Background:  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 HIV-1 virion-bearing media 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 after treatment with purified gp120 envelope proteins or virus-containing media from HIV-1-infected macrophages.  Moieties within the TNF/TNF R1 and Fas/Fas ligand pathways were demonstrated, and suggested that both are engaged in neuronal cell apoptosis.

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: AIDS Dementia Complex; Neurons; Genomics