HIV-1-mediated apoptosis of neuronal cells: Proximal molecular mechanisms of HIV-1-induced encephalopathy

The induction of neuronal cell death in vivo has been recognized asa prominent feature of HIV type I (HIV-1) infection leading toHIV-1-induced encephalopathy. Viral and host cell products, releasedfrom HIV-1-infected cells, have been implicated as inducersof neuronal cell apoptosis. It is unclear which is more important inthis process. Neuronal cells were treated with media bearing HIV-1virions derived from infected T cells and macrophage or the sameset of media depleted of virions. T cell media bearing virus inducedhigh levels of apoptosis, whereas that depleted of virions did not.In contrast, neurons treated with media from infected macrophagesinduced cell death whether virions were present or depletedby ultracentrifugation. The former initiated a repeatedlyand significantly higher degree of apoptosis. These data suggestthat exposure of neurons to viral products is critical for theinduction of apoptosis, in addition to putative host factors releasedfrom virally infected cells. Protein-array analyses identified hostcell factors up-regulated from infected macrophages, versus theiruninfected counterparts, and these host cell factors may be primecandidates for contributing to neuronal apoptosis. Gene-arrayanalyses also identified mRNAs up-regulated in human neuronsafter treatment with purified HIV-1 gp120 envelope protein orvirus-containing media from HIV-1-infected macrophages. Theseanalyses suggest molecular mechanisms for the induction of apoptosisrelating to the exposure of viral and host cell factors andrationally designed approaches toward neuroprotection