Lentivirus infection in the brain induces matrix metalloproteinase expression: role of envelope diversity.
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 brain-derived 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.
Johnston
J B
JB
Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada.
Jiang
Y
Y
van Marle
G
G
Mayne
M B
MB
Ni
W
W
Holden
J
J
McArthur
J C
JC
Power
C
C
D015526:AIDS Dementia Complex / Q000201:enzymology / Q000821:virology; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000821:virology*; D002415:Cats; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D015752:Genes, env / Q000235:genetics*; D014644:Genetic Variation; D006678:HIV / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015658:HIV Infections / Q000201:enzymology / Q000821:virology; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016086:Lentivirus / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016180:Lentivirus Infections / Q000201:enzymology* / Q000821:virology; D008264:Macrophages / Q000201:enzymology / Q000821:virology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism; D014779:Virus Replication
D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014759:Viral Envelope Proteins; D011505:Protein-Tyrosine Kinases; D020782:Matrix Metalloproteinases