It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

Cricket paralysis virus is a member of a group of insect picorna-like viruses. Cloning and sequencing of the single plus-strand RNA genome revealed the presence of two nonoverlapping open reading frames, ORF1 and ORF2, that encode the nonstructural and structural proteins, respectively. We show that each ORF is preceded by one internal ribosome entry site (IRES). The intergenic IRES is located 6,024 nucleotides from the 5 end of the viral RNA and is more active than the IRES located at the 5 end of the RNA, providing a mechanistic explanation for the increased abundance of structural proteins relative to nonstructural proteins in infected cells. Mutational analysis of this intergenic-region IRES revealed that ORF2 begins with a noncognate CCU triplet. Complementarity of this CCU triplet with sequences in the IRES is important for IRES function, pointing to an involvement of RNA-RNA interactions in translation initiation. Thus, the cricket paralysis virus genome is an example of a naturally occurring, functionally dicistronic eukaryotic mRNA whose translation is controlled by two IRES elements located at the 5 end and in the middle of the mRNA. This finding argues that eukaryotic mRNAs can express multiple proteins not only by polyprotein processing, reinitiation and frameshifting but also by using multiple IRES elements.

SUMMARY Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii . This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine.

Background Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. Objective We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. Methods PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. Results We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ–induced gene expression, but we found impaired responses to IFN-γ restimulation. Conclusion Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ–mediated inflammation.

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It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

Varicella-zoster virus (VZV) open reading frame 63 (ORF63)protein is expressed during latency in human sensory ganglia. Deletion of ORF63 impairs virus replication in cell culture and establishment of latency in cotton rats. We found that cells infected with a VZV ORF63 deletion mutant yielded low titers of cell-free virus and produced very few enveloped virions detectable by electron microscopy compared with those infected with parental virus. Microarray analysis of cells infected with a recombinant adenovirus expressing ORF63 showed that transcription of few human genes was affected by ORF63; a heat shock 70-kDa protein gene was downregulated, and several histone genes were upregulated. In experiments using VZV transcription arrays, deletion of ORF63 from VZV resulted in a fourfold increase in expression of ORF62, the major viral tran- Varicella-zoster virus (VZV) causes chicken pox upon primary infection and then establishes latency in cranial nerve and dorsal root ganglia and can reactivate to cause shingles (herpes zoster). The lifetime risk of shingles is 10 to 20% for adults in the United States who are seropositive for VZV (14). Transcripts corresponding to VZV open reading frames (ORFs) 4, 21, 29, 62, 63, and 66 have been detected in latently infected human ganglia (8,10,24,25,36). ORF63 is the most frequently detected and most abundant of these transcripts (10, 25). ORF63 protein has also been detected in latently infected human (25,31,33) and rodent (11, 22) ganglia.ORF63 encodes a virion tegument protein (28, 38), but the function of this protein is unclear. ORF63 protein enhances the activation of the minimal gI promoter by VZV ORF62 protein (32) and represses other viral genes (3,20). In transient-transfection assays, ORF63 protein represses promoters containing typical TATA boxes (12), including VZV ORF4 and ORF28, heterologous viral promoters, and the human interleukin-8 promoter. The VZV gI promoter, which contains an atypical TATA box, is only slightly repressed. In contrast, ORF63 protein activates the cellular elongation factor 1 (EF-1) alpha promoter in some cell types (53).A recombinant VZV in which 90% of both ORF63 and its duplicate gene, ORF70, are deleted is viable but impaired for growth in cell culture and latency in cotton rats (5). Analysis of additional ORF63 mutants showed that viruses that are impaired for replication in cell culture are also impaired for latency, while mutants that are not impaired for replication establish latencies at frequencies and copy numbers similar to those of parental virus (6).In this study, we examined the effects of VZV ORF63 on virion production and regulation of viral and cellular gene expression. We found that ORF63 downregulates transcription of ORF62 and that cells infected with VZV mutants impaired for replication and latency show increased transcription of ORF62, while cells infected with a mutant that is not impaired express wild-type levels of ORF62. MATERIALS AND METHODS Cells and viruses.Human diploid fibroblasts (MRC-5) were obtained from...

Mutations in the thymidine kinase gene (tk) of herpes simplex virus type 1 (HSV-1) explain most cases of virus resistance to acyclovir (ACV) treatment. Mucocutaneous lesions of patients with ACV resistance contain mixed populations of tk mutant and wild-type virus. However, it is unknown whether human ganglia also contain mixed populations since the replication of HSV tk mutants in animal neurons is impaired. Here we report the detection of mutated HSV tk sequences in human ganglia. Trigeminal and dorsal root ganglia were obtained at autopsy from an immunocompromised woman with chronic mucocutaneous infection with ACV-resistant HSV-1. The HSV-1 tk open reading frames from ganglia were amplified by PCR, cloned, and sequenced. tk mutations were detected in a seven-G homopolymer region in 11 of 12 ganglia tested, with clonal frequencies ranging from 4.2 to 76% HSV-1 tk mutants per ganglion. In 8 of 11 ganglia, the mutations were heterogeneous, varying from a deletion of one G to an insertion of one to three G residues, with the two-G insertion being the most common. Each ganglion had its own pattern of mutant populations. When individual neurons from one ganglion were analyzed by laser capture microdissection and PCR, 6 of 14 HSV-1-positive neurons were coinfected with HSV tk mutants and wild-type virus, 4 of 14 were infected with wild-type virus alone, and 4 of 14 were infected with tk mutant virus alone. These data suggest that diverse tk mutants arise independently under drug selection and establish latency in human sensory ganglia alone or together with wild-type virus.The deoxyguanosine homolog acyclovir (ACV) is the most common drug used to treat herpes simplex virus (HSV) infections. After being taken up into cells, ACV is sequentially converted into ACV monophosphate, ACV diphosphate, and finally its active form, ACV triphosphate. The first step of the sequential phosphorylations requires HSV-encoded thymidine kinase (TK); however, cellular enzymes perform the additional phosphorylations. ACV triphosphate is more efficiently incorporated into replicating DNA by HSV DNA polymerase than by the cellular DNA polymerase (8). These characteristics of ACV result in its selectivity for virus-infected cells and its extremely low toxicity to uninfected cells. However, if HSV loses its TK function (including an alteration in substrate specificity or the loss of TK activity) or its DNA polymerase has altered substrate affinity, the virus becomes ACV resistant (Acv r ). While viral TK function is crucial for ACV activity, TK is not essential for HSV to replicate in dividing cells (22) such as human epithelial cells, presumably due to the abundance of nucleotides in these cells. Thus, a TK Ϫ HSV mutant that is resistant to ACV therapy can still replicate in epithelial cells and cause lesions. In contrast, TK activity is important for virus replication in resting cells or neurons (22,38). Though Acv r HSV infection rarely has clinical significance in immunocompetent individuals (7,15,24,27,37), severe disease can occur in...