Cell Death & Differentiation

Gougeon, M-L

doi: 10.1038/sj.cdd.4401616pmid: 15832178

Nardacci, R; Antinori, A; Kroemer, G; Piacentini, M

doi: 10.1038/sj.cdd.4401590pmid: 15846379

Petrovas, C; Mueller, Y M; Katsikis, P D

doi: 10.1038/sj.cdd.4401595pmid: 15818412

Kfoury, Y; Nasr, R; Hermine, O; de Thé, H; Bazarbachi, A

doi: 10.1038/sj.cdd.4401624pmid: 15846376

Kaul, M; Zheng, J; Okamoto, S; Gendelman, H E; Lipton, S A

doi: 10.1038/sj.cdd.4401623pmid: 15832177

Infection with the human immunodeficiency virus-1 (HIV-1) can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. After infiltrating peripheral immune competent cells, in particular macrophages, HIV-1 provokes a neuropathological response involving all cell types in the brain. HIV-1 also incites activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes and glutamate receptor-mediated excitotoxicity, all of which can trigger numerous downstream signaling pathways and disrupt neuronal and glial function. This review will discuss recently uncovered pathologic neuroimmune and degenerative mechanisms contributing to neuronal damage induced by HIV-1 and potential approaches for development of future therapeutic intervention.

Mattson, M P; Haughey, N J; Nath, A

doi: 10.1038/sj.cdd.4401577pmid: 15761472

Many patients infected with human immunodeficiency virus type-1 (HIV-1) suffer cognitive impairment ranging from mild to severe (HIV dementia), which may result from neuronal death in the basal ganglia, cerebral cortex and hippocampus. HIV-1 does not kill neurons by infecting them. Instead, viral proteins released from infected glial cells, macrophages and/or stem cells may directly kill neurons or may increase their vulnerability to other cell death stimuli. By binding to and/or indirectly activating cell surface receptors such as CXCR4 and the N-methyl-D-aspartate receptor, the HIV-1 proteins gp120 and Tat may trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations. Membrane lipid metabolism and inflammation may also play important roles in determining whether neurons live or die in HIV-1-infected patients. Drugs and diets that target oxidative stress, excitotoxicity, inflammation and lipid metabolism are in development for the treatment of HIV-1 patients.

D'Agostino, D M; Silic-Benussi, M; Hiraragi, H; Lairmore, M D; Ciminale, V

doi: 10.1038/sj.cdd.4401576pmid: 15761473

p13II of human T-cell leukemia virus type 1 (HTLV-1) is an 87-amino-acid protein that is targeted to the inner mitochondrial membrane. p13II alters mitochondrial membrane permeability, producing a rapid, membrane potential-dependent influx of K+. These changes result in increased mitochondrial matrix volume and fragmentation and may lead to depolarization and alterations in mitochondrial Ca2+ uptake/retention capacity. At the cellular level, p13II has been found to interfere with cell proliferation and transformation and to promote apoptosis induced by ceramide and Fas ligand. Assays carried out in T cells (the major targets of HTLV-1 infection in vivo) demonstrate that p13II-mediated sensitization to Fas ligand-induced apoptosis can be blocked by an inhibitor of Ras farnesylation, thus implicating Ras signaling as a downstream target of p13II function.

Perfettini, J-L; Castedo, M; Roumier, T; Andreau, K; Nardacci, R; Piacentini, M; Kroemer, G

doi: 10.1038/sj.cdd.4401584pmid: 15719026

The envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) can induce apoptosis by a cornucopia of distinct mechanisms. A soluble Env derivative, gp120, can kill cells through signals that are transmitted by chemokine receptors such as CXCR4. Cell surface-bound Env (gp120/gp41), as present on the plasma membrane of HIV-1-infected cells, can kill uninfected bystander cells expressing CD4 and CXCR4 (or similar chemokine receptors, depending on the Env variant) by at least three different mechanisms. First, a transient interaction involving the exchange of lipids between the two interacting cells (‘the kiss of death’) may lead to the selective death of single CD4-expressing target cells. Second, fusion of the interacting cells may lead to the formation of syncytia which then succumb to apoptosis in a complex pathway involving the activation of several kinases (cyclin-dependent kinase-1, Cdk1; checkpoint kinase-2, Chk2; mammalian target of rapamycin, mTOR; p38 mitogen-activated protein kinase, p38 MAPK; inhibitor of NF-κB kinase, IKK), as well as the activation of several transcription factors (NF-κB, p53), finally resulting in the activation of the mitochondrial pathway of apoptosis. Third, if the Env-expressing cell is at an early stage of imminent apoptosis, its fusion with a CD4-expressing target cell can precipitate the death of both cells, through a process that may be considered as contagious apoptosis and which does not involve Cdk1, mTOR, p38 nor p53, yet does involve mitochondria. Activation of some of the above- mentioned lethal signal transducers have been detected in patients’ tissues, suggesting that HIV-1 may indeed trigger apoptosis through molecules whose implication in Env-induced killing has initially been discovered in vitro.