Herpesvirus

Herpetoviridae Herpesvirus herpes types 1 and 2 ophthalmic, central nervous system, genital cutaneous, oral, upper respiratory... 

Cytomegalovirus (CMV) is a herpesvirus, which causes an inapparent infection in immunocompetent persons. Worldwide, approximately 40% of people are infected with CMV. In immunocompromised patients, transplant recipients and neonates, CMV can cause serious and potentially lethal disease manifestations like pneumonia, retinitis and blindness, hepatitis, infections of the digestive tract, deafness or mental retardation. 

Varizella zoster vitus (VZV) is a highly contagious herpesvirus causing chickenpox upon primary infection. After recovery, the vims stays dormant in nerve roots. Weakening of the immune system, e.g. in people over the age of 60 or under immunosuppressive therapy, can lead to reactivation of VZV. This recurrence causes shingles (herpes zoster), a painful rash that develops in a well-defined band corresponding to the area enervated by the affected nerve cells. 

However, acyclic nucleotide analogs (acyclic nucleoside phosphonates) have been developed, which carry one phosphonate moiety and require only the two subsequent phosphorylation steps (De Clercq et al. 1978). Independent of virus-encoded kinases, they display a broader spectrum of efficacy. This class comprises important drugs against HIV (tenofovir) and HBV (adefovir, tenofovir), as well as cidofovir, which is approved for use against CMV retinitis, but also displays an exceptionally broad efficacy profile against many herpesviruses, adenovirus, poxviruses, and papillomaviruses (De Clercq and Holy 2005). 

Fig. 1 Stractural formulae of acyclic nucleoside analogues (anti-herpesvirus agents)...

Carbocyclic gnanosine analogues have been described to inhibit HSV-1, HSV-2, VZV, CMV, and/or other herpesviruses [viz. HHV-6 (human herpesvirus type 6)],... 

Cidofovir (Fig. 2) has been formally approved for the treatment of CMV retinitis in AIDS patients, where it is administered intravenously at a dose not exceeding 5 mg/kg once weekly during the first two weeks (and every other week thereafter). Cidofovir is also used off label for the treatment of human papilloma virus (HPV) infections (i.e., cutaneous warts, anogenital warts, laryngeal and pharyngeal papilloma), polyomavirus [i.e., progressive (i.e., multifocal leukoencephalopathy (PML)], adenovirus, herpesvirus, and poxvirus (i.e., molluscum contagiosum) infections, where it can be administered intravenously (at a dose of < 5 mg/kg once weekly or every other week) or topically as a 1% gel or cream (De Clercq and Holy 2005). Especially in immunosuppressed patients (i.e., transplant recipients), local treatment of HPV-associated lesions has often yielded spectacular results (Bonatti etal.2007). 

Shimba N, Nomura AM, Mamett AB, Craik CS (2004) Herpesvirus protease inhibition by dimer disruption. J Virol 78 6657-6665... 

F%. 2 Herpesvirus DNA-rephcation fork showing the site of action of helicase/primase inhibitors... 

Since the pioneering work of Kleymann et al. (2002), Betz et al. (2002), Baumeister et al. (2007), and Crute et al. (2002), who showed that compounds identified as inhibitors of the helicase-primase enzyme complex could alleviate herpesvirus-induced disease in animal models, the attention of researchers developing antiviral compounds has been drawn more and more towards the virus-encoded helicases, particularly those of Herpes viruses and of RNA viruses such as Hepatitis C Virus (HCV) and SAKS coronavirus (SARS-CoV). Enzyme activity is usually assayed by measuring NTPase activity in the presence of an appropriate nucleic acid co-substrate although, more recently, novel fiuorimetric and luminescence principles have been applied to the measurement of strand unwinding and/or translocation of the protein along the nucleic acid (Frick 2003, 2006). 

A recent review stated There are no HCV helicase inhibitors currently in development. Most experts believe that it will be difQcult, if not impossible, to develop helicase inhibitors (Hepatitis C Support project 2006). Whether or not this is a valid statement remains to be seen, but the potential success of compounds with a similar target in the herpesviruses suggests that the possibility of developing inhibitors of HCV helicase should not be dismissed quite so lightly. 

Apart from offering a new and highly specific approach to the inhibition of herpesviruses, this new mechanism of action could potentially also have beneficial immunological consequences. During treatment with BAY 38-4766, viral protein synthesis continues, but due to the lack of monomeric genomic length DNA, only empty particles (dense bodies) can be formed. It is conceivable that these non-infections viral particles could aid the establishment of an antiviral immune response, leading to better control of the virus by the host. This mechanism appears... 

Terminase inhibition is an antiviral approach that may also be of consequence for other members of the herpesvirus group. In addition, since a similar DNA maturation process does not occur in higher cells, this principle offers the potential for high selectivity, in contrast to many of the viral DNA polymerase inhibitors, which also interact with cellular enzymes and hence can have severe side effects. 

Furlini G, Vignoli M, Ramazzotti E, Re MC, Visani G, La P (1996) A concurrent human herpesvirus-6 infection renders two human hematopoietic progenitor (TF-1 and KG-1) ceU lines susceptible to human immunodeficiency virus type-1. Blood 87(ll) 4737-4745... 

Rucker J, Edinger AL, Sharron M et al (1997) Utilization of chemokine receptors, orphan receptors, and herpesvirus-encoded receptors by diverse human and simian immunodefidency viruses. J Virol 71 8999-9007... 

Over 20 infectious agents have been incriminated as etiologic agents for many the causal relationship has been disproved, and for others there is conflicting evidence. Human herpesvirus 6 (HHV-6) is currently the most likely causative virus. HHV-6 may initiate the autoimmune processes of MS in one of two ways. First, HHV-6 is structurally similar to myelin basic protein. When T cells become sensitive to HHV-6, the cells may attack myelin basic protein. Second, HHV-6 may directly stimulate the complement cascade, activating autoimmune processes.5 Infection with HHV-6 alone cannot fully explain MS, because HHV-6 is found in 75% of all people, but MS is much more rare. 

Gram-negative bacteria Gram-positive bacteria Herpesvirus Histoplasma... 

Kledal TN, Rosenkilde MM, Coulin F, et al. A broad-spectrum chemokine antagonist encoded by Kaposi s sarcoma-associated herpesvirus. Science 1997 277 1656-9. 

Burger M, Burger JA, Hoch RC, Oades Z, Takamori H, Schraufstatter IU. Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi s sarcoma herpesvirus-G protein-coupled receptor. 1 Immunol 1999 163(4) 2017-2022. 

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