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Viruses manipulate host cells to ensure their own survival and, at late stages of the viral life cycle, they kill the infected target cell to ensure their propagation. In addition, some viruses induce a bystander killing, a viral strategy to escape from the host's innate and cognate defense systems. In HIV-infection, the disabling of the immune system is initially due to the preferential depletion by apoptosis of virus-specific CD4⁺ T cells in lymphoid tissues, followed by the destruction of non-infected bystander cells. Both the extrinsic and the intrinsic pathways are activated, and this is the consequence of systemic immune activation. This review presents recent developments showing that the gastrointestinal tract is the major reservoir of infected cells and the site of rapid and profound loss of CD4 T cells, and that microbial translocation from the gastrointestinal tract is the cause of immune activation. Furthermore, apoptosis mechanisms involved in HIV-induced neuropathological disorders are discussed, including the role of syncytia that involve the sequential activation of ATM, p38MAPK and p53. Finally, HIV-associated dementia (HAD) was recently found in monkey models to be linked to inhibition of autophagy in neurons, suggesting that homeostasis of autophagy is a reliable security factor for neurons, and challenging the development of new therapeutics aimed at boosting neuronal autophagy to prevent HAD.

The hepatitis B virus protein HBx is a promiscuous transactivator implicated in both cell growth and death and in the development of hepatocellular carcinoma. We recently reported that HBx can potentiate c-myc-induced liver oncogenesis in a transgenic model where low level expression of HBx induces no pathology. To assess if HBx could affect the hepatocyte turnover, we investigated the HBx-elicited apoptotic responses in transgenic livers and in primary hepatocyte cultures. Here we show that transgenic expression of HBx is associated with a twofold increase of spontaneous cell death in the mouse liver. The finding that apoptosis was enhanced to similar extents in HBx mice carrying homozygous p53 null mutations implied that functionally intact p53 was not required to transduce the death signal. A direct, dose-dependent apoptotic function of HBx was demonstrated in transient transfections of liver-derived cell lines. We further show that stable expression of HBx at low, presumably physiological levels in primary hepatocytes, induced cellular susceptibility to diverse apoptotic insults, including growth factor deprivation, treatment with anti-Fas antibodies or doxorubicine and oxidative stress. HBx expression, but not p53 status profoundly affected the commitment of cells to die upon apoptotic stimuli. These data strengthen the notion that HBX may contribute to HBV pathogenesis by enhancing apoptotic death in the chronically infected liver.

Dendritic cells (DCs) initiate immune responses by transporting antigens and migrating to lymphoid tissues to initiate T-cell responses. DCs are located in the mucosal surfaces that are involved in human immunodeficiency virus (HIV) transmission and they are probably among the earliest targets of HIV-1 infection. DCs have an important role in viral transmission and dissemination, and HIV-1 has evolved different strategies to evade DC antiviral activity. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein that can act as an alarmin, a danger signal to alert the innate immune system for the initiation of host defense. It is the prototypic damage-associated molecular pattern molecule, and it can be secreted by innate cells, including DCs and natural killer (NK) cells. The fate of DCs is dependent on a cognate interaction with NK cells, which involves HMGB1 expressed at NK–DC synapse. HMGB1 is essential for DC maturation, migration to lymphoid tissues and functional type-1 polarization of naïve T cells. This review highlights the latest advances in our understanding of the impact of HIV on the interactions between HMGB1 and DCs, focusing on the mechanisms of HMGB1-dependent viral dissemination and persistence in DCs, and discussing the consequences on antiviral innate immunity, immune activation and HIV pathogenesis.

Viruses have evolved numerous mechanisms to evade the host immune system and one of the strategies developed by HIV is to activate apoptotic programmes that destroy immune effectors. Not only does the HIV genome encode pro-apoptotic proteins, which kill both infected and uninfected lymphocytes through either members of the tumour-necrosis factor family or the mitochondrial pathway, but it also creates a state of chronic immune activation that is responsible for the exacerbation of physiological mechanisms of clonal deletion. This review discusses the molecular mechanisms by which HIV manipulates the apoptotic machinery to its advantage, assesses the functional consequences of this process and evaluates how new therapeutics might counteract this strategy.

