Simian Immunodeficiency Virus Encephalitis in the White Matter and Degeneration of the Cerebral Cortex Occur Independently in Simian Immunodeficiency Virus-Infected Monkey

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.

Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells

“…Six macaques ( #1-6 ) were infected with SHIV -SF162.P4 that was inserted the HIV-related genes, and three macaques ( #7-9 ) were infected with SIV sm543-3 . These two virus strains made rhesus macaques to appear similar brain pathological changes with previous SIVmac239-infected rhesus macaques [10, 22–23]. Four macaques ( #10-13) were used as controls.…”

“…In the present study, we used different viral strains that have similar pathological features compared with previous SIVmac239 [10, 22–23]. In the SHIV -SF162.P4 and SIV sm543-3 - infected macaques, gliosis was observed in cortical layers II–V using IHC against GFAP (Figure 3A).…”

“…Our animals developed systemic AIDS and showed high viral loads in their plasma. There was no correlation between viral RNA load in plasma and pathological changes in cerebral cortical of SIVmac239 and SHIV-RT-infected rhesus macaques using ISH or by the polymerase chain reaction detection of SIV genomes of extracted DNA from microdissected tissue samples [10, 22–23]. In the present study, we have compared the cortical changes of two new different SIV virus, SHIV-162.P4 and SIV sm543-3 .…”

“…The animals were sacrificed at various times after infection, at a time point when they became morbid. The methods used have been previously described [10, 22–23]. This study was carried out in rigorous accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and in accordance with the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines.…”

Apoptosis in SIV infection

“…136 In vitro studies have also identified a positive correlation between CD4 T-cell depletion and infection by syncytium inducing HIV-1 137,138 or SIV variants. 75,[139][140][141] In addition, multinucleated giant cells, a pathological hallmark of AIDS encephalopathy are also found during SIV-encephalitis 142,143 and these cells revealed DNA fragmentation. 144 The HIV envelope protein has also been reported to cause apoptosis by binding to a chemokine coreceptor.…”