The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly up-regulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, alpha1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function.

No abstract

The idea that CNS ramified microglia are quiescent has been challenged by studies that show that microglia without the classic signs of activation can be phagocytic and appear with shorter, thicker ramifications. These semi-activated cells may constitute a form of microglia that has not been previously recognized in neuropathological conditions and may contribute to the pathology and dysfunction in these disorders. This study investigated the expression of CD 163, a cell surface marker whose normal expression is restricted to monocytes/macrophages, in cases of HIV or SIV encephalitis (HIVE/SIVE), Alzheimer disease, and variant Creutzfeldt-Jakob disease. In HIVE/SIVE, in addition to reacting with CNS macrophages, CD163 antibody staining was shown to highlight ramified microglia. Such reactivity was especially notable in grey matter ramified microglia and was greater than that of another typically used marker, HLA-DR. CD163 expression was only observed in infected/affected tissue, in contrast to that shown with another microglia marker, GLUT5, which has recently been shown to identify all microglia regardless of disease state. Although activated microglia were present in the other disorders, as evidenced by strong HLA-DR expression, there was very little CD163 immunoreactivity. The activation state identified by CD163 has not been previously recognized and may have a positive or negative impact on neuronal damage shown in HIV-associated dementia.

No abstract

There exists a significant limitation in the variety of organisms for which microarrays have been developed because of a lack of genomic sequence data. A near-term solution to this limitation is to use microarrays designed for one species to analyze RNA samples from closely related species. The assumption is that conservation of gene sequences between species will be sufficient to generate a reasonable amount of goodquality data. While there have been relatively few published reports describing the use of microarrays for cross-species hybridizations, this technique is potentially a powerful tool for understanding genomics in model organisms such as nonhuman primates. Here we describe the analysis and comparison of hybridization characteristics and data variability from a set of crossspecies (rhesus macaque) and same-species (human) hybridization experiments using human high-density Affymetrix oligonucleotide arrays. The data reveal that a large fraction of probe sets are effective at transcript detection in the cross-species hybridization, validating the application of cross-species hybridizations for nonhuman primate genomics research.