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Differences in host ACE2 genes may affect the host range of SARS-CoV-2-related coronaviruses (SC2r-CoVs) and further determine the tropism of host ACE2 for the infection receptor. However, the factor(s) responsible for determining the host tropism of SC2r-CoVs, which may in part be determined by the tropism of host ACE2 usage, remains unclear. Here, we use the pseudoviruses with the spike proteins of two Laotian SC2r-CoVs, BANAL-20-236 and BANAL-20-52, and the cells expressing ACE2 proteins of eight different Rhinolophus bat species, and show that these two spikes have different tropisms for Rhinolophus bat ACE2. Through structural analysis and cell culture experiments, we demonstrate that this tropism is determined by residue 493 of the spike and residues 31 and 35 of ACE2. Our results suggest that SC2r-CoVs exhibit differential ACE2 tropism, which may be driven by adaptation to different Rhinolophus bat ACE2 proteins.

The emergence of the Omicron variant of SARS-CoV-2 is an urgent global health concern1. In this study, our statistical modelling suggests that Omicron has spread more rapidly than the Delta variant in several countries including South Africa. Cell culture experiments showed Omicron to be less fusogenic than Delta and than an ancestral strain of SARS-CoV-2. Although the spike (S) protein of Delta is efficiently cleaved into two subunits, which facilitates cell–cell fusion2,3, the Omicron S protein was less efficiently cleaved compared to the S proteins of Delta and ancestral SARS-CoV-2. Furthermore, in a hamster model, Omicron showed decreased lung infectivity and was less pathogenic compared to Delta and ancestral SARS-CoV-2. Our multiscale investigations reveal the virological characteristics of Omicron, including rapid growth in the human population, lower fusogenicity and attenuated pathogenicity.

The SARS-CoV-2 B.1.617 variant emerged in the Indian state of Maharashtra in late 2020. There have been fears that 2 key mutations seen in the receptor-binding domain, L452R and E484Q, would have additive effects on evasion of neutralizing antibodies. We report that spike bearing L452R and E484Q confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies following either first or second dose. The effect is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. These data demonstrate reduced sensitivity to vaccine-elicited neutralizing antibodies by L452R and E484Q but lack of synergistic loss of sensitivity.

Neutralization of the SARS-CoV-2 Mu Variant The mu variant of SARS-CoV-2 was 10.6 times as resistant to neutralization by serum samples obtained from persons who had recovered from Covid-19 as the ...

Soon after the emergence and global spread of the SARS-CoV-2 Omicron lineage BA.1, another Omicron lineage, BA.2, began outcompeting BA.1. The results of statistical analysis showed that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralization experiments revealed that immunity induced by COVID vaccines widely administered to human populations is not effective against BA.2, similar to BA.1, and that the antigenicity of BA.2 is notably different from that of BA.1. Cell culture experiments showed that the BA.2 spike confers higher replication efficacy in human nasal epithelial cells and is more efficient in mediating syncytia formation than the BA.1 spike. Furthermore, infection experiments using hamsters indicated that the BA.2 spike-bearing virus is more pathogenic than the BA.1 spike-bearing virus. Altogether, the results of our multiscale investigations suggest that the risk of BA.2 to global health is potentially higher than that of BA.1.

On August 30, 2021, the WHO classified the SARS-CoV-2 Mu variant (B.1.621 lineage) as a new variant of interest. The WHO defines "comparative assessment of virus characteristics and public health risks" as primary action in response to the emergence of new SARS-CoV-2 variants (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Here, we demonstrate that the Mu variant is highly resistant to sera from COVID-19 convalescent and BNT162b2-vaccinated individuals. Direct comparison of different SARS-CoV-2 spike proteins revealed that Mu spike is more resistant to serum-mediated neutralization than all other currently recognized variants of interest (VOI) and concern (VOC). This includes the Beta variant (B.1.351) that has been suggested to represent the most resistant variant to convalescent and vaccinated sera to date (e.g., Collier et al, Nature, 2021; Wang et al, Nature, 2021). Since breakthrough infection by newly emerging variants is a major concern during the current COVID-19 pandemic (Bergwerk et al., NEJM, 2021), we believe that our findings are of significant public health interest. Our results will help to better assess the risk posed by the Mu variant for vaccinated, previously infected and naive populations.

After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of the BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in the BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2.

