Tubular cell HIV-entry through apoptosed CD4 T cells: A novel pathway (original) (raw)
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HIV-1 Expression Induces Tubular Cell G2/M Arrest and Apoptosis
Renal Failure, 2008
Human renal biopsy studies suggest the presence of HIV-1 and associated signs of injury in renal tubular epithelial cells. Because renal epithelial cells lack conventional HIV-1 receptors, the modus operandi of HIV-1 in the induction of tubular cell injury remains a mystery. In the present study, we evaluated the role of HIV-1 gene expression in human proximal tubular cell apoptosis and cell cycle progression. HIV-1-or vector-transduced cells were assayed for cellular injury and cell cycle defect. HIV-1-transduced cells showed the progressive loss of viability in a time-dependent manner. Similarly, HIV-1-transduced cells showed greater apoptosis when compared with vector-transduced cells. A higher number of HIV-1 expressing cells showed cell cycle arrest at G2/M phase and enhanced tubular cell expression of phospho-p53(ser15), phospho-cdc-2(Tyr 15), and phospho-chk-2 (Thr 68). These findings suggest that in addition to the activation of apoptotic pathway, HIV-1induced G2/M arrest may also contribute to tubular cell injury.
Journal of Virology, 2001
proposed as an important mechanism contributing to HIV pathogenesis. However, interpretation of in vitro studies aimed at understanding HIV-related apoptosis has been complicated by the use of high concentrations of recombinant proteins or by direct cytopathic effects of replicating virus. We have developed an inactivation procedure that destroys retroviral infectivity while preserving the structural and functional integrity of the HIV surface proteins. These noninfectious virions interact authentically with target cells, providing a powerful tool to dissect mechanisms of HIV pathogenesis that do or do not require viral replication. Noninfectious CXCR4tropic HIV-1 virions, but not microvesicles, partially activated freshly isolated CD4 ؉ and CD8 ؉ peripheral blood mononuclear cell T lymphocytes to express FasL and Fas, but not CD69 or CD25 (interleukin-2 receptor alpha) and eventually die via apoptosis starting 4 to 6 days postexposure. These effects required conformationally intact virions, as heat-denatured virions or equivalent amounts of recombinant gp120 did not induce apoptosis. The maximal apoptotic effect was dependent on major histocompatibility complex (MHC) class II proteins being present on the virion, but was not MHC restricted. The results suggest that the immunopathogenesis of HIV infection may not depend solely on direct cytopathic effects of HIV replication, but that effects due to noninfectious HIV-1 virions may also contribute importantly.
Interactions of HIV-1 with antigen-presenting cells
Immunology and Cell Biology, 1999
Human immunodeficiency virus (HIV) infects about 40 million people worldwide. HIV is the causative agent of acquired immunodeficiency syndrome (AIDS). AIDS is characterised by a progressive decline in protective immunity that leads to opportunistic infection and eventually death. Although HIV-1 causes a decline in CD4' T-cell number and this undoubtedly contributes to the general immune deficit of AIDS, CD4+ T-cell loss does not completely explain the pathogenesis of AIDS. Death and anergy of uninfected T-cells is observed in AIDS, as are deficits in innate and specific immunity. Antigen presenting cells (APCs, including macrophages and dendritic cells, DCs, which are infectable by M-tropic strains of HIV-1 via the CCR-5 chemokine receptor) play a key role in orchestrating innate and adaptive immune responses and controlling T-cell activities including activation, anergy, deletion, tolerisation and memory by the provision of appropriate signals. APC dysregulation results in deficits of innate and adaptive immune responses. It is known that HIV-1 can cause APC dysregulation; this thesis examines some mechanisms by which this might occur. The HIV-1 envelope glycoprotein gpl20 mediates HIV-1 infection by binding to target cells via CD4 and CCR-5 and is focussed on throughout this work. Because gpl20 is found on the surface of HIV-1 and dissolved in the serum of HIV-1 infected patients, it has the ability to disrupt the function of both infected and uninfected APCs. Data in this thesis demonstrate that gp 120 causes a decline of cell-surface CD4 from human macrophages in vitro. A mechanism for this loss is proposed based on observations that it is significantly more substantial when CCR-5-binding gpl20, derived from M-tropic HIV-1 is used as opposed to CXCR-4-binding gpl20. CD4 loss is absent from macrophages that fail to express surface CCR-5 due to homozygosity for the naturally occurring ccr5A32 mutation. It appears that CD4 loss by this novel CCR-5-dependent mechanism requires cross-linking of CCR-5, CD4 and gp 120 at the cell surface leading to receptor-mediated endocytosis of this protein complex. Confocal microscopy was used to visualise these endocytosed proteins inside macrophages and RT-PCR was used to investigate transcriptional regulation of CD4 and CCR-5 recovery. Endocytosis of the protein complex may change antigen presentation efficiencies. Possible implications for protective-and auto¬ immunity are discussed. This thesis also presents evidence that pre-treatment with gp!20 leads to reduction in an APC's ability to stimulate antigen-specific proliferation of a T-cell line. Because this effect is not dependent on the tropism of the HIV-1 strain from which the gpl20 is derived, an alternative mechanism to CD4-loss was sought. The hypothesis that APC dysfunction is due to HIV-1 subversion of physiological mechanisms involving prostaglandin and the Notch signalling pathway, leading to inappropriate tolerance induction, was examined. Treatment of macrophages and DCs with gpl20 caused the transcriptional up-regulation of genes involved in the Notch pathway including Notch ligands, the presence of which on an APC has previously been shown to abrogate T-cell activation by the induction of an anergic phenotype. Preventing HIV-1 infection of APCs and the subsequent dysregulation of immune responses is a therapeutic goal. Branched, synthetic peptides based on discontinuous epitopes of gpl20 and previously demonstrated to disrupt binding to CD4 and CCR-5 are shown to protect macrophages from infection with M-tropic HIV-1Bal-Possible refinements to peptide structure and their utility as anti-HIV-1 therapeutics or vaccines are discussed. 2 DECLARATION I hereby declare that the work presented in this thesis is my own, except where stated in the text. The work has not been submitted in any previous application for a degree.
