmac239-infected animals, most of the infected cells were localized in the T-cell-rich paracortex, whereas in the Deltanef-infected animals, most were localized in B-cell-rich follicles and in the border region between the paracortex and the follicles. Analyses by double staining of CD68(+) macrophages and SIV Gag(+) cells and by double staining of CD3(+) T cells and SIV Env(+) cells revealed that SIV-infected cells were identified as CD4(+) T cells in either the SIVmac239 or the Deltanef infection. Whereas the many functions of Nef protein were reported from in vitro studies, our finding of SIVmac239 replication in the T-cell-rich paracortex in the lymph nodes supports the reported roles of Nef protein in T-cell activation and enhancement of viral infectivity. Furthermore, the abundance of SIVmac239 infection and the paucity of Deltanef infection in the T-cell-rich paracortex accounted for the differences in viral replication and pathogenicity between SIVmac239 and the Deltanef mutant. Thus, our in vivo study indicated that the nef gene enhances SIV replication by robust productive infection in memory CD4(+) T cells in the T-cell-rich region in lymphoid tissues.