SummarySARS-CoV-2 Lambda, a new variant of interest, is now spreading in some South American countries; however, its virological features and evolutionary trait remain unknown. Here we reveal that the spike protein of the Lambda variant is more infectious and it is attributed to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino-acid deletion mutation in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the insertion of the RSYLTPGD246-253N mutation is closely associated with the massive infection spread of the Lambda variant in South America.HighlightsLambda S is highly infectious and T76I and L452Q are responsible for this propertyLambda S is more susceptible to an infection-enhancing antibodyRSYLTPGD246-253N, L452Q and F490S confer resistance to antiviral immunityGraphical Abstract

SummaryDuring the current SARS-CoV-2 pandemic, a variety of mutations have been accumulated in the viral genome, and at least five variants of concerns (VOCs) have been considered as the hazardous SARS-CoV-2 variants to the human society. The newly emerging VOC, the B.1.617.2 lineage (delta variant), closely associates with a huge COVID-19 surge in India in Spring 2021. However, its virological property remains unclear. Here, we show that the B.1.617 variants are highly fusogenic and form prominent syncytia. Bioinformatic analyses reveal that the P681R mutation in the spike protein is highly conserved in this lineage. Although the P681R mutation decreases viral infectivity, this mutation confers the neutralizing antibody resistance. Notably, we demonstrate that the P681R mutation facilitates the furin-mediated spike cleavage and enhances and accelerates cell-cell fusion. Our data suggest that the P681R mutation is a hallmark characterizing the virological phenotype of this newest VOC, which may associate with viral pathogenicity.HighlightsP681R mutation is highly conserved in the B.1.617 lineagesP681R mutation accelerates and enhances SARS-CoV-2 S-mediated fusionPromotion of viral fusion by P681R mutation is augmented by TMPRSS2

As the hosts of lentiviruses, almost 40 species of felids (family Felidae) are distributed around the world, and more than 20 feline species test positive for feline immunodeficiency virus (FIV), a lineage of lentiviruses. These observations suggest that FIVs globally infected a variety of feline species through multiple cross-species transmission events during a million-year history. Cellular restriction factors potentially inhibit lentiviral replication and limit cross-species lentiviral transmission, and cellular APOBEC3 deaminases are known as a potent restriction factor. In contrast, lentiviruses have evolutionary-acquired viral infectivity factor (Vif) to neutralize the APOBEC3-mediated antiviral effect. Because the APOBEC3-Vif interaction is strictly specific for viruses and their hosts, a comprehensive investigation focusing on Vif-APOBEC3 interplay can provide clues that will elucidate the roles of this virus-host interplay on cross-species transmission of lentiviruses. Here, we performed a comprehensive investigation with 144 patterns of a round robin test using 18 feline APOBEC3Z3 genes, an antiviral APOBEC3 gene in felid, and 8 FIV Vifs and derived a matrix showing the interplay between feline APOBEC3Z3 and FIV Vif. We particularly focused on the interplay between the APOBEC3Z3 of three felids (domestic cat, ocelot, and Asian golden cat) and an FIV Vif (strain Petaluma), and revealed that residues 65 and 66 of the APOBEC3Z3 protein of multiple felids are responsible for the counteraction triggered by FIV Petaluma Vif. Altogether, our findings can be a clue to elucidate not only the scenarios of the cross-species transmissions of FIVs in felids but also the evolutionary interaction between mammals and lentiviruses. IMPORTANCE Most of the emergences of new virus infections originate from the cross-species transmission of viruses. The fact that some virus infections are strictly specific for the host species indicates that certain “species barriers” in the hosts restrict cross-species jump of viruses, while viruses have evolutionary acquired their own “arms” to overcome/antagonize/neutralize these hurdles. Therefore, understanding of the molecular mechanism leading to successful cross-species viral transmission is crucial for considering the menus of the emergence of novel pathogenic viruses. In the field of retrovirology, APOBEC3-Vif interaction is a well-studied example of the battles between hosts and viruses. Here, we determined the sequences of 11 novel feline APOBEC3Z3 genes and demonstrated that all 18 different feline APOBEC3Z3 proteins tested exhibit anti-feline immunodeficiency virus (FIV) activity. Our comprehensive investigation focusing on the interplay between feline APOBEC3 and FIV Vif can be a clue to elucidate the scenarios of the cross-species transmissions of FIVs in felids.

SummaryDuring the current SARS-CoV-2 pandemic that is devastating the modern societies worldwide, many variants that naturally acquire multiple mutations have emerged. Emerging mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has recently been investigated, that to human leukocyte antigen (HLA)-restricted cellular immunity remains unaddressed. Here we demonstrate that two recently emerging mutants in the receptor binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429) and Y453F (in B.1.298), can escape from the HLA-24-restricted cellular immunity. These mutations reinforce the affinity to viral receptor ACE2, and notably, the L452R mutation increases protein stability, viral infectivity, and potentially promotes viral replication. Our data suggest that the HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes, and the escape from cellular immunity can be a further threat of the SARS-CoV-2 pandemic.Graphical Abstract

