Divya Kapoor

Human herpesviruses (HHVs) are notorious, ubiquitous intracellular pathogens that establish lifelong infections in the host. They tightly manipulate host signaling pathways that play central roles in key cellular processes such as cell survival, metabolism, immune responses, and oncogenic transformation. Among the many pathways explored, the phosphatidylinositol-3-kinase (PI3K)/Akt signaling axis has emerged as a central and conserved target exploited by all eight HHVs. Herpesviruses can induce PI3K/Akt signaling at multiple stages of their life cycle, beginning at viral entry and extending through lytic replication, latency maintenance, immune evasion, and virus-associated tumorigenesis. Mechanistically, herpesviruses engage both host cell receptors and viral effector proteins to activate PI3K, drive Akt phosphorylation, and thereby orchestrate downstream signaling pathways that favor viral replication, survival, and immune evasion. Transient activation of this pathway supports viral replication, whereas sustained signaling promotes latent infection and oncogenesis, particularly in Epstein–Barr virus and Kaposi’s sarcoma-associated herpesvirus. This review provides a comparative analysis of PI3K/Akt pathway manipulation across all HHVs, highlighting shared strategies and virus-specific adaptations. We further discuss ongoing clinical trials and therapeutic opportunities targeting the PI3K/Akt axis, emphasizing its potential as a host-directed antiviral and anticancer strategy.

Neutrophil extracellular traps (NETs) are net-like structures released from neutrophils. NETs predominantly contain cell-free deoxyribonucleic acid (DNA) decorated with histones and neutrophil granule proteins. Numerous extrinsic and intrinsic stimuli can induce the formation of NETs such as pathogens, cytokines, immune complexes, microcrystals, antibodies, and other physiological stimuli. The mechanism of NETosis induction can either be ROS-dependent or independent based on the catalase producing activity of the pathogen. NADPH is the source of ROS production, which in turn depends on the upregulation of Ca2+ production in the cytoplasm. ROS-independent induction of NETosis is regulated through toll-like receptors (TLRs). Besides capturing and eliminating pathogens, NETs also aggravate the inflammatory response and thus act as a double-edged sword. Currently, there are growing reports of NETosis induction during bacterial and fungal ocular infections leading to different pathologies, but there is no direct report suggesting its role during herpes simplex virus (HSV) infection. There are innumerable independent reports showing that the major effectors of NETosis are also directly affected by HSV infection, and thus, there is a strong possibility that HSV interacts with these facilitators that can either result in virally mediated modulation of NETosis or NETosis-mediated suppression of ocular HSV infection. This review focuses on the mechanism of NETs formation during different ocular pathologies, with its prime focus on highlighting their potential implications during HSV ocular infections and acting as prospective targets for the treatment of ocular diseases.

Herpes Simplex Virus 1 (HSV-1) is a neurotropic human virus that belongs to the Alphaherpesvirinae subfamily of Herpesviridae. Establishment of its productive infection and progression of disease pathologies depend largely on successful release of virions from the virus-producing cells. HSV-1 is known to exploit many host factors for its release. Recent studies have shown that heparanase (HPSE) is one such host enzyme that is recruited for this purpose. It is an endoglycosidase that cleaves heparan sulfate (HS) from the surface of infected cells. HS is a virus attachment coreceptor that is commonly found on cell surfaces as HS proteoglycans e.g., syndecan-1 (SDC-1). The current model suggests that HSV-1 during the late stage of infection upregulates HPSE, which in turn enhances viral release by removing the virus-trapping HS moieties. In addition to its role in directly enabling viral release, HPSE accelerates the shedding of HS-containing ectodomains of SDC-1, which enhances HSV-1 release via a similar mechanism by upregulating CREB3 and COPII proteins. This review outlines the role of HPSE and SDC-1 as newly assigned host factors that facilitate HSV-1 release during a lytic infection cycle.

