Acyclovir-Resistant Herpes Simplex Virus Infections in Patients with the Acquired Immunodeficiency Syndrome

Erlich, Kim S.; Mills, John; Chatis, Pamela A.; Mertz, Grégory; Busch, David F.; Follansbee, Stephen; Grant, Robert M.; Crumpacker, Clyde S.

doi:10.1056/nejm198902023200506

Cited by 441 publications

(166 citation statements)

References 26 publications

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“…In the case of aciclovir resistance, the preferred treatment is foscarnet [116,117], a pyrophosphate analog and selective inhibitor of viral DNA polymerase that does not require phosphorylation for its antiviral activity [118][119][120]. After binding to viral DNA polymerase, foscarnet prevents the cleavage of the pyrophosphate moiety from deoxynucleotide triphosphates, thereby abridging chain elongation.…”

Section: Antiviral Medicationmentioning

confidence: 99%

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

2016

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Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be lifesaving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.

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Section: Antiviral Medicationmentioning

confidence: 99%

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

2016

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“…Expression of the TK gene from ACV-susceptible clinical isolates resulted in Leishmania susceptibility to GCV, whereas expression of a TK gene with frameshift mutations or nucleotide substitutions from ACV-resistant isolates gave rise to parasites with high levels of GCV resistance. The expression of the HSV TK gene in Leishmania provides an easy, reliable, and sensitive assay for evaluating HSV susceptibility to nucleoside analogues and for assessing the role of specific viral TK mutations.Acyclovir (ACV)-resistant herpes simplex viruses (HSV) infections are relatively frequent and can be associated with significant morbidity among immunocompromised patients (14,15,17,37,38). Resistance to ACV can be the result of point mutations within the viral thymidine kinase (TK) gene, encoding the enzyme responsible for the initial phosphorylation of ACV into ACV-monophosphate or, more rarely, mutations within the viral DNA polymerase (pol) gene (4, 10).…”

mentioning

confidence: 99%

“…Acyclovir (ACV)-resistant herpes simplex viruses (HSV) infections are relatively frequent and can be associated with significant morbidity among immunocompromised patients (14,15,17,37,38). Resistance to ACV can be the result of point mutations within the viral thymidine kinase (TK) gene, encoding the enzyme responsible for the initial phosphorylation of ACV into ACV-monophosphate or, more rarely, mutations within the viral DNA polymerase (pol) gene (4, 10).…”

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confidence: 99%

Highly Reliable Heterologous System for Evaluating Resistance of Clinical Herpes Simplex Virus Isolates to Nucleoside Analogues

Bestman-Smith

Schmit

Papadopoulou

et al. 2001

J Virol

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Clinical resistance of herpes simplex virus (HSV) types 1 and 2 to acyclovir (ACV) is usually caused by the presence of point mutations within the coding region of the viral thymidine kinase (TK) gene. The distinction between viral TK mutations involved in ACV resistance or part of viral polymorphism can be difficult to evaluate with current methodologies based on transfection and homologous recombination. We have developed and validated a new heterologous system based on the expression of the viral TK gene by the protozoan parasite Leishmania, normally devoid of TK activity. The viral TK genes from 5 ACV-susceptible and 13 ACV-resistant clinical HSV isolates and from the reference strains MS2 (type 2) and KOS (type 1) were transfected as part of an episomal expression vector in Leishmania. The susceptibility of TK-recombinant parasites to ganciclovir (GCV), a closely related nucleoside analogue, was evaluated by a simple measurement of the absorbance of Leishmania cultures grown in the presence of the drug. Expression of the TK gene from ACV-susceptible clinical isolates resulted in Leishmania susceptibility to GCV, whereas expression of a TK gene with frameshift mutations or nucleotide substitutions from ACV-resistant isolates gave rise to parasites with high levels of GCV resistance. The expression of the HSV TK gene in Leishmania provides an easy, reliable, and sensitive assay for evaluating HSV susceptibility to nucleoside analogues and for assessing the role of specific viral TK mutations.Acyclovir (ACV)-resistant herpes simplex viruses (HSV) infections are relatively frequent and can be associated with significant morbidity among immunocompromised patients (14,15,17,37,38). Resistance to ACV can be the result of point mutations within the viral thymidine kinase (TK) gene, encoding the enzyme responsible for the initial phosphorylation of ACV into ACV-monophosphate or, more rarely, mutations within the viral DNA polymerase (pol) gene (4, 10). The former mechanism is most frequently seen in the clinic (8,16,17,29), probably because TK is not essential for viral replication in most tissues and culture cells (36). However, several reports have demonstrated that TK activity facilitates HSV reactivation from latency in neural ganglia (11,13,44,46).Changes in the TK gene can result in viruses producing no or partial amounts of TK or with an altered substrate specificity (4, 23). Darby et al. have proposed a preliminary model for the active center of the HSV type 1 (HSV-1) TK enzyme including three distinct regions: an ATP-binding site (amino acids 51 to 63), a nucleoside-binding site (amino acids 168 to 176), and amino acid 336 (12). Indeed, single-point mutations in one or more of these conserved regions have been found in ACVresistant HSV isolates (16,20,25,30,41,42). Furthermore, Sasadeusz et al. have identified mutational hot spots consisting of frameshift mutations within homopolymer nucleotide stretches of G's and C's (41). Recent studies by our group (16) and others (25) have demonstrated that about 50% o...

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“…Today, in the treatment of herpes virus infections, antiviral drugs like acyclovir (ACV), vidara-bine (ara-A) and ganciclovir (DHPG) are used (3,4). The mechanism of action of these drugs is basically dependent on their abilities to inhibit the virus-specific enzymes, thymidine kinase and the+ DNA polymerase (5,6).Because of their cytotoxic effects, these drugs except of acycloir are not widely used (7). In recent years, however, acyclovir and other drugs have been reported to be inefficient in treating genital herpes infections.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Potential Antiviral Activity of the Hydroalcoholic Extract of Lemon Balm L. against Herpes Simplex Virus Type 1

et al. 2010

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Background and Aims: Lemon Balm L (Lamiaceae) has been used in a variety of practical applications in medical sciences. Its antiviral activity against herpes simplex virus type-1 (HSV-1) was investigated in cell culture. Lemon Balm hydroalcoholic extract was found to be non-toxic to Vero cells up to concentration 800 ug/ml and inhibited the growth and development of HSV-1 in dose-dependent manner in Vero cells. Methods: In order to study the possible mechanisms of the antiviral activity of Lemon Balm extract, cells were treated with extract before, during and after infection, and the viral titers were tested by TCID50 assay. Results: The antiviral effects in treatment of post and during virus infection were more remarkable than the treatment of preinfection. For further investigation indirect immunofluorescence technique was used to elucidate the antiviral mechanism of the extract by infecting Vero cells at different times and monitoring the synthesis of viral proteins. Conclusion: Although the precise mechanism has not yet to be defined, our work indicated that lemon Balm L. extract could inhibit growth and development of HSV-1 in cells in vitro.

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Acyclovir-Resistant Herpes Simplex Virus Infections in Patients with the Acquired Immunodeficiency Syndrome

Cited by 441 publications

References 26 publications

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

Highly Reliable Heterologous System for Evaluating Resistance of Clinical Herpes Simplex Virus Isolates to Nucleoside Analogues

Evaluation of Potential Antiviral Activity of the Hydroalcoholic Extract of Lemon Balm L. against Herpes Simplex Virus Type 1

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