AEGiS-15IAC: HIV-1-Mediated apoptosis of neurons: the proximal mechanisms of HIV-1-Induced encephalopathy.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

HIV-1-Mediated apoptosis of neurons: the proximal mechanisms of HIV-1-Induced encephalopathy.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. TuOrA1181)

Pomerantz RJ, Xu Y, Sullivan J, Kulkosky J
Thomas Jefferson University, Philadelphia, United States

Introduction: The induction of neuronal cell death in vivo has been recognized as a prominent feature of HIV-1 infection leading to HIV-1-induced encephalopathy. Viral and host cells proteins, released from HIV-1-infected cells, have been implicated as the inducers of neuronal cell apoptosis.

METHODS: Murine and human neurons were utilized, with T-cell and macrophage-expressed HIV-1 and recombinant lentiviral proteins. Analyses included TUNEL assays for apoptosis, plus gene microarrays and proteomics techniques.

RESULTS: Neuronal cells, both human and mouse, were treated with media-bearing HIV-1 virions derived from infected CD4+ T-cells and macrophages, or the same set of media depleted of virions. T-lymphocyte media bearing virus induced high levels of apoptosis, while that depleted of virions did not. In contrast, neurons treated with media from infected macrophages induced cell-death whether virions were present or depleted by ultracentrifugation. Nonetheless, the former initiated a significantly higher degree of apoptosis. Proteomics analysis identified host cells factors up-regulated from infected macrophages, versus their uninfected counterparts; including interleukin-5, I-309, interleukin-6, MCP3 and GM-CSF, which are all critical in macrophage activation and migration. Gene chip analysis also identified critical mRNAs up-regulated in human neuronal cells, such as moieties within the TNF/TNF R1 and Fas/Fas ligand pathways.

CONCLUSIONS: These data suggest that the exposure of neurons to viral products may be more critical for the induction of apoptosis relative to putative host factors released from the virally-infected cells, and denote direct molecular mechanisms for the induction of apoptosis in neurons relating to the exposure of viral and host cell factors. As such, relevant rationally-designed targets can now begin to be designed for interdicting in HIV-1-induced neuronal cell loss.

Keywords: AEGIS, HIV-1, Apoptosis, Neurons, In Situ Nick-End Labeling, HIV Infections, Macrophages, T-Lymphocytes, Membrane Glycoproteins, Cell Death, Tumor Necrosis Factor-alpha, Brain Diseases, FasL protein, Humans, Animal, Mice

040711
TuOrA1181