Herpes simplex virus type-1 (HSV-1) exploits several host factors to enhance its replication and release from infected cells. It induces the production of host enzyme heparanase (HPSE) to aid in egress. While the mechanism by which HPSE assists in viral release is well-characterized, other host factors that are recruited along with HPSE for viral release are less well understood. In this study, we identify cyclic-AMP-responsive element-binding protein3 (CREB3) as a key player in HPSE-facilitated HSV-1 egress. When CREB3 is transiently upregulated in human corneal epithelial cells, HSV-1 release from the infected cells is correspondingly enhanced. This activity is linked to HPSE expression such that HPSE-transfected corneal epithelial (HCE) cells more highly express CREB3 than wild-type cells while the cells knocked out for HPSE show very little CREB3 expression. CREB3-transfected HCE cells showed significantly higher export of HPSE upon infection than wild-type cells. Our data suggests that coat protein complex II (COPII), which mediates HPSE trafficking, is also upregulated via a CREB3-dependent pathway during HSV-1 infection. Finally, the co-transfection of CREB3 and HPSE in HCE cells shows the highest viral release compared to either treatment alone, establishing CREB3 as a key player in HPSE-facilitated HSV-1 egress.

Very little knowledge exists on virus-specific host cell intrinsic mechanisms that prevent hyperproliferation of primary HSV type 2 (HSV-2) genital infections. In this study, we provide evidence that the Nemo-related protein, optineurin (OPTN), plays a key role in restricting HSV-2 infection both in vitro and in vivo. Contrary to previous reports regarding the proviral role of OPTN during Sendai virus infection, we demonstrate that lack of OPTN in cells causes enhanced virus production. OPTN deficiency negatively affects the host autophagy response and results in a marked reduction of CCL5 induction. OPTN knockout (OPTN−/−) mice display exacerbated genital disease and dysregulated T cell frequencies in infected tissues and lymph nodes. A human transcriptomic profile dataset provides further credence that a strong positive correlation exists between CCL5 upregulation and OPTN expression during HSV-2 genital infection. Our findings underscore a previously unknown OPTN/CCL5 nexus that restricts hyperproliferative spread of primary HSV-2 infection, which may constitute an intrinsic host defense mechanism against herpesviruses in general.

High-protein intake is common in Western societies and generally considered healthy. However, results from some epidemiological studies suggest elevated protein intake is associated with increased risk for ischemic cardiovascular diseases. In addition, results from studies conducted in mice show that a high protein, compared with a standard Western diet, increases atherosclerosis burden and lesion complexity. The adverse effect of protein ingestion on plaque biology in mice is mediated by amino acid-mammalian target of rapamycin (mTOR)-dependent inhibition of autophagy in macrophages. Here, we evaluate the effect of graded amounts of protein ingestion on this amino acid-mTORC1-autophagy mechanism in human monocytes/macrophages and identify leucine as the key amino acid responsible for activating mTORC1 in macrophages. We describe the presence of a threshold effect of high protein intake on this deleterious signaling pathway wherein protein content greater than about 22% of total energy, which is consumed by nearly 1/4^th of the population in Western societies, acutely activates mTORC1 signaling in monocytes/macrophages. Furthermore, we identify leucine as the critical amino acid modulator and threshold indicator, capable of the dose-dependent mTORC1 activation and downstream functional effects. Finally, by designing specific mouse diets with protein contents mimicking graded levels of protein ingestion in our study participants, we demonstrate the presence of a dietary protein threshold effect in driving atherosclerosis in mouse models. These data demonstrate the potential deleterious impact of excessive protein intake on macrophages and atherosclerotic plaque progression.

Heparan sulfate (HS) and heparan sulfate proteoglycans (HSPGs) are considered important for the entry of many different viruses. Previously, we demonstrated that heparanase (HPSE), the host enzyme responsible for cleaving HS chains, is upregulated by herpes simplex virus-1 (HSV-1) infection. Higher levels of HPSE accelerate HS removal from the cell surface, facilitating viral release from infected cells. Here, we study the effects of overexpressing HPSE on viral entry, cell-to-cell fusion, plaque formation, and viral egress. We provide new information that higher levels of HPSE reduce syncytial plaque formation while promoting egress and extracellular release of the virions. We also found that transiently enhanced expression of HPSE did not affect HSV-1 entry into host cells or HSV-1-induced cell-to-cell fusion, suggesting that HPSE activation is tightly regulated and facilitates extracellular release of the maturing virions. We demonstrate that an HSPG-shedding agonist, PMA; a protease, thrombin; and a growth factor, EGF as well as bacterially produced recombinant heparinases resulted in enhanced HSV-1 release from HeLa and human corneal epithelial (HCE) cells. Our findings here underscore the significance of syndecan-1 functions in the HSV-1 lifecycle, provide evidence that the shedding of syndecan-1 ectodomain is another way HPSE works to facilitate HSV-1 release, and add new evidence on the significance of various HSPG shedding agonists in HSV-1 release from infected cells.