RNA viruses exploit all known mechanisms of genetic variation to ensure their survival. Distinctive features of RNA virus replication include high mutation rates, high yields, and short replication times. As a consequence, RNA viruses replicate as complex and dynamic mutant swarms, called viral quasispecies. Mutation rates at defined genomic sites are affected by the nucleotide sequence context on the template molecule as well as by environmental factors. In vitro hypermutation reactions offer a means to explore the functional sequence space of nucleic acids and proteins. The evolution of a viral quasispecies is extremely dependent on the population size of the virus that is involved in the infections. Repeated bottleneck events lead to average fitness losses, with viruses that harbor unusual, deleterious mutations. In contrast, large population passages result in rapid fitness gains, much larger than those so far scored for cellular organisms. Fitness gains in one environment often lead to fitness losses in an alternative environment. An important challenge in RNA virus evolution research is the assignment of phenotypic traits to specific mutations. Different constellations of mutations may be associated with a similar biological behavior. In addition, recent evidence suggests the existence of critical thresholds for the expression of phenotypic traits. Epidemiological as well as functional and structural studies suggest that RNA viruses can tolerate restricted types and numbers of mutations during any specific time point during their evolution. Viruses occupy only a tiny portion of their potential sequence space. Such limited tolerance to mutations may open new avenues for combating viral infections.

RNA virus mutations and fitness for survival

Summary Herpes simplex viruses types 1 and 2 (HSV1 and HSV2) and varicella-zoster virus (VZV) establish latent infection in dorsal root ganglia for the entire life of the host. From this reservoir they can reactivate to cause human morbidity and mortality. Although the viruses vary in the clinical disorders they cause and in their molecular structure, they share several features that affect the course of infection of the human nervous system. HSV1 is the causative agent of encephalitis, corneal blindness, and several disorders of the peripheral nervous system; HSV2 is responsible for meningoencephalitis in neonates and meningitis in adults. Reactivation of VZV, the pathogen of varicella (chickenpox), is associated with herpes zoster (shingles) and central nervous system complications such as myelitis and focal vasculopathies. We review the biological, medical, and neurological aspects of acute, latent, and reactivated infections with the neurotropic herpes viruses.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(07)70267-3.pdf

The neurotropic herpes viruses: herpes simplex and varicella-zoster

Herpes simplex viruses (HSV) type 1 and type 2 are responsible for recurrent orolabial and genital infections. The standard therapy for the management of HSV infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valacyclovir and famciclovir. These compounds are phosphorylated by the viral thymidine kinase (TK) and then by cellular kinases. The triphosphate forms selectively inhibit the viral DNA polymerase (DNA pol) activity. Drug-resistant HSV isolates are frequently recovered from immunocompromised patients but rarely found in immunocompetent subjects. The gold standard phenotypic method for evaluating the susceptibility of HSV isolates to antiviral drugs is the plaque reduction assay. Plaque autoradiography allows the associated phenotype to be distinguished (TK-wild-type, TK-negative, TK-lowproducer, or TK-altered viruses or mixtures of wild-type and mutant viruses). Genotypic characterization of drug-resistant isolates can reveal mutations located in the viral TK and/or in the DNA pol genes. Recombinant HSV mutants can be generated to analyze the contribution of each specific mutation with regard to the drug resistance phenotype. Most ACV-resistant mutants exhibit some reduction in their capacity to establish latency and to reactivate, as well as in their degree of neurovirulence in animal models of HSV infection. For instance, TK-negative HSV mutants establish latency with a lower efficiency than wild-type strains and reactivate poorly. DNA pol HSV mutants exhibit different degrees of attenuation of neurovirulence. The management of ACV- or PCV-resistant HSV infections includes the use of the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir. There is a need to develop new antiherpetic compounds with different mechanisms of action. Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are responsible for recurrent orolabial and genital infections. In the United States, the seroprevalence of HSV-1 and HSV-2 infections has been estimated to be approximately 50% and 20%, respectively (243). Transmission occurs by contact with secretions from an infected person with either overt infection or asymptomatic excretion of virus. After primary infection, HSV establishes long-term latency in the ganglia of sensory nerves, from which it can reactivate episodically. These reactivations may be accompanied by symptoms or may be clinically silent. The most common clinical manifestations of HSV infections are vesicular lesions affecting the mucous membranes principally of the mouth, nose, or eyes for HSV-1 and the anogenital region for HSV-2. However, an increasing proportion of genital infections are caused by HSV-1 (243). The symptoms associated with both viruses are usually self-limiting, and the goals of treatment are to accelerate lesion healing and to prevent transmission in immunocompetent individuals (61). Both HSV-1 and HSV-2 can also cause infrequent but serious diseases, such as encephalitis and disseminated neonatal infections. HSV infections may be severe in immunocompromised patients, particularly those with defects in cell-mediated immunity. In patients with HIV infection and in recipients of solid organ or bone marrow transplants, herpetic lesions can be extensive, tend to persist for longer periods, and have the potential to disseminate. Recurrences tend to be more frequent and may be atypical in appearance (140). In addition to persistent mucocutaneous lesions, HSV can also lead to disseminated visceral infections, such as esophagitis, hepatitis, or pneumonia, as well as meningoencephalitis, in immunocompromised hosts (94, 99, 174).

