The HIV-1 Rev protein plays a key role in the late phase of virus replication. It binds to the Rev Response Element found in underspliced HIV mRNAs, and drives their nuclear export by the CRM1 receptor pathway. Moreover, mounting evidence suggests that Rev has additional functions in viral replication. Here we employed proteomics and statistical analysis to identify candidate host cell factors that interact with Rev. For this we studied Rev complexes assembled in vitro with nuclear or cytosolic extracts under conditions emulating various intracellular environments of Rev. We ranked the protein-protein interactions by combining several statistical features derived from pairwise comparison of conditions in which the abundance of the binding partners changed. As a validation set, we selected the eight DEAD/H box proteins of the RNA helicase family from the top-ranking 5% of the proteins. These proteins all associate with ectopically expressed Rev in immunoprecipitates of cultured cells. From gene knockdown approaches, our work in combination with previous studies indicates that six of the eight DEAD/H proteins are linked to HIV production in our cell model. In a more detailed analysis of infected cells where either DDX3X, DDX5, DDX17, or DDX21 was silenced, we observed distinctive phenotypes for multiple replication features, variously involving virus particle release, the levels of unspliced and spliced HIV mRNAs, and the nuclear and cytoplasmic concentrations of these transcripts. Altogether the work indicates that our top-scoring data set is enriched in Rev-interacting proteins relevant to HIV replication. Our more detailed analysis of several Revinteracting DEAD proteins suggests a complex set of functions for the helicases in regulation of HIV mRNAs. HIV-1 utilizes many host cell factors for its replication (1-3), similar to other viruses. There is strong interest in identifying and understanding these components to shed light on the molecular mechanisms of virus replication. Moreover, this can provide the potential for developing new therapeutics. The HIV Rev protein is a key regulator of viral replication that is critical for the late stages of virus replication (4, 5). The bestcharacterized function of Rev involves its potent stimulation of the nuclear export of unspliced and singly spliced ("underspliced") HIV transcripts that encode the viral structural proteins and accessory factors (5). In the absence of Rev, these transcripts are retained in the nucleus because of their incomplete splicing. At the molecular level, Rev binds and oligomerizes along the 351-nt Rev Response Element (RRE) 1 (6) in the env gene that is present in all underspliced HIV transcripts. Rev contains a classical leucine-rich nuclear export sequence that recruits CRM1, a transport receptor of the karyopherin family (7,8). CRM1 commonly is used for nuclear export of cellular proteins, and only infrequently is involved in cellular mRNA export (9, 10). Upon binding to the RRE together with the GTP-bound form of Ran, CRM1 forms the core ...
Review CMAJ• Inflammation that destroys the bulge of the outer root sheath destroys the hair follicle and leads to cicatricial alopecia.• Primary cicatricial alopecia is an inflammatory disorder of unknown cause that leads to irreversible hair loss.• The natural history is for the alopecia to extend slowly over the scalp and eventually burn out. The rate of extension and the final severity are extremely variable and difficult to predict.• A number of treatments are used empirically; however, they are not supported by data from clinical trials.
BackgroundCoccidioidomycosis, a disease endemic to the southwestern United States, is associated with significant morbidity, especially in patients in the extremes of age and patients with immunodeficiency or other comorbidities. This review aims to study the disease burden in infants and young children.MethodsRetrospective review of coccidioidomycosis cases in patients younger than 2 years of age seen at Valley Children’s Hospital over a 10-year period, between June 1, 2007 and December 31, 2017.ResultsForty cases were identified. Median age was 10.9 months (IQR, 5.3– 15.8); majority were males (60%), Hispanic (80%), and without comorbid conditions (93%). Fever and cough were the most common symptoms occurring in 83% and 75% of the cases, respectively; Erythema nodosum was seen in only 10% of the patients. Forty percent of the patients had disseminated disease, while 58% had pulmonary disease alone. The most commonly involved extra-pulmonary sites were: bone (12%), central nervous system (10%), larynx (7%), and skin (7%). Majority of patients required hospitalization (75%) and received antifungal therapy (95%), with 55% of them requiring two or more drugs. Patients with disseminated disease presented at a younger age than those with pulmonary disease alone (median 6.7 vs. 12.5 months, P = 0.07); had higher coccidioidal complement fixation titer at the time of diagnosis (median 1:32 vs. 1:16, P = 0.05); required longer duration of hospitalization (median 79 vs. 2 days, P = 0.002); and were more frequently treated with combination antifungal therapy (87% vs. 36%, P = 0.001). In regards to outcome, disease resolution was achieved in 75% of the cases while 25% had active but stable disease on maintenance therapy. A relapse occurred in 5% of the cases. No deaths occurred in this cohort.ConclusionCoccidioidomycosis in children younger than 2 years of age is associated with significant morbidity and healthcare utilization. Disseminated disease is frequently encountered in this age group and should be considered when formulating the plan for treatment and diagnostic investigations.Disclosures All authors: No reported disclosures.
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