HSV

Herpes Simplex. There are two types of herpes simplex vims (HSV) that infect humans. Type I causes orofacial lesions and 30% of the U.S. population suffers from recurrent episodes. Type II is responsible for genital disease and anywhere from 3 x 3 x 10 cases per year (including recurrent infections) occur. The primary source of neonatal herpes infections, which are severe and often fatal, is the mother infected with type II. In addition, there is evidence to suggest that cervical carcinoma may be associated with HSV-II infection (78—80). 

BVdU differs from IdU and F TdU by being specifically phosphorylated in the 5 -position by herpes simplex vims type-1 (HSV-1) induced thymidine kinase. This restricts its action to cells infected by HSV-1. It is less active against genital herpes (HSV-2). HSV-l-induced thymidine kinase converts BVdU to the corresponding 5 -mono- and diphosphate, but HSV-2-induced thymidine kinase stops at the stage of the 5 -phosphate of BVdU. Apparendy, cellular kinases phosphorylate BVdU-5 -diphosphate to the corresponding 5 -triphosphate, which inhibits HSV-1 DNA polymerase to a greater extent than similar cellular DNA polymerases. 

BVdU is incorporated into DNA, but since it is phosphorylated specifically in the viraHy infected cell, incorporation is mainly confined to such cells. Evidence suggests that BVdU also inhibits the biosynthesis of HSV-1 glycoproteins, which may contribute to the inhibition of the HSV-1 vims (32). 

This selective activity is due in large part to the HSV-encoded thymidine kinase. Clinical studies... 

Topical apphcation of ara-HxMP, C2QH23N40gP, significantly inhibited the development of keratitis-induced HSV-1, HSV-2, or vaccinia vims in the eyes of rabbits. Ara-HxMP also significantly controlled the development of HSV-1 or vaccinia viral-induced encephaUtis in mice and was also active in preventing equine abortion viral deaths in hamsters. Clinical trials with ara-HxMP have not yet been reported. 

Ara-A is phosphorylated in mammalian cells to ara-AMP by adenosine kinase and deoxycytidine kinase. Further phosphorylation to the di- and triphosphates, ara-ADP and ara-ATP, also occurs. In HSV-1 infected cells, ara-A also is converted to ara-ATP. Levels of ara-ATP correlate directly with HSV rephcation. It has recently been suggested that ara-A also may exhibit an antiviral effect against adenovims by inhibiting polyadenylation of viral messenger RNA (mRNA), which may then inhibit the proper transport of the viral mRNA from the cell nucleus. 

It is likely that ara-HxMP similarly exerts its antiviral activity in the form of the triphosphate, ara-HxTP, since ara-HxTP inhibits HSV-1 DNA polymerase (49). Another possible explanation of the antiviral activity of ara-HxTP is that it is metaboHcaHy converted to ara-AMP. In fact, it has been shown at Wellcome Research Laboratories that ara-HxMP is a substrate for adenylosuccinate synthetase, and that the resulting arabinofuranosyladenylosuccinate is cleaved to ara-AMP by adenylosuccinate lyase (1). The selective action of ara-A against HSV appears to be a consequence of the preferential inhibition of ara-ATP against HSV-1 and HSV-2 polymerases. Ara-ATP also inhibits normal cellular DNA polymerases, which may be the reason for its cellular toxicity. Also, it has been observed that ara-A is incorporated uniformly throughout the HSV-1 genome, which may result in defective viral DNA (50). 

Of considerable interest is the xylofuranosyl analogue (26) [64526-29-0] C22H24N4O4, of tubercidin [69-33-0] (53). When (26) was administered intraperitoneaHy at 50 mg/kg per day, a significant reduction of the mortaUty rate of mice infected with HSV-2 was achieved (54). Compound (26) appHed topically in 1% DMSO to intracutaneous HSV-2 in hairless mice gave 100% survivors without observable toxicity. This nucleoside would appear to have considerable potential for topical treatment of HSV-2 infections. 

The cychc phosphonate of ( -HPMPA, [( -cHPMPA [106941-26-8], C H 2N50 P, 28] also is active against HSV-1 and HSV-2 infection in mice. Both (27) and (28) are reported to be efficacious against adenovims, vaccinia vims, as weU as variceUa-2oster vims infections (58). 

Acyclovir is more effective the more serious the disease and the earher it is given. It has been shown to be efficacious when used systemicaHy in the prophylaxis of HSV infections in immunosuppressed patients, ie, bone marrow transplant recipients (67). Acyclovir therapy appears to be superior to ara-A in the treatment of herpes simplex encephaUtis in humans (68). 

The antiviral mechanism of action of acyclovir has been reviewed (72). Acyclovir is converted to the monophosphate in herpes vims-infected cells (but only to a limited extent in uninfected cells) by viral-induced thymidine kinase. It is then further phosphorylated by host cell guanosine monophosphate (GMP) kinase to acyclovir diphosphate [66341 -17-1], which in turn is phosphorylated to the triphosphate by unidentified cellular en2ymes. Acyclovir triphosphate [66341 -18-2] inhibits HSV-1 viral DNA polymerase but not cellular DNA polymerase. As a result, acyclovir is 300 to 3000 times more toxic to herpes vimses in an HSV-infected cell than to the cell itself. Studies have shown that a once-daily dose of acyclovir is effective in prevention of recurrent HSV-2 genital herpes (1). HCMV, on the other hand, is relatively uninhibited by acyclovir. 

The incorporation of acyclovir triphosphate into calf thymus DNA primer template has been shown to be much more rapid and extensive with HSV-1 DNA polymerase than with vero cell DNA polymerase a. This incorporation of acyclovir ceased after 15 min since the template is chain terminated by the acyclovir incorporation, as there is no 3 -hydroxyl group on which to continue elongation. The viral DNA polymerase is also inactivated by tight binding to the terminated template. 

Acute infection with Hetpes simplex viruses (HSV) results in painful rashes on skin and mucous membranes. HSV-1 mainly causes cold sores around the mouth (hetpes labialis) or eyes (keratitis), whereas infection by HSV-2 mostly results in sores in the genital or anal area. Less frequently, HSV also causes severe infections in newborns or potentially fatal encephalitis. HSV remains latent and can be reactivated by stress, suppression of the immune system or other infections. 

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