Nanotechnology is increasingly playing important roles in various fields including virology. The emerging use of metal or metal oxide nanoparticles in virus targeting formulations shows the promise of improved diagnostic or therapeutic ability of the agents while uniquely enhancing the prospects of targeted drug delivery. Although a number of nanoparticles varying in composition, size, shape, and surface properties have been approved for human use, the candidates being tested or approved for clinical diagnosis and treatment of viral infections are relatively less in number. Challenges remain in this domain due to a lack of essential knowledge regarding the in vivo comportment of nanoparticles during viral infections. This review provides a broad overview of recent advances in diagnostic, prophylactic and therapeutic applications of metal and metal oxide nanoparticles in Human Immunodeficiency Virus, Hepatitis virus, influenza virus and Herpes virus infections. Types of nanoparticles commonly used and their broad applications have been explained in this review.

Herpes simplex virus type 1 (HSV-1) causes recurrent mucocutaneous lesions in the eye that may advance to corneal blindness. Nucleoside analogs exemplified by acyclovir (ACV) form the primary class of antiherpetic drugs, but this class suffers limitations due to the emergence of viral resistance and other side effects. While studying the molecular basis of ocular HSV-1 infection, we observed that BX795, a commonly used inhibitor of TANK-binding kinase 1 (TBK1), strongly suppressed infection by multiple strains of HSV-1 in transformed and primary human cells, cultured human and animal corneas, and a murine model of ocular infection. Our investigations revealed that the antiviral activity of BX795 relies on targeting Akt phosphorylation in infected cells, leading to the blockage of viral protein synthesis. This small-molecule inhibitor, which was also effective against an ACV-resistant HSV-1 strain, shows promise as an alternative to existing drugs and as an effective topical therapy for ocular herpes infection. Collectively, our results obtained using multiple infection models and virus strains establish BX795 as a promising lead compound for broad-spectrum antiviral applications in humans.

Herpes simplex virus type-1 (HSV-1) is a neurotropic, double-stranded DNA virus that can cause a wide variety of diseases, including many ocular pathologies. It is one of the leading causes of infectious blindness in the United States. Because of its ubiquitous nature and its potential to cause serious ocular maladies, there is a significant need for more effective antiviral therapies against ocular HSV-1. In this review, we discuss the lifecycle of HSV-1 as it pertains to corneal infections and the clinically approved as well as emerging treatments to combat HSV-1 infections. We also highlight some newly identified host targets for the antiviral drug development.

Cytomegalovirus retinitis (CMVR) is a severe, vision-threatening disease that primarily affects immunosuppressed patients. CMVR is the most common ocular opportunistic infection in human immunodeficiency virus (HIV) infected patients and is the leading cause of blindness in this group; however, the incidence of CMVR in HIV patients has dramatically decreased with antiretroviral therapy. Other causes of immunosuppression, including organ transplantation, hematologic malignancies, and iatrogenic immunosuppression, can also lead to the development of CMVR. Herein, we describe the pathogenesis of CMVR and compare clinical features, epidemiology, and risk factors in HIV and non-HIV infected individuals with CMVR.

Herpes simplex virus (HSV) can infect a broad host range and cause mild to life threating infections in humans. The surface glycoproteins of HSV are evolutionarily conserved and show an extraordinary ability to bind more than one receptor on the host cell surface. Following attachment, the virus fuses its lipid envelope with the host cell membrane and releases its nucleocapsid along with tegument proteins into the cytosol. With the help of tegument proteins and host cell factors, the nucleocapsid is then docked into the nuclear pore. The viral double stranded DNA is then released into the host cell’s nucleus. Released viral DNA either replicates rapidly (more commonly in non-neuronal cells) or stays latent inside the nucleus (in sensory neurons). The fusion of the viral envelope with host cell membrane is a key step. Blocking this step can prevent entry of HSV into the host cell and the subsequent interactions that ultimately lead to production of viral progeny and cell death or latency. In this review, we have discussed viral entry mechanisms including the pH-independent as well as pH-dependent endocytic entry, cell to cell spread of HSV and use of viral glycoproteins as an antiviral target.

