Early pathological changes in the central nervous system of acutely feline-immunodeficiency-virus-infected cats.

The animal model of feline immunodeficiency virus (FIV) infection of cats was used to dissect the pathogenic role of microglia within the first 6 months of infection. Applying real-time PCR, microglia-associated FIV replication was first detectable at 14 days past inoculation (dpi) and remained at elevated levels throughout the whole observation period. In contrast, FIV RNA levels within paired serum samples declined again after an initial peak between 14 dpi and 28 dpi. Concomitant with the onset of viral reproduction, microglia transiently upregulated expression of MHC class I and class II molecules. Virus-induced microglial activation was followed by a mild infiltration of peripheral leukocytes into the CNS parenchyma. The presented data suggest that microglia is infected by FIV very early after peripheral entry of the virus. Virus replicating microglia withstands eradication by brain-infiltrating leukocytes resulting in formation of a brain-resident virus reservoir, which probably cannot be cleared by peripheral chemotherapy.

Ramified feline microglia selects for distinct variants of feline immunodeficiency virus during early central nervous system infection.

It is widely accepted that human immunodeficiency virus (HIV) invades the central nervous system (CNS) shortly after peripheral infection to establish a persistent infection of tissue-resident microglial cells. To what extent this early CNS infection is of pathogenic relevance is a matter of discussion. It is conceivable, however, that infected microglia releases virus variants of enhanced neurotropism and/or neurovirulence compared to peripheral isolates. Moreover, microglial variants may exhibit high resistance to antiviral therapeutics that poorly penetrate into brain tissue. The molecular basis of these biological properties is suspected to be associated with specific sequences in the viral env gene, particularly within the V3 loop. Therefore, we analyzed in the animal model of feline immunodeficiency virus (FIV) infection of cats lentiviral V3 sequences in highly purified microglial cells and blood from acutely infected animals. Compared to the inoculated virus, nucleotide sequence alterations in serum samples were rarely detectable, if at all. In contrast, up to 19 nucleotide exchanges could be identified within FIV V3 from microglia, resulting in a mutation frequency of up to 14.5% with respect to the deduced amino acid sequence. These findings suggest selection of specific virus variants by brain-resident target cells that might have implications for antiretroviral drug design.

Association of human polyomavirus JC with peripheral blood of immunoimpaired and healthy individuals.

JC virus (JCV) infection is regularly asymptomatic in healthy individuals. In contrast, in immunocompromised individuals, highly activated virus replication may lead to PML. Peripheral blood cells (PBCs) are found to harbor JCV DNA in healthy and diseased individuals and it is discussed that they might be responsible for dissemination of the virus to the central nervous system (CNS) during persistence. To better understand the role of JCV DNA in PBCs for persistent infection and pathogenesis, the authors characterized the extent of JCV infection in Ficoll-gradient purified blood cells (peripheral blood mononuclear cells [PBMCs]) of healthy and human immunodeficiency virus type 1 (HIV-1)-infected individuals. Virus activation in PBMCs from healthy JCV-infected individuals was found at a rate of 0% to 38% at low polymerase chain reaction (PCR) sensitivity. In progressive multifocal leukoencephalopathy (PML) patients, a stronger signal was found, indicating increased virus activation. JCV DNA was regularly detected in T and B lymphocytes and in monocytes at low levels. However, granulocytes were shown to be the predominant reservoir of JCV DNA harboring high copy numbers. Although the overall distribution of viral genomes holds true for the population studied, in the individual, a markedly changed pattern of distribution can be found.