Human immunodeficiency virus type 1 (HIV-1) and related primate lentiviruses are known to enter the central nervous system (CNS) during the primary phase of infection. Neuroinvasion by simian immunodeficiency virus and simian human immunodeficiency virus (SHIV) is characterized by transient meningitis and astrocytosis. In this report, we used targeted cytokine cDNA arrays to analyze cortical brain tissue from four pig-tailed macaques inoculated for 2 weeks with pathogenic SHIV(50OLNV) and a normal age-matched pig-tailed macaque. Our results revealed that eight genes were significantly upregulated in all four macaques. These included: leukocyte interferon inducible peptide, corticotrophin releasing factor receptor 1, interleukin 6, CDW40 antigen, cysteine-rich fibroblast growth factor, neurotrophin 3, ciliary neurotrophin factor receptor and cripto-1. The upregulation of three of these genes was confirmed by reverse transcriptase PCR (RT-PCR). Since cripto-1 had not been previously identified within specific cell types within the primate central nervous system, we performed immunohistochemical studies, which revealed the presence of cripto-1 in neurons. RT-PCR studies demonstrated that cripto-1 mRNA was widely expressed in the CNS. These results indicate that immunomodulatory genes are upregulated during the primary phase of infection of the central nervous system. Cripto-1, which acts as a survival factor in tumor cells and may be neuroprotective, is expressed in neurons within the CNS and is upregulated during viral invasion.