Cytomegalovirus infection resistance

Acyclovir is useful for treating infections caused by HSV, herpes zoster, and for VZV infections (Whitley and Roizman, 2001). Although HCMV is relatively resistant to acyclovir, some cytomegalovirus infections have responded marginally to large doses of acyclovir, and it seems to be effective for the prophylaxis of cytomegalovirus infections in immunocompromised patients. Epstein-Barr virus is not sensitive to acyclovir, and clinical infections do not respond to the drug. 

Anwar F, Erice A, Jessurun J. Are there cytopathic features associated with cytomegalovirus infection predictive of resistance to antiviral therapy Ann Diag Pathol. 1999 3 19-22. 

Warren AP, Ducroq DH, Lehner PJ, Borysiewicz LK (1994) Human cytomegalovirus-infected cells have unstable assembly of major histocompatibility complex class I complexes and are resistant to lysis by cytotoxic T lymphocytes. J Virol 68 2822 2829... 

Jabs DA (1995) Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 93 623-683 Jabs DA, Enger C, Dunn JP, Forman M (1998a) Cytomegalovirus retinitis and viral resistance ganciclovir resistance. J Infect Dis 177 770-773... 

Foscamet is used for the treatment of cytomegalovirus (CMV) retinitis and mucocutaneous acyclovir-resistant herpes simplex virus (HSV) infections. It may also be beneficial in other types of CMV or HSV infections (Wagstaff and Bryson, 1994). 

Impaired cell-mediated immunity leaves the host prey to many (opportunistic) infections including candidiasis, coccidioidomycosis, cryptosporidiosis, cytomegalovirus disease, herpes simplex, histoplasmosis, Pneumocystis carinii pneumonia, toxoplasmosis and tuberculosis (with multiply-resistant organisms). Treatment of these conditions is referred to elsewhere in this text for a comprehensive review of the antinticrobial prophylaxis of opportunistic infections in patients with HIV infection, readers are referred to Kovacs Masur 2000 New England Journal of Medicine 342 1416. 

Jacobson MA, Drew WL, Feinberg J, O Donnell JJ, Whitmore PV, Miner RD, Parenti D. Foscamet therapy for ganciclovir-resistant cytomegalovirus retinitis in patients with AIDS. J Infect Dis I99I I63(6) I348-5I. 

Snoeck, R., Andrei, G., and De Clercq, E. (1996) Patterns of resistance and sensitivity to antiviral compounds of drug-resistant strains of human cytomegalovirus selected in vitro. Ear. J. Clin. Microbiol. Infect. Dis. 15, 574-579. 

In a pilot study of HIV-infected adults, hypericin was administered at doses of 0.25 mg/kg or 0.5 mg/kg intravenously twice weekly, 0.25 mg/kg intravenously thrice weekly, or 0.5 mg/kg/d orally for up to 24 wk. No regimen displayed antiretroviral activity based on CD4 lymphocyte counts, p24 antigen, or HIV RNA titers (Gulick et al., 1999). In vitro studies suggest that St. John s wort may have activity against cytomegalovirus(CMV), herpes simplex, influenza A (USP, 1998a), and methicillin resistant Staphylococcus aureus (Schempp et al., 1999). 

Jabs DA, Martin BK, Forman MS, et al. Mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Infect Dis 2001 183 333-337. 

Trifluridine, C10H11F3N2O5, (5-trifluoromethyl-2,-deoxyuridine [70-00-8], F3TdU, 14) was first prepared (30) in 1962. It is used for topical therapy of herpes virus-infected eyes. It is especially useful for treating infections that are resistant to IdU therapy. Like IdU, trifluridine is incorporated into DNA in place of thymidine in both infected and uninfected cells. But it is 10 times more potent than IdU against herpes keratitis in rabbits and 10 times more soluble in water. Trifluridine is also useful in treating human cytomegalovirus (HCMV), but its toxicity to bone marrow may limit its clinical use. 

Foscamet is an antiviral agent that inhibits replication of all known herpes viruses, including cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpes virus 6 (HHV-6), Epstein-Barr virus (EBV) and varicella-zoster virus (VZV). It is indicated in the treatment of CMV retinitis in patients with AIDS treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients and as combination therapy with ganciclovir for patients who have relapsed after monotherapy with either drug. 

Clinical uses and toxicity The drug is used for prophylaxis and treatment of cytomegalovirus (CMV) infections (including CMV retinitis) and has activity against ganciclovir-resistant strains of this virus (Table 49-1). Foscarnet inhibits herpes DNA polymerase in acyclovir-resistant strains that are thymidine kinase-deficient and may suppress such resistant herpetic infections in patients with AIDS. Adverse effects include nephrotoxicity (30% incidence) with disturbances in electrolyte balance (especially hypocalcemia), genitourinary ulceration, and CNS effects (headache, hallucinations, seizures). 

Besides the role of retinoids in host immune defenses to viral infections (see [6] for review), retinoids may also affect virus replication. Angulo et al. [44] characterized three RA response elements in the promoter region of human cytomegalovirus (hCMV) and demonstrated the necessity for RAR and RXR in the viral promoter s positive response to RA. In contrast, the replication of herpes simplex virus-1 (HSV-1) in cultured Vero cells was inhibited by isomers of RA, but not retinol inhibition occurred without evident induction of IFN-a or IFN-p gene expression [45]. RA also protected HL-60 and WISH cells from infection with vesicular stomatitis virus (VSV) [46] however, in this case RA significantly increased the ability of IFN-a to decrease virus replication. These apparently contrasting effects of RA on hCMV as compared to HSV-1 or VSV replication further illustrate the potential for retinoids to act either positively or negatively in host resistance to viral infection and anti-viral immunity. Retinoid-IFN interactions are further discussed later in this chapter. 

To date the antiviral activity of interferon has been demonstrated only in tissue culture or in animal systems and not in man. In one study (16) interferon Induced by measles vaccine was found not to affect the shedding of cytomegalovirus of chronically infected children. However, this was not unexpected since this virus is highly resistant to the effect of interferon in tissue culture. 

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