Zika virus (ZIKV) is an emerging mosquito-borne flavivirus of significant public health concern. ZIKV shares a high degree of sequence and structural homology compared with other flaviviruses, including dengue virus (DENV), resulting in immunological cross-reactivity. Improving our current understanding of the extent and characteristics of this immunological cross-reactivity is important, as ZIKV is presently circulating in areas that are highly endemic for dengue. To assess the magnitude and functional quality of cross-reactive immune responses between these closely related viruses, we tested acute and convalescent sera from nine Thai patients with PCRconfirmed DENV infection against ZIKV. All of the sera tested were cross-reactive with ZIKV, both in binding and in neutralization. To deconstruct the observed serum cross-reactivity in depth, we also characterized a panel of DENV-specific plasmablast-derived monoclonal antibodies (mAbs) for activity against ZIKV. Nearly half of the 47 DENV-reactive mAbs studied bound to both whole ZIKV virion and ZIKV lysate, of which a subset also neutralized ZIKV. In addition, both sera and mAbs from the dengue-infected patients enhanced ZIKV infection of Fc gamma receptor (FcγR)-bearing cells in vitro. Taken together, these findings suggest that preexisting immunity to DENV may impact protective immune responses against ZIKV. In addition, the extensive cross-reactivity may have implications for ZIKV virulence and disease severity in DENV-experienced populations. (2-4). However, the more recent outbreaks have caused severe neurological complications including GuillainBarré Syndrome in adults and an increase in congenital microcephaly and other adverse birth outcomes in Brazil (5-7). The Pan American Health Organization has reported that as of May 2016, local transmission of ZIKV had spread to over 38 countries or territories in the Americas. In addition, a recent WHO report states that 44 new countries are experiencing their first ZIKV outbreak since 2015. Despite the improving surveillance of the virus, accurate diagnosis has been challenging given the similarities in the clinical presentation of ZIKV to other arboviral infections endemic in these regions, among other factors.During the viremic period, ZIKV can be found in patient blood, saliva, urine, and other bodily fluids early after symptom onset (8-10). During the Yap Islands epidemic in 2007, anti-ZIKV IgM ELISAs and ZIKV plaque reduction neutralization titer (PRNT) assays were performed to confirm infection in RT-PCR negative cases (2, 8). However, as these studies showed, the cross-reactivity between ZIKV and other flaviviruses makes confirmation of infection difficult, especially when patients may have had flavivirus exposures before their suspected ZIKV infection (2,8). Given the overlapping presence of DENV and other flaviviruses in a majority of ZIKV epidemic regions (11), there are great challenges in serology-based testing of flavivirus-immune patients (12).The DENV envelope (E) protein, considered a major imun...

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HIGHLIGHTSd Cross-sectional study of 44 hospitalized COVID-19 patients d RBD-specific IgG responses detectable in all patients 6 days after PCR confirmation d Neutralizing titers are detectable in all patients 6 days after PCR confirmation d RBD-specific IgG titers correlate with the neutralizing potency

T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1 + Tcf-1 + CD8 + T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that downregulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two subsets. Stem-like Tcf-1 + CD8 + T cells initially differentiated into a transitory population of CD101 À Tim3 + cells that later converted into CD101 + Tim3 + cells. Recently generated CD101 À Tim3 + cells proliferated in vivo, contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B. PD-1 pathway blockade increased the numbers of CD101 À Tim3 + CD8 + T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy.

Proteins that bind both DNA and RNA epitomize the ability to perform multiple functions by a single gene product. Such DNA- and RNA-binding proteins (DRBPs) regulate many cellular processes, including transcription, translation, gene silencing, microRNA biogenesis and telomere maintenance. Proteins that bind RNA were typically considered as functionally distinct from proteins that bind DNA and studied independently. This practice is becoming outdated, in part due to the discovery of long non-coding RNAs (lncRNAs) that target DNA-binding proteins. DRBPs have unique functional characteristics that stem from their specific structural attributes; these have evolved early in evolution and are widely conserved.

The nuclear receptor Liver Receptor Homolog-1, LRH-1, plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for treatment of diabetes and hepatic diseases. LRH-1 is known to bind phospholipids (PLs) but the role of PLs in controlling LRH-1 activation remains highly debated. Here we describe the structure of both apo LRH-1 and the protein in complex with the antidiabetic dilauroylphosphatidylcholine (DLPC). Our studies show that DLPC binding is a novel dynamic process that alters coregulator selectivity and that the lipid-free receptor interacts with widely expressed corepressors. These observations greatly enhance our understating of LRH-1 regulation and highlight its importance as a novel therapeutic target for controlling diabetes.

A newly discovered negative glucocorticoid response element (nGRE) mediates DNA-dependent transrepression by the glucocorticoid receptor (GR) across the genome and plays a major role in immunosuppressive therapy. The nGRE differs dramatically from activating response elements and the mechanism driving GR binding and transrepression is unknown. To unravel the mechanism of nGRE-mediated transrepression by the glucocorticoid receptor, we characterize the interaction between GR and a nGRE in the thymic stromal lymphopoetin (TSLP) promoter. We show using structural and mechanistic approaches that nGRE binding represents a new mode of sequence recognition by human GR and that nGREs prevent receptor dimerization through a unique GR-binding orientation and strong negative cooperativity, ensuring the presence of monomeric GR at repressive elements.

The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection-or vaccine-induced antibodies. We compared antibody binding and live virus neutralization of sera from naturally infected and Moderna-vaccinated individuals against two SARS-CoV-2 variants: B.1 containing the spike mutation D614G and the emerging B.1.351 variant containing additional spike mutations and deletions. Sera from acutely infected and convalescent COVID-19 patients exhibited a 3-fold reduction in binding antibody titers to the B.1.351 variant receptor-binding domain of the spike protein and a 3.5-fold reduction in neutralizing antibody titers against SARS-CoV-2 B.1.351 variant compared to the B.1 variant. Similar results were seen with sera from Moderna-vaccinated individuals. Despite reduced antibody titers against the B.1.351 variant, sera from infected and vaccinated individuals containing polyclonal antibodies to the spike protein could still neutralize SARS-CoV-2 B.1.351, suggesting that protective humoral immunity may be retained against this variant.