Argentine hemorrhagic fever is a potentially lethal disease that is caused by Junin virus (JUNV). There are currently around 5 million individuals at risk of infection within regions of endemicity in Argentina. The live attenuated vaccine strain Candid #1 (Can) is approved for use in regions of endemicity and has substantially decreased the number of annual Argentine hemorrhagic fever (AHF) cases. The glycoprotein (GPC) gene is primarily responsible for attenuation of the Can strain, and we have shown that the absence of an N-linked glycosylation motif in the subunit G1 of the glycoprotein complex of Can, which is otherwise present in the wild-type pathogenic JUNV, causes GPC retention in the endoplasmic reticulum (ER). Here, we show that Can GPC aggregates in the ER of infected cells, forming incorrect cross-chain disulfide bonds, which results in impaired GPC processing into G1 and G2. The GPC fails to cleave into its G1 and G2 subunits and is targeted for degradation within lysosomes. Cells infected with the wild-type Romero (Rom) strain do not produce aggregates that are observed in Can infection, and the stress on the ER remains minimal. While the mutation of the N-linked glycosylation motif (T168A) is primarily responsible for the formation of aggregates, other mutations within G1 that occurred earlier in the passage history of the Can strain also contribute to aggregation of the GPC within the ER.
IMPORTANCE The development of vaccines and therapeutics to combat viral hemorrhagic fevers remains a top priority within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. The Can strain, derived from the pathogenic XJ strain of JUNV, has been demonstrated to be both safe and protective against AHF. While the vaccine strain is approved for use in regions of endemicity within Argentina, the mechanisms of Can attenuation have not been elucidated. A better understanding of the viral genetic determinants of attenuation will improve our understanding of the mechanisms contributing to disease pathogenesis and provide critical information for the rational design of live attenuated vaccine candidates for other viral hemorrhagic fevers.
Lassa fever is a zoonotic disease endemic in some West African countries. It is exported to countries in America, Asia, and Europe. Antivirals against Lassa fever are important to provide a cure in patients with the disease and provide protection against it. In addition, due to the potential utilization of Lassa virus as a bioterrorism agent, vaccines against the disease can be utilized as a counterterrorism measure. Developing antiviral compounds and vaccines against the disease requires understanding of the pathogenesis of Lassa fever and its disease course, including the signs, symptoms, complications, and sequelae. An important sequela of Lassa fever is ataxia. A few cases of postviral ataxia following Lassa fever have been described in the literature. This review focuses on highlighting these cases, the gaps in scientific knowledge where further research is needed, and possible ways of diagnosing postviral ataxia after Lassa fever in resource-limited settings.
People with HIV (PWH) have a >2‐fold greater risk for development of cardiovascular disease (CVD), which may be associated with abnormalities in 24‐h ambulatory blood pressure measurement (ABPM) profile. We conducted a nested case‐control study of ABPM in 137 PWH and HIV‐uninfected controls with normal and high clinic blood pressure (BP) in Tanzania. Nocturnal non‐dipping of heart rate (HR) was significantly more common among PWH than HIV‐uninfected controls (p = .01). Nocturnal non‐dipping of BP was significantly more common in PWH with normal clinic BP (p = .048). Clinical correlates of nocturnal non‐dipping were similar in PWH and HIV‐uninfected adults and included higher BMI, higher CD4+ cell count, and high C‐reactive protein for HR and markers of renal disease for BP. In conclusion, nocturnal non‐dipping of both BP and HR was more common in PWH but further research is needed to determine causes and consequences of this difference.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.