Lentivirus infection in the brain induces matrix metalloproteinase expression: Role of envelope diversity

Infection of the brain by lentiviruses, including human immunodeficiency vi rus (HIV) and feline immunodeficiency virus (FIV), causes inflammation and results in neurodegeneration. Molecular diversity within the lentivirus env elope gene has been implicated in the regulation of cell tropism and the ho st response to infection. Here, we examine the hypothesis that envelope seq uence diversity modulates the expression of host molecules implicated in le ntivirus-induced brain disease, including matrix metalloproteinases (MMP) a nd related transcription factors. Infection of primary macrophages by chime ric HIV clones containing brain-derived envelope fragments from patients wi th HIV-associated dementia (HAD) or nondemented AIDS patients (HIV-ND) show ed that MMP-2 and -9 levels in conditioned media were significantly higher for the HAD clones. Similarly, STAT-1 and JAK-1 levels were higher in macro phages infected by HAD clones. Infections of primary feline macrophages by the neurovirulent FIV strain (V1CSF), the less neurovirulent strain (Petalu ma), and a chimera containing the V1CSF envelope in a Petaluma background ( FIV-Ch) revealed that MMP-2 and -9 levels were significantly higher in cond itioned media from V1CSF- and FIV-Ch-infected macrophages, which was associ ated with increased intracellular STAT-1 and JAK-1 levels. The STAT-1 inhib itor fludarabine significantly reduced MMP-2 expression, but not MMP-9 expr ession, in FIV-infected macrophages. Analysis of MMP mRNA and protein level s in brain samples from HIV-infected persons or FIV-infected cats showed th at MMP-2 and -9 levels were significantly increased in lentivirus-infected brains compared to those of uninfected controls. Elevated MMP expression wa s accompanied by significant increases in STAT-1 and JAK-1 mRNA and protein levels in the same brain samples. The present findings indicate that two l entiviruses, HIV and FIV, have common mechanisms of MMP-2 and -9 induction, which is modulated in part by envelope sequence diversity and the STAT-1/J AK-1 signaling pathway.