Within host RNA virus persistence : mechanisms and consequences

RER is funded by the Wellcome Trust, UK (Grant 101788/Z/13/Z) and DEG by US National Institutes of Health (R01 NS038932).In a prototypical response to an acute viral infection it would be expected that the adaptive immune response would eliminate all virally infected cells within a few weeks of infection. However many (non-retrovirus) RNA viruses can establish “within host” persistent infections that occasionally lead to chronic or reactivated disease. Despite the importance of “within host” persistent RNA virus infections, much has still to be learnt about the molecular mechanisms by which RNA viruses establish persistent infections, why innate and adaptive immune responses fail to rapidly clear these infections, and the epidemiological and potential disease consequences of such infections.Publisher PDFPeer reviewe

SPECIFICITY OF THE INFLAMMATORY RESPONSE IN VIRAL ENCEPHALITIS : I. ADOPTIVE IMMUNIZATION OF IMMUNOSUPPRESSED MICE INFECTED WITH SINDBIS VIRUS

The viral-induced perivascular inflammatory response in Sindbis virus encephalitis of mice was shown to be immunologically specific. Mice were inoculated intracerebrally with Sindbis virus, and 24 hr later a single dose of cyclophosphamide was given which ablated the inflammatory response. 3 days after virus inoculation, cells and/or sera from specifically and nonspecifically sensitized donor mice were given, and the inflammatory reactions, virus content, and antibody response of recipients were examined 5 days later. Reconstitution of the viral inflammatory response required virus-specific sensitized lymph node cells and was enhanced when these lymph node cells were combined with bone marrow cells. Reconstitution was not achieved with Sindbis virus immune serum even when combined with nonspecifically sensitized cells. Combination of immune serum with Sindbis virus-sensitized cells did not produce an accentuation of the reaction. In distinction, reconstitution of the inflammatory reaction surrounding the stab wound was reconstituted with bone marrow cells from mice inoculated with Sindbis virus or control antigens. Reconstitution of the perivascular reaction was associated with a reduction in brain virus content. Although the transfer of Sindbis virus-sensitized lymph node cells and bone marrow cells resulted in the limited production of neutralizing antibody in the immunosuppressed recipient, the reduction in virus was significantly greater with the transfers of Sindbis virus-sensitized lymph node cells than with the passive transfer of immune serum alone

Mental Health Assessment of Minors in the Juvenile Justice System

Recent reports recognize that children and adolescents with undiagnosed mental illnesses make up a significant proportion of youth in the juvenile justice system. In determining how to rehabilitate youth in the juvenile justice system, judges, lawyers, and probation officers are starting to look at mental health problems as one element contributing to delinquent behavior. It is becoming more common for attorneys to request “mental health assessments” for their juvenile clients. Problems arise, however, in determining what specifically constitutes such an assessment, and in deciding what to do with this information once it is obtained. In 2001, the Illinois Cook County Juvenile Court convened the interdisciplinary Juvenile Justice Committee on Mental Health Assessments to address this issue. Specifically, the committee attempted to define the components and protocol for mental health assessments, how to handle the results of such assessments, and, ultimately, what to do with the youth. The following summarizes the committee’s findings, and outlines its relevance to interdisciplinary clinical legal education

Heparin-binding and patterns of virulence for two recombinant strains of Sindbis virus

AbstractE2 is an important determinant of Sindbis virus neurovirulence. Increased heparan sulfate (HS) binding is associated with rapid clearance of viremia and usually with decreased virulence. However, substitution of histidine for arginine at E2-157 (R157H) or glutamate for lysine at E2-159 (K159E) produces viruses with decreases in heparin-Sepharose binding and increases in viremia but different levels of binding to HS-expressing cells and virulence phenotypes in newborn CD-1 mice (Byrnes, A.P., Griffin, D.E., 2000. Large-plaque mutants of Sindbis virus show reduced binding to heparan sulfate, heightened viremia and slower clearance from the circulation. J. Virol. 74, 644–651). To identify mechanisms of virulence, R157H and K159E were studied in newborn CD-1 and BALB/c mice. Subcutaneous inoculation of R157H caused 100% and K159E 60% mortality in 2-day-old CD-1 mice. R157H caused 25% and K159E no mortality in 2-day-old BALB/c mice. R157H and K159E replicated similarly at the site of inoculation with the same level of viremia, but clearance was slower in CD-1 than BALB/c mice. R157H replicated better than K159E in the central nervous system (CNS) after subcutaneous and intracerebral inoculation and in undifferentiated neurons. These studies show a genetic restriction of replication in newborn BALB/c mice, and that amino acid substitutions affecting binding to proteoglycans may differ in importance for CNS infection and viremia

The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses

Emerging and re-emerging viral diseases pose continuous public health threats, and effective control requires a combination of non-pharmacologic interventions, treatment with antivirals, and prevention with vaccines. The COVID-19 pandemic has demonstrated that the world was least prepared to provide effective treatments. This lack of preparedness has been due, in large part, to a lack of investment in developing a diverse portfolio of antiviral agents, particularly those ready to combat viruses of pandemic potential. Here, we focus on a drug target called macrodomain that is critical for the replication and pathogenesis of alphaviruses and coronaviruses. Some mutations in alphavirus and coronaviral macrodomains are not tolerated for virus replication. In addition, the coronavirus macrodomain suppresses host interferon responses. Therefore, macrodomain inhibitors have the potential to block virus replication and restore the host’s protective interferon response. Viral macrodomains offer an attractive antiviral target for developing direct acting antivirals because they are highly conserved and have a structurally well-defined (druggable) binding pocket. Given that this target is distinct from the existing RNA polymerase and protease targets, a macrodomain inhibitor may complement current approaches, pre-empt the threat of resistance and offer opportunities to develop combination therapies for combating COVID-19 and future viral threats