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease

Acyclovir, penciclovir, and their prodrugs have been widely used during the past two decades for the treatment of herpesvirus infections. In spite of the distribution of over 2.3 × 10 6 kg of these nucleoside analogues, the prevalence of acyclovir resistance in herpes simplex virus isolates from immunocompetent hosts has remained stable at approximately 0.3%. In immuncompromised patients, in whom the risk for developing resistance is much greater, the prevalence of resistant virus has also remained stable but at a higher level, typically 4 to 7%. These observations are examined in the light of characteristics of the virus, the drugs, and host factors.

Herpes Simplex Virus Resistance to Acyclovir and Penciclovir after Two Decades of Antiviral Therapy

Fourteen cases of severe acyclovir-resistant herpes simplex virus type 1 (HSV-1) infection, 7 of which showed resistance to foscarnet, were diagnosed among 196 allogeneic stem cell transplant recipients within a 29-month period. Recipients of unrelated stem cell transplants were at higher risk. All patients received foscarnet; 8 subsequently received cidofovir. Strains were initially foscarnet-resistant in 3 patients and secondarily so in 4 patients. In vitro resistance to acyclovir or foscarnet was associated with clinical failure of these drugs; however, in vitro susceptibility to foscarnet was associated with complete response in only 5 of 7 patients. No strain from any of the 7 patients was resistant in vitro to cidofovir; however, only 3 of 7 patients achieved complete response. Therefore, acyclovir- and/or foscarnet-resistant HSV-1 infections after allogeneic stem cell transplantation have become a concern; current strategies need to be reassessed and new strategies must be evaluated in this setting.

Resistant Herpes Simplex Virus Type 1 Infection: An Emerging Concern after Allogeneic Stem Cell Transplantation

Detection of Epstein-Barr virus DNA by in situ hybridization and polymerase chain reaction in salivary gland biopsy specimens from patients with Sjögren's syndrome.

The following six methods for detecting rotavirus in human faecal samples were compared: electron microscopy, immune electron microscopy, immunofluorescence in cell culture, two enzyme immunoassays (Rotazyme, Enzygnost) and a latex agglutination test (Rotalex). Specimens were collected from 112 children with diarrhoea. The relative sensitivities of the different assays for human rotavirus were as follows: electron microscopy, 84%; immunofluorescence, 86%; Rotalex, 88%; Rotazyme, 89%; immune electron microscopy, 93%; Enzygnost, 98%. According to our findings Enzygnost is the most sensitive method, but Rotalex is more valuable for screening a small number of faecal samples. No false-positive results were observed in the two enzyme immunoassays or in Rotalex.

/pdf/comparison-of-six-methods-for-detecting-human-rotavirus-in-3qt4v82ssy.pdf

Comparison of six methods for detecting human rotavirus in stools

Chronic varicella zoster infection in acquired immunodeficiency syndrome

OBJECTIVE To measure changes in HIV-1 virus load following zidovudine therapy, and to investigate the relationship between these changes and clinical progression. DESIGN Prospective study of 18 symptomatic, zidovudine-naive patients, with CD4 count 50% decrease in ICD-p24 Ag levels or > 1 log10 decrease in plasma or cellular viraemia titres from baseline values. CD4 and CD8 cell counts, and beta 2-microglobulin levels were also measured. Disease progression was defined as the time to a new AIDS-defining event or death. RESULTS At enrolment, 13 out of 18 (72%) patients had positive ICD-p24 Ag and positive plasma viraemia, with a mean of 44 median tissue culture infective dose (TCID50) per ml; all patients had positive cellular viraemia with a mean TCID50 of 230 per 10(6)/l cells. Median CD4 cell count was 43 x 10(6)/l. Ten patients developed a new AIDS-defining event and eight died during a median follow-up of 15 months on zidovudine. Baseline prognostic markers for development of a new AIDS-defining event included ICD-p24 Ag, CD4 and CD8 cell counts, but only CD4 cell count remained predictive on multivariate analysis (P = 0.003). When each laboratory marker was analysed as a time-dependent covariate, only CD4 (P = 0.002) and CD8 (P = 0.001) cell counts predicted the occurrence of a new AIDS-defining event. Eight out of 13 (61.5%) patients had an ICD-p24 Ag response, and seven out of 13 (54%) a plasma viraemia response, but only cellular viraemia responders (five out of 18; 28%) had a 5.6-fold decrease in their risk of developing an AIDS-defining event (90% confidence interval, 1-33; P = 0.05). None of these markers correlated with survival. CONCLUSIONS Plasma viraemia and ICD-p24 Ag, while providing useful short-term markers of zidovudine antiviral activity in vivo, do not correlate with disease progression in patients with advanced HIV infection. CD4 cell count remained the best initial and time-dependent predictor for development of new AIDS-defining events. Interestingly, a high CD8 cell count and a decrease in cellular viraemia titres also appear to be predictive of improved clinical outcome in this population.

Quantification of HIV-1 virus load under zidovudine therapy in patients with symptomatic HIV infection: relation to disease progression.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Frédéric Morinet

Author Tools

Chat about Author