Human immunodeficiency virus (HIV) invades the brain early during infection and generates a chronic inflammatory microenvironment that can eventually result in neurological disease, even in the absence of significant viral replication. Thus, HIV-1 infection of the brain has been characterized both as a neuroimmunological and neurodegenerative disorder. While the brain and central nervous system (CNS) have historically been regarded as immune privileged or immunologically quiescent, newer concepts of CNS immunity suggest an important if not defining role for innate immune responses generated by glial cells. Innate immunity may be the first line of defense against HIV infection of the brain and CNS, with multiple cellular elements providing responses that can be anti-viral and neuroprotective, but also potentially neurotoxic, impairing neurogenesis and promoting neuronal apoptosis. To investigate the effects of HIV exposure on neurogenesis and neuronal survival, we have studied the responses of human neuroepithelial progenitor (NEP) cells, which undergo directed differentiation into astrocytes and neurons in vitro. We identified a group of genes that were differentially expressed in NEP-derived cells during virus exposure. This included genes that are strongly related to interferon-induced responses and antigen presentation. Moreover, we observed that the host factor apolipoprotein E influences the innate immune response expressed by these cells, with a more robust response in the apolipoprotein E3/E3 genotype cultures compared to the apolipoprotein E3/E4 counterparts. Thus, neuroepithelial progenitors and their differentiated progeny recognize HIV and respond to it by mounting an innate immune response with a vigor that is influenced by the host factor apolipoprotein E.