RNA modulating factors not only regulate multiple steps of cellular RNA metabolism, but also emerge as key effectors of the immune response against invading viral pathogens including human immunodeficiency virus type-1 (HIV-1). However, cellular RNA binding proteins involved in the establishment and maintenance of latent HIV-1 reservoirs have not been extensively studied. Here, we screened a panel of 62 cellular RNA binding proteins and identified NEDD4 binding protein 1 (N4BP1) as potent interferon-inducible inhibitor of HIV-1 in primary T cells and macrophages. N4BP1 harbors a prototypical PIN-like RNase domain and inhibits HIV-1 replication by interacting with and degrading viral mRNA species. Upon activation of CD4 + T cells, however, N4BP1 undergoes rapid cleavage at Arg509 by the paracaspase MALT1. Mutational analyses and knockout studies revealed that MALT1-mediated inactivation of N4BP1 facilitates the reactivation of latent HIV-1 proviruses. Taken together, our findings demonstrate that the RNase N4BP1 is an efficient restriction factor of HIV-1 and suggest that inactivation of N4BP1 by induction of MALT1 activation might facilitate elimination of latent HIV-1 reservoirs.

Background The immune profile against SARS-CoV-2 has dramatically diversified due to a complex combination of exposure to vaccines and infection by various lineages/variants, likely generating a heterogeneity in protective immunity in a given population. To further complicate this, the Omicron variant, with numerous spike mutations, has emerged. These circumstances have created the need to assess the potential of immune evasion by the Omicron in individuals with various immune histories. Methods The neutralization susceptibility of the variants including the Omicron and their ancestor was comparably assessed using a panel of plasma/serum derived from individuals with divergent immune histories. Blood samples were collected from either mRNA vaccinees or from those who suffered from breakthrough infections by the Alpha/Delta with multiple time intervals following vaccination. Findings The Omicron was highly resistant to neutralization in fully vaccinated individuals without a history of breakthrough infections. In contrast, robust cross-neutralization against the Omicron were induced in vaccinees that experienced breakthrough infections. The time interval between vaccination and infection, rather than the variant types of infection, was significantly correlated with the magnitude and potency of Omicron-neutralizing antibodies. Conclusions Immune histories with breakthrough infections can overcome the resistance to infection by the Omicron, with the vaccination-infection interval being the key determinant of the magnitude and breadth of neutralization. The diverse exposure history in each individual warrants a tailored and cautious approach to understanding population immunity against the Omicron and future variants. Funding This study was supported by grants from the Japan Agency for Medical Research and Development (AMED).

The main purpose of the present work was to study in detail the outflux of P32 from excitable tissues accompanying membrane depolarization or electrical excitation. With the use of P32 as a tracer, it has been demonstrated that orthophosphate and a number of organic phosphates slowly diffuse out of nerve and muscle even after 2 hr of exposure to Ringer's solution. On exposure to calcium-free or potassium-rich media, or during electrical excitation, there is a considerable increase in the outflux of a number of acid-soluble phosphates, particularly orthophosphate and adenosinetriphosphate. Further evidence in support of this concept was based on the fact that the radioactive specific activity of the diffusible phosphates was greater than the internal phosphates of excitable tissues. Since all these procedures are known to result in depolarization of excitable tissues, there was reason to believe that the outflux of muscle phosphates was somehow related to the physicochemical changes associated with membrane depolarization. The changes in the outflux of P32 from the muscle or nerve, either stimulated or soaked in calcium-free or potassium-rich media, appear to be related to the changes in the membrane potential.

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