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Mouse mammary tumor virus (MMTV) has previously been shown to encode a functional homolog of the human immunodeficiency virus-1 (HIV-1) nuclear export protein Rev, termed Rem. Here, we show that deletion of the rem gene from a MMTV molecular clone interfered with the nucleo-cytoplasmic transport of genomic length viral mRNA and resulted in a loss of viral capsid (Gag) protein production. Interestingly, nuclear export of single-spliced env mRNA was only moderately affected, suggesting that this transcript is, at least to some extent, transported via a distinct, Rem-independent export mechanism. To identify and characterize a cis-acting RNA element required for Rem responsiveness (RmRE), extensive computational and functional analyses were performed. By these means a region of 490 nt corresponding to positions nt 8517–nt 9006 in the MMTV reference strain was identified as RmRE. Deletion of this fragment, which spans the env-U3 junction region, abolished Gag expression. Furthermore, insertion of this sequence into a heterologous HIV-1-based reporter construct restored, in the presence of Rem, HIV-1 Gag expression to levels determined for the Rev/RRE export system. These results clearly demonstrate that the identified region, whose geometry resembles that of other retroviral-responsive elements, is capable to functionally substitute, in the presence of Rem, for Rev/RRE and thus provide unequivocal evidence that MMTV is a complex retrovirus.

Background V591 (TMV-083) is a live recombinant measles vector-based vaccine candidate expressing a pre-fusion stabilized SARS-CoV-2 spike protein. Methods We performed a randomized, placebo-controlled Phase I trial with an unblinded dose escalation and a double-blind treatment phase at 2 sites in France and Belgium to evaluate the safety and immunogenicity of V591. Ninety healthy SARS-CoV-2 sero-negative adults (18-55 years of age) were randomized into 3 cohorts, each comprising 24 vaccinees and 6 placebo recipients. Participants received two intramuscular injections of a low dose vaccine (1 × 10 5 median Tissue Culture Infectious Dose [TCID 50 ]), one or two injections of a high dose vaccine (1 × 10 6 TCID 50 ), or placebo with a 28 day interval. Safety was assessed by solicited and unsolicited adverse events. Immunogenicity was measured by SARS-CoV-2 spike protein-binding antibodies, neutralizing antibodies, spike-specific T cell responses, and anti-measles antibodies. ClinicalTrials.gov, NCT04497298. Findings Between Aug 10 and Oct 13, 2020, 148 volunteers were screened of whom 90 were randomized. V591 showed a good safety profile at both dose levels. No serious adverse events were reported. At least one treatment-related adverse event was reported by 15 (20.8%) participants receiving V591 vs. 6 (33.3%) of participants receiving placebo. Eighty-one percent of participants receiving two injections of V591 developed spike-binding antibodies after the second injection. However, neutralizing antibodies were detectable on day 56 only in 17% of participants receiving the low dose and 61% receiving the high dose (2 injections). Spike-specific T cell responses were not detected. Pre-existing anti-measles immunity had a statistically significant impact on the immune response to V591, which was in contrast to previous results with the measles vector-based chikungunya vaccine. Interpretation While V591 was generally well tolerated, the immunogenicity was not sufficient to support further development.

Thirty-five patients with autoimmune diseases who were on long-term immunoadsorption therapy participated in a prospective, randomized study. Results and conclusions. Infections were rare but similar in frequency in patients receiving combined immunoadsorption and intravenous immunoglobulins (intervention group, n=17, 1.3 infections per patient-year) and in a control group (n=18, 0.9 infections per patient-year) treated by immunoadsorption alone. The reduction in IgG achieved with two immunoadsorptions within 3 days was 95.0+/-2.5%. The extent of removal of pathogenic autoantibodies was similar to the removal of IGG: Substitution of immunoglobulins was not associated with an increased circulating IgG level before the following immunoadsorption. Infusion of immunoglobulins at a dose of 0.14 g/kg (interquartile range 0.12-0.16) body weight in patients in whom circulating immunoglobulins had been depleted was associated with a high incidence of serious side-effects; these necessitated the termination of treatment in 24% of the patients. No evidence was found that immunoglobulin administration had any beneficial effect with respect to autoantibody resynthesis after immunoadsorption.

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