Cytomegalovirus Retinitis and Response to Therapy with Ganciclovir

Henderly, Dale E.; Freeman, William R.; Causey, Dennis M.; Rao, Narsing A.

doi:10.1016/s0161-6420(87)33454-2

Cited by 191 publications

(41 citation statements)

References 26 publications

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“…Ribavirin has been used in treatment ofrespiratory syncytial virus infection (10), influenza (1 1), and Lassa fever (12), and ribavirin, like AZT and ddl, is currently under evaluation for its effectiveness in treatment ofHIV disease (13,14). Ganciclovir, which has activity against many herpes group viruses, is the first effective drug for treatment ofcytomegalovirus retinitis in patients with AIDS (15).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of immune functions by antiviral drugs.

Heagy

Crumpacker²,

Lopez³

et al. 1991

J. Clin. Invest.

132

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Immune functions were evaluated in vitro for PBMC isolated from healthy donors and cultured with the antiviral agents, 3'-azido-3'-deoxythymidine (AZT), ribavirin, ganciclovir, 2'3'-dideoxyinosine (ddl), or acyclovir. To identify methods for assessing the effects of antiviral drugs on immune cells, the PBMC response to mitogens, Con A, or phytohemagglutinin was evaluated from measurements of [Hjthymidine and 11[Cleucine incorporation, cell growth, cellular RNA, DNA, and protein levels, and the PBMC proliferative cycle (i.e., progression from GO --G1 --S -G2 + M).At clinically relevant concentrations, AZT, ribavirin, or ganciclovir diminished PBMC responsiveness to mitogen. The numbers of proliferating cells in G1, S., and G2 + M phases of the cell cycle, DNA content, and VHjthymidine uptake were decreased in cultures treated with AZT, ribavirin, or ganciclovir. AZT or ribavirin but not ganciclovir reduced RNA and protein in the cultures and inhibited cell growth. Whereas AZT, ribavirin, or ganciclovir were antiproliferative, ddI or acyclovir had little, if any, effect on PBMC mitogenesis. The inhibitory effects of antivirals on immune cells may contribute to the immune deterioration observed in patients following prolonged use of the drugs. (J. Clin.

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Section: Introductionmentioning

confidence: 99%

Inhibition of immune functions by antiviral drugs.

Heagy

Crumpacker²,

Lopez³

et al. 1991

J. Clin. Invest.

132

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show abstract

“…The drug is also mitogenic in mammalian cells and carcinogenic and embryotoxic in animals (467). In humans, ganciclovir causes a reversible bone marrow toxicity in approximately 25% of patients, a factor that frequently limits its use (62,208,422 (47,74,138,197,208,217,271). Almost all relapse, however, unless maintenance therapy is instituted, and even then many patients experience breakthrough disease or cannot tolerate the medication.…”

Section: Ganciclovirmentioning

confidence: 99%

Antiviral therapy: current concepts and practices

Bean

1992

Clin Microbiol Rev

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Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future.

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“…A limited number of drugs are available for the treatment of HCMV infection, including ganciclovir (GCV); its orally available derivative, valganciclovir; cidofovir (CDV); foscarnet (FOS); and fomivirsen (35,59). Among these drugs, GCV is the most widely used to treat most HCMV infections.…”

mentioning

confidence: 99%

RNA Interference-Mediated Targeting of Human Cytomegalovirus Immediate-Early or Early Gene Products Inhibits Viral Replication with Differential Effects on Cellular Functions

Xiaofei

Stadler

Debatis

et al. 2012

J Virol

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Viral drug toxicity, resistance, and an increasing immunosuppressed population warrant continued research into new avenues for limiting diseases associated with human cytomegalovirus (HCMV). In this study, a small interfering RNA (siRNA), siX3, was designed to target coding sequences within shared exon 3 of UL123 and UL122 transcripts encoding IE1 and IE2 immediate-early proteins of HCMV. Pretreatment of cells with siX3 reduced the levels of viral protein expression, DNA replication, and progeny virus production compared to control siRNA. Two siRNAs against UL54 and overlapping transcripts ( UL55-57 ) were compared to siX3 in HCMV infection and were also found to be effective at inhibiting HCMV replication. Further investigation into the effects of the siRNAs on viral replication showed that pretreatment with each of the siRNAs resulted in an inhibition in the formation of mature replication compartments. The ability of these siRNAs to prevent or reduce certain cytopathic effects associated with HCMV infection was also examined. Infected cells pretreated with siX3, but not siUL54, retained promyelocytic leukemia (PML) protein in cellular PML bodies, an essential component of this host intrinsic antiviral defense. DNA damage response proteins, which are localized in nuclear viral replication compartments, were reduced in the siX3- and siUL54-treated cells. siX3, but not siUL54, prevented DNA damage response signaling early after infection. Therapeutic efficacy was demonstrated by treating cells with siRNAs after HCMV replication had commenced. Together, these findings suggest that siRNAs targeting exon 3 of the major IE genes or the UL54-57 transcripts be further studied for their potential development into anti-HCMV therapeutics.

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Cytomegalovirus Retinitis and Response to Therapy with Ganciclovir

Cited by 191 publications

References 26 publications

Inhibition of immune functions by antiviral drugs.

Inhibition of immune functions by antiviral drugs.

Antiviral therapy: current concepts and practices

RNA Interference-Mediated Targeting of Human Cytomegalovirus Immediate-Early or Early Gene Products Inhibits Viral Replication with Differential Effects on Cellular Functions

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