Lentivirus Infection in the Brain Induces Matrix Metalloproteinase Expression: Role of Envelope Diversity

Abstract

Infection of the brain by lentiviruses, including human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV), causes inflammation and results in neurodegeneration. Molecular diversity within the lentivirus envelope gene has been implicated in the regulation of cell tropism and the host response to infection. Here, we examine the hypothesis that envelope sequence diversity modulates the expression of host molecules implicated in lentivirus-induced brain disease, including matrix metalloproteinases (MMP) and related transcription factors. Infection of primary macrophages by chimeric HIV clones containing brainderived envelope fragments from patients with HIV-associated dementia (HAD) or nondemented AIDS patients (HIV-ND) showed 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 macrophages infected by HAD clones. Infections of primary feline macrophages by the neurovirulent FIV strain (V 1 CSF), the less neurovirulent strain (Petaluma), and a chimera containing the V 1 CSF envelope in a Petaluma background (FIV-Ch) revealed that MMP-2 and -9 levels were significantly higher in conditioned media from V 1 CSF-and FIV-Ch-infected macrophages, which was associated with increased intracellular STAT-1 and JAK-1 levels. The STAT-1 inhibitor fludarabine significantly reduced MMP-2 expression, but not MMP-9 expression, in FIV-infected macrophages. Analysis of MMP mRNA and protein levels in brain samples from HIV-infected persons or FIV-infected cats showed that MMP-2 and -9 levels were significantly increased in lentivirus-infected brains compared to those of uninfected controls. Elevated MMP expression was 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 lentiviruses, 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/JAK-1 signaling pathway.

HIV-1 infection and AIDS: consequences for the central nervous system

“…90 Importantly, increased expression and activation of MMPs, including MMP-2 and MMP-9, were detected in HIV-infected macrophages and also in post-mortem brain specimens from AIDS patients compared with uninfected controls. 91 As elegantly shown by Power and colleagues, MMP-2 released from HIV-infected macrophages is able to proteolytically remove four amino acids from the N-terminus of SDF-1. This truncated form of SDF-1 no longer binds CXCR4 and is an even more powerful neurotoxin than full-length SDF-1.…”

HIV-1 Vpr Causes Neuronal Apoptosis andIn VivoNeurodegeneration

“…Autopsied frozen and fixed brain tissue (frontal lobe) from HIV-1 B clade seropositive (all were acquired immunodeficiency syndrome-defined) and seronegative individuals, collected with consent and stored in the Laboratory for Neurological Infection and Immunity Brain Bank were used for RNA extraction for real-time PCR and immunohistochemistry, respectively, as described previously (Johnston et al, 2000;Tsutsui et al, 2004).…”

CD8+ Lymphocyte-Mediated Injury of Dorsal Root Ganglion Neurons during Lentivirus Infection: CD154-Dependent Cell Contact Neurotoxicity

“…The FIV strain used in this study was the infectious neurovirulent recombinant molecular clone, V1-Ch, derived by transfection of CrFK cells and amplification in feline peripheral blood mononuclear cells (PBMCs), as described previously (Johnston et al, 2000). Culture supernatants from FIV-infected feline PBMC, which served as sources of infectious virus for these experiments, were cleared of cellular debris by centrifugation and titered by limiting dilution, as described previously (Power et al, 1998).…”

“…Genomic DNA derived from cultured CD4ϩ and CD8ϩ T cells and RNA from the supernatants of FIV-infected and uninfected PBLs were used to amplify the viral pol gene for both proviral DNA in PBLs and viral RNA in PBL culture supernatant (Johnston et al, 2000). A real-time PCR protocol using primers that detect the FIV pol gene was used to determine the number of copies of viral RNA/ml as reported previously (Kennedy et al, 2004).…”