Virology, 2009
Renal biopsy data suggest that renal tubular cells may serve as a reservoir for HIV-1, however the mechanism underlying this finding has not been studied. Here we show that primary human renal proximal tubular epithelial cells (HRPTECs) have the potential to harbor HIV-1 through the DEC-205 receptor. The interaction of HIV-1 with DEC-205 results in the rapid internalization of the virus for lysosomal degradation, without establishing a productive infection. However, a small fraction of incoming virus escapes degradation and can be rescued by T cells. Since pH-modulating agents and an inhibitor of endosomal transport increased HIV-1 accumulation and trans-infection to T cells, it appears that HRPTECs endocytic compartments may be the site of viral persistence and transmission to target cells. The ability of T cells to rescue the virus from HRPTECs further supports the hypothesis that these cells have the potential to serve as a reservoir for HIV-1.
Journal of the American Society of Nephrology, 2007
HIV-1 infection of renal cells has been proposed to play a role in HIV-1-associated nephropathy. Renal biopsy data further suggest that renal tubular cells may serve as reservoir for HIV-1. The mechanism by which HIV-1 enters these cells has not been identified. Renal tubular cells do not express any of the known HIV-1 receptors, and our results confirmed lack of the expression of CD4, CCR5, CXCR4, DC-SIGN, or mannose receptors in tubular cells. The aim of this study, therefore, was to determine the mechanism that enables viral entry into renal tubular cells. An in vitro model was used to study the HIV-1 infection of human kidney tubular (HK2) cells and to identify the receptor that enables the virus to enter these cells.
Journal of Virology, 2004
Apoptosis of uninfected bystander CD4 ؉ T cells contributes to T-cell depletion during human immunodeficiency virus type 1 (HIV-1) pathogenesis. The viral and host mechanisms that lead to bystander apoptosis are not well understood. To investigate properties of the viral envelope glycoproteins (Env proteins) that influence the ability of HIV-1 to induce bystander apoptosis, we used molecularly cloned viruses that differ only in specific amino acids in Env. The ability of these strains to induce bystander apoptosis was tested in herpesvirus saimiri-immortalized primary CD4 ؉ T cells (CD4/HVS), which resemble activated primary T cells. Changes in Env that increase affinity for CD4 or CCR5 or increase coreceptor binding site exposure enhanced the capacity of HIV-1 to induce bystander apoptosis following viral infection or exposure to nonreplicating virions. Apoptosis induced by HIV-1 virions was inhibited by CD4, CXCR4, and CCR5 antibodies or by the CXCR4 inhibitor AMD3100, but not the fusion inhibitor T20. HIV-1 virions with mutant Envs that bind CXCR4 but are defective for CD4 binding or membrane fusion induced apoptosis, whereas CXCR4 binding-defective mutants did not. These results demonstrate that HIV-1 virions induce apoptosis through a CXCR4-or CCR5-dependent pathway that does not require Env/CD4 signaling or membrane fusion and suggest that HIV-1 variants with increased envelope/receptor affinity or coreceptor binding site exposure may promote T-cell depletion in vivo by accelerating bystander cell death.
Blood, 2004
α and tumor-necrosis factor-γ cells producing both interferon-HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8+ T (5012 articles) Immunobiology (746 articles) Apoptosis Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at: digital object identifier (DOIs) and date of initial publication. the indexed by PubMed from initial publication. Citations to Advance online articles must include final publication). Advance online articles are citable and establish publication priority; they are appeared in the paper journal (edited, typeset versions may be posted when available prior to Advance online articles have been peer reviewed and accepted for publication but have not yet Short title: Cytotoxicity of HIV-1-specific CD8+ T cells Word counts: 198 words (abstract), 4387 words (manuscript) Scientific heading: Immunobiology This study was supported by grants from the National Institutes of Health (to M. A., E. S. R., J. Z., T. M. A. and B. D. W.), the Doris Duke Charitable Foundation (to M. A., E. S. R. and B. D. W.), the Foundation for AIDS and Immunology Research (to X. G. Y. and M. A.) and the Deutsche Forschungsgemeinschaft (to M. L.).