Lymphocytic choriomeningitis virus (LCMV) and Lassa virus can cause hemorrhagic fever and liver disease in primates. The WE strain of LCMV (LCMV-WE) causes a fatal Lassa fever-like disease in rhesus macaques and provides a model for arenavirus pathogenesis in humans. LCMV-WE delivered intravenously or intragastrically to rhesus macaques targets hepatocytes and induces high levels of liver enzymes, interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), and soluble tumor necrosis factor receptors (sTNFRI and -II) in plasma during acute infection. Proinflammatory cytokines TNF-␣ and IL-1 were not detected in plasma of infected animals, but increased plasma gamma interferon was noted in fatally infected animals. Immunohistochemistry of acute liver biopsies revealed that 25 to 40% of nuclei were positive for proliferation antigen Ki-67. The increases in IL-6, sIL-6R, sTNFR, and proliferation antigen that we observe are similar to the profile of incipient liver regeneration after surgical or toxic injury (N. Fausto, Am. J. Physiol. 277:G917-G921, 1999). Although IL-6 was not directly induced by virus infection in vitro, peripheral blood mononuclear cells from acutely infected monkeys produced higher levels of IL-6 upon lipopolysaccharide stimulation than did healthy controls. Our data confirm that acute infection is associated with weak inflammatory responses in tissues and initiates a program of liver regeneration in primates.
The Yellow Fever Vaccine 17D (YFV17D) has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) resulting in construction of YFV17D/LASV-GPC recombinant virus. The virus was replication-competent and processed the LASV-GPC in cell cultures. The recombinant replicated poorly in guinea pigs but still elicited specific antibodies against LASV and YFV17D antigens. A single subcutaneous injection of the recombinant vaccine protected strain 13 guinea pigs against fatal Lassa Fever. This study demonstrates the potential to develop an YFV17D-based bivalent vaccine against two viruses that are endemic in the same area of Africa.
The human immunodeficiency virus (HIV) Tat protein has a critical role in viral transcription, but this study focuses on its additional role as an extracellular effector of lymphocyte cell death. It is well known that Tat induces tumor necrosis factor-related apoptosis-induced ligand (TRAIL) in peripheral blood mononuclear cells (PBMC), and we show that the majority of TRAIL is produced by the monocyte subset of PBMC. Human monocytes and U937 monoblastoid cells did not take up soluble HIV Tat-86, as T cells did, yet produced more TRAIL than did T cells. TRAIL secretion was induced by Tat and by a cysteine-rich peptide of Tat but not by sulfhydryl-modified Tat toxoid. Although there was only a slight increase in cell surface expression of TRAIL on monocytes, sufficient TRAIL was secreted to be toxic for T cells. The cytotoxicity of Tat-stimulated monocyte medium could be blocked by a TRAIL-neutralizing antibody. T cells treated with Tat did not secrete enough TRAIL to mediate cell death in our assay. Remarkably, uninfected T cells are more susceptible to TRAIL than are HIV-infected T cells. The production of TRAIL by Tat-stimulated monocytes provides a mechanism by which HIV infection can destroy uninfected bystander cells.
Circulating V␥2V␦2 T-cell populations in healthy human beings are poised for rapid responses to bacterial or viral pathogens. We asked whether V␥2V␦2 T cells use the Toll-like receptor (TLR) family to recognize pathogen-associated molecular pattern molecules and to regulate cell functions. Analysis of expanded V␥2V␦2 T-cell lines showed the abundant presence of TLR2 mRNA, implying that these receptors are important for cell differentiation or function. However, multiple efforts to detect TLR2 protein on the cell surface or in cytoplasmic compartments gave inconsistent results.
Functional assays confirmed that human V␥2V␦2 T cells could respond to the TLR2 agonist (S)-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser(S)-
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