Apoptosis, or programmed cell death, is a physiological suicide mechanism that preserves homeostasis. New findings suggest that in HIV-infected patients, the loss of CD4 positive cells is associated with lymphocyte activation and this activation results in apoptosis.

We have used the Hepatitis B Virus DNA genome as a probe to identify genes clonally mutated in vivo, in human liver cancers. In a tumor, HBV-DNA was found to be integrated into the gene encoding Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA), which pumps calcium, an important intracellular messenger for cell viability and growth, from the cytosol to the endoplasmic reticulum. The HBV X gene promoter cis-activates chimeric HBV X/SERCA1 transcripts, with splicing of SERCA1 exon 11, encoding C-terminally truncated SERCA1 proteins. Two chimeric HBV X/SERCA1 proteins accumulate in the tumor and form dimers. In vitro analyses have demonstrated that these proteins localize to the ER, determine its calcium depletion and induce cell death. We have also shown that these biological effects are related to expression of the SERCA, rather than of the viral moiety. This report involves for the first time the expression of mutated SERCA proteins in vivo in a tumor cell proliferation and in vitro in the control of cell viability. Oncogene (2000).

Peripheral blood mononuclear cells and lymphoid tissues from HIV-infected individuals display high levels of ``tissue'' transglutaminase (tTG) with respect to seronegative persons. In asymptomatic individuals, >80% of the circulating CD4$^{+}$ T cells synthesize tTG protein and the number of these cells matches the level of apoptosis detected in the peripheral blood mononuclear cells from the same patients. In HIV-infected lymph nodes tTG protein is localized in large number of cells (macrophages, follicular dendritic cells, and endothelial cells), showing distinctive morphological and biochemical features of apoptosis as well as in lymphocytes and syncytia. These findings demonstrate that during the course of HIV infection, high levels of apoptosis also occur in the accessory cells of lymphoid organs. The increased concentration of $\\varepsilon $($\\gamma $-glutamyl)lysine isodipeptide, the degradation product of tTG cross-linked proteins, observed in the blood of HIV-infected individuals demonstrates that the enzyme accumulated in the dying cells actively cross-links intracellular proteins. The enhanced levels of $\\varepsilon $($\\gamma $-glutamyl)lysine in the blood parallels the progression of HIV disease, suggesting that the isodipeptide determination might be a useful method to monitor the in vivo rate of apoptosis.

Cell Death and Differentiation (2003) 10, 390-392. doi:10.1038/sj.cdd.4401199

Natural T (NT) lymphocytes recognize infected cells or microbial compounds without the classical genetic restriction of polymorphic major histocompatibility complex (MHC) molecules. NT cells are mainly composed of αβ and γδ T lymphocytes that express natural killer (NK) receptors and recognize preferentially various nonpeptidic antigens. Similar to NK cells, NT lymphocytes can see and kill target cells deficient in the expression of one or more MHC class I molecules. NT cells expressing the αβ TCR can recognize lipid and lipoglycan antigens presented in the context of nonpolymorphic CD1 molecules, whereas phosphocarbohydrates and alkylamines induce constitutive response of Vγ9Vδ2 T cells. The stimulation of Vγ9Vδ2 T cells with phosphocarbohydrates induces the production of cytokines (IFNγ and TNFα) and the release of chemokines with suppressive activity on HIV replication. In addition, stimulated Vγ9Vδ2 T cells exert a cytolytic activity against HIV-infected targets. In HIV-infected patients, a quantitative and qualitative alteration is observed early during the infection. Vγ9Vδ2 T cells are deleted and the remaining γδ cells are anergic. Th1 cytokines (IL-12 and IL-15) positively regulate cytokine production by Vγ9Vδ2 T cells but they are inefficient in restoring normal functions in patients’ γδ T cells. Interestingly, partial restoration of the immune system under highly active antiretroviral therapies (HAART) is associated to the recovery of functional Vγ9Vδ2 T cells. A large panel of phosphocarbohydrates able to selectively stimulate Vγ9Vδ2 T cells is currently available, and preliminary experiments in monkeys suggest their in vivo efficacy in helping to control SIV replication. These observations prompt the question of new immune intervention involving molecules that stimulate NT cells.