Class II fusion protein of alphaviruses drives membrane fusion through the same pathway as class I proteins

Viral fusion proteins of classes I and II differ radically in their initial structures but refold toward similar conformations upon activation. Do fusion pathways mediated by alphavirus E1 and influenza virus hemagglutinin (HA) that exemplify classes II and I differ to reflect the difference in their initial conformations, or concur to reflect the similarity in the final conformations? Here, we dissected the pathway of low pH–triggered E1-mediated cell–cell fusion by reducing the numbers of activated E1 proteins and by blocking different fusion stages with specific inhibitors. The discovered progression from transient hemifusion to small, and then expanding, fusion pores upon an increase in the number of activated fusion proteins parallels that established for HA-mediated fusion. We conclude that proteins as different as E1 and HA drive fusion through strikingly similar membrane intermediates, with the most energy-intensive stages following rather than preceding hemifusion. We propose that fusion reactions catalyzed by all proteins of both classes follow a similar pathway

A Comparative Study of Aerocapture Missions with a Mars Destination

Conventional interplanetary spacecraft use propulsive systems to decelerate into orbit. Aerocapture is an alternative approach for orbit capture, in which the spacecraft makes a single pass through a target destination's atmosphere. Although this technique has never been performed, studies show there are substantial benefits of using aerocapture for reduction of propellant mass, spacecraft size, and mission cost. The In-Space Propulsion (ISP) Program, part of NASA's Science Mission Directorate, has invested in aerocapture technology development since 2002. Aerocapture investments within ISP are largely driven by mission systems analysis studies, The purpose of this NASA-funded report is to identify and document the fundamental parameters of aerocapture within previous human and robotic Mars mission studies which will assist the community in identifying technology research gaps in human and robotic missions, and provide insight for future technology investments. Upon examination of the final data set, some key attributes within the aerocapture disciplines are identified

A Planetary Companion to gamma Cephei A

We report on the detection of a planetary companion in orbit around the primary star of the binary system $\gamma$ Cephei. High precision radial velocity measurements using 4 independent data sets spanning the time interval 1981--2002 reveal long-lived residual radial velocity variations superimposed on the binary orbit that are coherent in phase and amplitude with a period or 2.48 years (906 days) and a semi-amplitude of 27.5 m s$^{-1}$. We performed a careful analysis of our Ca II H & K S-index measurements, spectral line bisectors, and {\it Hipparcos} photometry. We found no significant variations in these quantities with the 906-d period. We also re-analyzed the Ca II $\lambda$8662 {\AA} measurements of Walker et al. (1992) which showed possible periodic variations with the ``planet'' period when first published. This analysis shows that periodic Ca II equivalent width variations were only present during 1986.5 -- 1992 and absent during 1981--1986.5. Furthermore, a refined period for the Ca II $\lambda$8662 {\AA} variations is 2.14 yrs, significantly less than residual radial velocity period. The most likely explanation of the residual radial velocity variations is a planetary mass companion with $M$ sin $i$ = 1.7 $M_{Jupiter}$ and an orbital semi-major axis of $a_2$ $=$ 2.13 AU. This supports the planet hypothesis for the residual radial velocity variations for $\gamma$ Cep first suggested by Walker et al. (1992). With an estimated binary orbital period of 57 years $\gamma$ Cep is the shortest period binary system in which an extrasolar planet has been found. This system may provide insights into the relationship between planetary and binary star formation.Comment: 19 pages, 15 figures, accepted in Ap. J. Includes additional data and improved orbital solutio

Evolution of T Cell Responses during Measles Virus Infection and RNA Clearance

Measles is an acute viral disease associated both with immune suppression and development of life-long immunity. Clearance of measles virus (MeV) involves rapid elimination of infectious virus during the rash followed by slow elimination of viral RNA. To characterize cellular immune responses during recovery, we analyzed the appearance, specificity and function of MeV-specific T cells for 6 months after respiratory infection of rhesus macaques with wild type MeV. IFN-γ and IL-17-producing cells specific for the hemagglutinin and nucleocapsid proteins appeared in circulation in multiple waves approximately 2-3, 8 and 18-24 weeks after infection. IFN-γ-secreting cells were most abundant early and IL-17-secreting cells late. Both CD4 and CD8 T cells were sources of IFN-γ and IL-17, and IL-17-producing cells expressed RORγt. Therefore, the cellular immune response evolves during MeV clearance to produce functionally distinct subsets of MeV-specific CD4 and CD8 T cells at different times after infection

Protective efficacy of a recombinant plague vaccine when co-administered with another sub-unit or live attenuated vaccine.

Vaccines against bioterrorism agents offer the prospect of providing high levels of protection against airborne pathogens. However, the diversity of the bioterrorism threat means that it may be necessary to use several vaccines simultaneously. In this study we have investigated whether there are changes to the protective immune response to a recombinant sub-unit plague vaccine when it is co-administered with other sub-unit or live attenuated vaccines. Our results indicate that the co-administration of these vaccines did not influence the protection afforded by the plague vaccine. However, the co-administration of the plague sub-unit vaccine with a live vaccine resulted in markedly increased levels of IgG2a subclass antibodies, and markedly reduced levels of IgG1 subclass antibodies, to the plague sub-unit vaccine. This finding might have implications when considering the co-administration of other vaccine combinations