18 research outputs found
Proinflammatory cytokine signaling required for the generation of natural killer cell memory
Although natural killer (NK) cells are classified as innate immune cells, recent studies demonstrate that NK cells can become long-lived memory cells and contribute to secondary immune responses. The precise signals that promote generation of long-lived memory NK cells are unknown. Using cytokine receptor-deficient mice, we show that interleukin-12 (IL-12) is indispensible for mouse cytomegalovirus (MCMV)-specific NK cell expansion and generation of memory NK cells. In contrast to wild-type NK cells that proliferated robustly and resided in lymphoid and nonlymphoid tissues for months after MCMV infection, IL-12 receptor–deficient NK cells failed to expand and were unable to mediate protection after MCMV challenge. We further demonstrate that a STAT4-dependent IFN-γ–independent mechanism contributes toward the generation of memory NK cells during MCMV infection. Understanding the full contribution of inflammatory cytokine signaling to the NK cell response against viral infection will be of interest for the development of vaccines and therapeutics
In silico toxicology protocols
The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information
Relationship between Human T Lymphotropic Virus (HTLV) Type 1/2 Viral Burden and Clinical and Treatment Parameters among Patients with HIV Type 1 and HTLV-1/2 Coinfection
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Adult T Cell Leukemia/Lymphoma Development in HTLV-1-Infected Humanized SCID Mice
Abstract
Abstract 1425
Poster Board I-448
Human T-lymphotropic virus type-1 (HTLV-1) is the first human retrovirus linked to cancer and is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4+ T cell malignancy. The molecular and genetic factors induced by HTLV-1 that initiate ATLL remain unclear, in part, due to the lack of an animal model which recapitulates leukemogenic events. In particular, early target cell infection and transformation events have not been identified or defined. Herein, we have created humanized NOD/SCID (HU-NOD/SCID) mice by inoculation of NOD/SCID mice with CD34+ hematopoietic progenitor and stem cells (CD34+ HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCID mice consistently developed CD4+ T cell lymphomas with characteristics similar to ATLL. Elevated proliferation of infected human stem cells (CD34+CD38−) in the bone marrow was observed in mice developing malignancies. Furthermore, examination of CD34+ HP/HSCs from HTLV-1-infected patients revealed proviral integrations suggesting a role of human bone marrow-derived stem cells in leukemogenesis. NOD/SCID mice reconstituted with CD34+ HP/HSCs transduced with a lentivirus vector (LV) expressing the HTLV-1 oncoprotein (Tax1) also developed CD4+ lymphomas. The recapitulation of a CD4+ T cell lymphoma in HTLV-1- and Tax1-HU-NOD/SCID mice suggest that hematopoietic stem cells serve as a viral reservoir in vivo and provide a cellular target for cell transformation in humans. This animal model of HTLV-1 induced ATLL will provide an important tool for the identification of molecular and cellular events that control the initiation and progression of the lymphoma and potential therapeutic targets to block tumor development.
Disclosures:
No relevant conflicts of interest to declare
Inhibition of HIV Type 1 Replication by Human T Lymphotropic Virus Types 1 and 2 Tax Proteins in Vitro
Comparison of Three Assays for Cytomegalovirus Detection in AIDS Patients at Risk for Retinitis
Recombinant human T-cell leukemia virus types 1 and 2 Tax proteins induce high levels of CC-chemokines and downregulate CCR5 in human peripheral blood mononuclear cells
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Relationship between human T lymphotropic virus (HTLV) type 1/2 viral burden and clinical and treatment parameters among patients with HIV type 1 and HTLV-1/2 coinfection.
BACKGROUND: Human T lymphotropic virus types 1 (HTLV-1) and 2 (HTLV-2) are frequent copathogens among individuals infected with human immunodeficiency virus type 1 (HIV-1). The long-term effects of coinfection are unknown, and little information exists regarding how levels of HTLV-1/2 viral burden are affected by antiretroviral medications. METHODS: Factors associated with HTLV-1/2 viral burden were examined in patients with HIV-HTLV-1/2 coinfection. A total of 72 subjects were evaluated. The variables analyzed included HTLV-1/2 proviral load, HTLV-1/2 tax/rex mRNA expression, HIV load, HTLV-1/2 viral antigen detection in peripheral blood mononuclear cell (PBMC) cultures, T cell subsets, demographic variables (age, race, sex, and reported use of injection drugs), and administration of highly active antiretroviral therapy. RESULTS: An HTLV-1/2 proviral DNA copy number >20,000 copies/10(6) PBMCs was significantly associated with the following variables: (1) a positive HTLV-1 Western blot test result, (2) a positive HTLV-1/2 PBMC culture result, (3) a positive tax/rex mRNA result, (4) an HIV load <10,000 copies/mL, and (5) higher CD4 cell counts among subjects with HIV-HTLV-1 coinfection. There was no correlation between HTLV-1/2 proviral copy number or HTLV-1/2 tax/rex mRNA detection and administration of antiretroviral therapy. CONCLUSIONS: HTLV-1/2 proviral burden was significantly higher among patients with HIV-HTLV-1 coinfection than among patients with HIV-HTLV-2 coinfection. Highly active antiretroviral therapy may be of limited value in controlling virus expression of HTLV-1/2 in patients with HIV-HTLV-1/2 coinfection
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Relationship between human T lymphotropic virus (HTLV) type 1/2 viral burden and clinical and treatment parameters among patients with HIV type 1 and HTLV-1/2 coinfection.
BACKGROUND: Human T lymphotropic virus types 1 (HTLV-1) and 2 (HTLV-2) are frequent copathogens among individuals infected with human immunodeficiency virus type 1 (HIV-1). The long-term effects of coinfection are unknown, and little information exists regarding how levels of HTLV-1/2 viral burden are affected by antiretroviral medications. METHODS: Factors associated with HTLV-1/2 viral burden were examined in patients with HIV-HTLV-1/2 coinfection. A total of 72 subjects were evaluated. The variables analyzed included HTLV-1/2 proviral load, HTLV-1/2 tax/rex mRNA expression, HIV load, HTLV-1/2 viral antigen detection in peripheral blood mononuclear cell (PBMC) cultures, T cell subsets, demographic variables (age, race, sex, and reported use of injection drugs), and administration of highly active antiretroviral therapy. RESULTS: An HTLV-1/2 proviral DNA copy number >20,000 copies/10(6) PBMCs was significantly associated with the following variables: (1) a positive HTLV-1 Western blot test result, (2) a positive HTLV-1/2 PBMC culture result, (3) a positive tax/rex mRNA result, (4) an HIV load <10,000 copies/mL, and (5) higher CD4 cell counts among subjects with HIV-HTLV-1 coinfection. There was no correlation between HTLV-1/2 proviral copy number or HTLV-1/2 tax/rex mRNA detection and administration of antiretroviral therapy. CONCLUSIONS: HTLV-1/2 proviral burden was significantly higher among patients with HIV-HTLV-1 coinfection than among patients with HIV-HTLV-2 coinfection. Highly active antiretroviral therapy may be of limited value in controlling virus expression of HTLV-1/2 in patients with HIV-HTLV-1/2 coinfection