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Herpes simplex virus 1 (HSV-1)-induced encephalitis is the most common cause of sporadic, fatal encephalitis in humans. HSV-1 has at least 10 different envelope glycoproteins, which can promote virus infection. The ligands for most of the envelope glycoproteins and the significance of these ligands in virus-induced encephalitis remain elusive. Here, we show that glycoprotein E (gE) binds to the cellular protein, annexin A1 (Anx-A1) to enhance infection. Anx-A1 can be detected on the surface of cells permissive for HSV-1 before infection and on virions. Suppression of Anx-A1 or its receptor, formyl peptide receptor 2 (FPR2), on the cell surface and gE or Anx-A1 on HSV-1 envelopes reduced virus binding to cells. Importantly, Anx-A1 knockout, Anx-A1 knockdown, or treatments with the FPR2 antagonist reduced the mortality and tissue viral loads of infected mice. Our results show that Anx-A1 is a novel enhancing factor of HSV-1 infection. Anx-A1-deficient mice displayed no evident physiology and behavior changes. Hence, targeting Anx-A1 and FPR2 could be a promising prophylaxis or adjuvant therapy to decrease HSV-1 lethality. Author summary: Herpes simplex virus 1 (HSV-1)-induced encephalitis is the most devastating consequence of HSV-1 infection, even in patients treated with anti-HSV-1 drugs. Moreover, encephalitis induced by drug-resistant HSV-1 has been reported in immunocompromised patients. Identifying the cellular factors in promoting HSV-1 replication, especially those increasing virus attachment and entry, could facilitate the development of alternative or adjuvant therapy. Here, we identified annexin A1 (Anx-A1) and its receptor, formyl peptide receptor 2 (FPR2), facilitating HSV-1 attachment to the cell surface. Suppression of Anx-A1 or blockage of FPR2 impaired HSV-1 attachment to cells, viral yields in cells, and HSV-1 lethality in mice. Moreover, blocking FPR2 decreased the replication of drug-resistant HSV-1 in BABL/c nude mice. Hence, targeting Anx-A1 and FPR2 could be alternative or adjuvant therapy for HSV-1 infection. [ABSTRACT FROM AUTHOR]

Bortezomib suppressing NF‐κB activity is an effective therapy for patients with myeloma or lymphoma. However, this drug can cause adverse effects, neutropenia, and recurrent infections of herpes viruses. Among herpes viruses, HSV‐1 can reactivate to induce mortality. The important issues regarding how bortezomib diminishes neutrophils, whether bortezomib can induce HSV‐1 reactivation, and how bortezomib exacerbates HSV‐1 infection, need investigation. Using the murine model, we found that bortezomib induced HSV‐1 reactivation. Bortezomib diminished neutrophil numbers in organs of uninfected and HSV‐1‐infected mice and turned a nonlethal infection to lethal with elevated tissue viral loads. In vitro results showed that bortezomib and HSV‐1 collaborated to enhance the death and apoptosis of mouse neutrophils. The leukocyte deficiency induced by chemotherapies is generally believed to be the cause for aggravating virus infections. Here we show the potential of pathogen to exacerbate chemotherapy‐induced leukocyte deficiency. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 1 (HSV-1) infection is the most common cause of sporadic, fatal encephalitis, but current understanding of how the virus interacts with cellular factors to regulate disease progression is limited. Here, we show that HSV-1 infection induced the expression of the cellular transcription factor early growth response 1 (Egr-1) in a human neuronal cell line. Egr-1 increased viral replication by activating promoters of viral productive cycle genes through binding to its corresponding sequences in the viral promoters. Mouse studies confirmed that Egr-1 expression was enhanced in HSV-1-infected brains and that Egr-1 functions to promote viral replication in embryonic fibroblasts. Furthermore, Egr-1 deficiency or knockdown of Egr-1 by a DNA-based enzyme greatly reduced the mortality of HSV-1-infected mice by decreasing viral loads in tissues. This study provides what we believe is the first evidence that Egr-1 increases the mortality of HSV-1 encephalitis by enhancing viral replication. Moreover, blocking this cellular machinery exploited by the virus could prevent host mortality. [ABSTRACT FROM AUTHOR]