Humans express seven heparan sulfate (HS) 3-O-sulfotransferases that differ in substrate specificity and tissue expression. Although genetic studies have indicated that 3-O-sulfated HS modulates many biological processes, ligand requirements for proteins engaging with HS modified by 3-O-sulfate (3-OS) have been difficult to determine. In particular, the context in which the 3-OS group needs to be presented for binding is largely unknown. We describe herein a modular synthetic approach that can provide structurally diverse HS oligosaccharides with and without 3-OS. The methodology was employed to prepare 27 hexasaccharides that were printed as a glycan microarray to examine ligand requirements of a wide range of HS-binding proteins. The binding selectivity of antithrombin-III (AT-III) compared well with anti-Factor Xa activity supporting robustness of the array technology. Many of the other examined HS-binding proteins required an IdoA2S-GlcNS3S6S sequon for binding but exhibited variable dependence for the 2-OS and 6-OS moieties, and a GlcA or IdoA2S residue neighboring the central GlcNS3S. The HS oligosaccharides were also examined as inhibitors of cell entry by herpes simplex virus type 1, which, surprisingly, showed a lack of dependence of 3-OS, indicating that, instead of glycoprotein D (gD), they competitively bind to gB and gC. The compounds were also used to examine substrate specificities of heparin lyases, which are enzymes used for depolymerization of HS/heparin for sequence determination and production of therapeutic heparins. It was found that cleavage by lyase II is influenced by 3-OS, while digestion by lyase I is only affected by 2-OS. Lyase III exhibited sensitivity to both 3-OS and 2-OS.

Heparan sulfate (HS) is ubiquitously expressed on mammalian cells. It is a polysaccharide that binds growth factors, cytokines, and chemokines, and thereby controls several important physiological functions. Ironically, many human pathogens including viruses interact with it for adherence to host cells. HS functions can be regulated by selective modifications and/or selective cleavage of the sugar chains from the cell surface. In mammals, heparanase (HPSE) is the only known enzyme capable of regulating HS functions via a selective endoglycosidase activity that cleaves polymeric HS chains at internal sites. During homeostasis, HPSE expression and its endoglycosidase activity are tightly regulated; however, under stress conditions, including infection, its expression may be upregulated, which could contribute directly to the onset of several disease pathologies. Here we focus on viral infections exemplified by herpes simplex virus, dengue virus, human papillomavirus, respiratory syncytial virus, adenovirus, hepatitis C virus, and porcine respiratory and reproductive syncytial virus to summarize recent advances in understanding the highly significant, but emerging roles, of the enzyme HPSE in viral infection, spread and pathogenesis.

Herpes simplex virus type 1 (HSV-1) is an important factor for vision loss in developed countries. A challenging aspect of the ocular infection by HSV-1 is that common treatments, such as acyclovir, fail to provide effective topical remedies. Furthermore, it is not very clear whether the viral glycoproteins, required for HSV-1 entry into the host, can be targeted for an effective therapy against ocular herpes in vivo. Here, we demonstrate that HSV-1 envelope glycoprotein gD, which is essential for viral entry and spread, can be specifically targeted by topical applications of a small DNA aptamer to effectively control ocular infection by the virus. Our 45-nt-long DNA aptamer showed high affinity for HSV-1 gD (binding affinity constant [Kd] = 50 nM), which is strong enough to disrupt the binding of gD to its cognate host receptors. Our studies showed significant restriction of viral entry and replication in both in vitro and ex vivo studies. In vivo experiments in mice also resulted in loss of ocular infection under prophylactic treatment and statistically significant lower infection under therapeutic modality compared to random DNA controls. Thus, our studies validate the possibility that targeting HSV-1 entry glycoproteins, such as gD, can locally reduce the spread of infection and define a novel DNA aptamer-based approach to control HSV-1 infection of the eye.