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The host enzyme heparanase (HPSE) facilitates the release of herpes simplex virus type 2 (HSV-2) from target cells by cleaving the viral attachment receptor heparan sulfate (HS) from infected cell surfaces. HPSE 2, an isoform of HPSE, binds to but does not possess the enzymatic activity needed to cleave cell surface HS. Our study demonstrates that HSV-2 infection significantly elevates HPSE 2 protein levels, impacting two distinct stages of viral replication. We show that higher HPSE 2 negatively affects HSV-2 replication which may be through the regulation of cell surface HS. By acting as a competitive inhibitor of HPSE, HPSE 2 may be interfering with HPSE's interactions with HS. We demonstrate that the enhanced expression of HPSE 2, either via viral infection or plasmid transfection, reduces HPSE's ability to cleave HS, thereby hindering viral egress. Conversely, low HPSE 2 levels achieved through siRNA transfection allow HPSE to cleave more HS, reducing viral entry. Altogether, we propose a hypothetical model in which the modulation of HPSE 2 impedes HSV-2 replication by regulating HS availability on the cell surface. This dual role of HPSE 2 in viral replication and potential tumor suppression underscores its significance in cellular processes and viral pathogenesis. [ABSTRACT FROM AUTHOR]