The presence of an ORF6 gene distinguishes sarbecoviruses such as SARS-CoV and SARS-CoV-2 from other betacoronaviruses. Here, we show that ORF6 inhibits the induction of innate immune signaling including upregulation of type I IFN upon viral infection, as well as type I and III IFN signaling. Intriguingly, ORF6 proteins from SARS-CoV-2 lineages are more efficient antagonists of innate immunity than their orthologs from SARS-CoV lineages. Mutational analyses identified residues E46 and Q56 as important determinants of the antagonistic activity of SARS-CoV-2 ORF6. Moreover, we show that the anti-innate immune activity of ORF6 depends on its C-terminal region and ORF6 inhibits the nuclear translocation of IRF3. Finally, we identify naturally occurring frameshift/nonsense mutations that result in an inactivating truncation of ORF6 in approximately 0.2% of SARS-CoV-2 isolates. Altogether, our findings suggest that ORF6 contributes to the poor IFN activation observed in COVID-19 patients., Graphical Abstract, Kimura et al. show that the coronaviral ORF6 gene encodes an interferon antagonist and is unique to sarbecoviruses including SARS-CoV-2. Although the antagonistic activity of SARS-CoV-2 ORF6 depends on its C-terminal region, approximately 0.2% of all SARS-CoV-2 genomes isolated during the current COVID-19 pandemic harbor premature stop codons in ORF6.

The APOBEC3 deaminases are potent inhibitors of virus replication and barriers to cross-species transmission. For simian immunodeficiency virus (SIV) to transmit to a new primate host, as happened multiple times to seed the ongoing HIV-1 epidemic, the viral infectivity factor (Vif) must be capable of neutralizing the APOBEC3 enzymes of the new host. Although much is known about current interactions of HIV-1 Vif and human APOBEC3s, the evolutionary changes in SIV Vif required for transmission from chimpanzees to gorillas and ultimately to humans are poorly understood. Here, we demonstrate that gorilla APOBEC3G is a factor with the potential to hamper SIV transmission from chimpanzees to gorillas. Gain-of-function experiments using SIVcpzPtt Vif revealed that this barrier could be overcome by a single Vif acidic amino acid substitution (M16E). Moreover, degradation of gorilla APOBEC3F is induced by Vif through a mechanism that is distinct from that of human APOBEC3F. Thus, our findings identify virus adaptations in gorillas that preceded and may have facilitated transmission to humans., Author summary Humans are exposed continuously to a menace of viral diseases such as Ebola virus and coronaviruses. Such emerging/re-emerging viral outbreaks can be triggered by cross-species viral transmission from wild animals to humans. HIV-1, the causative agent of AIDS, most likely originated from related precursors found in chimpanzees and gorillas (SIVcpzPtt or SIVgor), approximately 100 years ago. Additionally, SIVgor most likely emerged through the cross-species jump of SIVcpzPtt from chimpanzees to gorillas. However, it remains unclear how primate lentiviruses successfully transmitted among different species. To limit cross-species lentiviral transmission, cellular "restriction factors", including tetherin, SAMHD1, and APOBEC3 proteins potentially inhibit lentiviral replication. In contrast, primate lentiviruses have evolutionary acquired their own "arms" to antagonize the antiviral effect of restriction factors. Here we show that gorilla APOBEC3G potentially plays a role in inhibiting SIVcpzPtt replication. To our knowledge, this is the first report suggesting that a great ape APOBEC3 protein can potentially restrict the cross-species transmission of great ape lentiviruses and how lentiviruses overcame this species barrier.

One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays reveal that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identify a natural variant in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect COVID-19 pathogenesis., Graphical Abstract, Highlights • ORF3b proteins of SARS-CoV-2 and related animal viruses are IFN antagonists • SARS-CoV-2 ORF3b suppresses IFN more efficiently than its SARS-CoV ortholog • The anti-IFN activity of ORF3b depends on the length of its C terminus • An ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases, COVID-19 pathogenesis is characterized by impaired IFN responses. Konno et al. identify ORF3b proteins of SARS-CoV-2 and related animal viruses as IFN antagonists. Their anti-IFN activity depends on the C-terminal length, and a natural ORF3b variant with increased IFN-suppressive activity was isolated from two severe COVID-19 cases.

One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in itsORF3bgene. Here, we show that SARS-CoV-2ORF3bis a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays revealed that SARS-CoV-2-related viruses from bats and pangolins also encode truncatedORF3bgene products with strong anti-interferon activity. Furthermore, analyses of more than 15,000 SARS-CoV-2 sequences identified a natural variant, in which a longerORF3breading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients, but also describe a possibility of the emergence of natural SARS-CoV-2 quasispecies with extendedORF3bthat may exacerbate COVID-19 symptoms.HighlightsORF3b of SARS-CoV-2 and related bat and pangolin viruses is a potent IFN antagonistSARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV orthologThe anti-IFN activity of ORF3b depends on the length of its C-terminusAn ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases

Numerous genes are aberrantly expressed in tumors, but its cause remains unclear. Human endogenous retroviruses (HERVs) are repetitive elements in the genome and have a potential to work as enhancers modulating adjacent genes. Since numerous HERVs are activated epigenetically in tumors, their activation could alter gene expression globally in tumors and change the tumor characteristics. Here, we show the HERV activation in tumors is associated with the upregulation of hundreds of transcriptional suppressors, Krüppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by the adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Many KZFPs could suppress the progressive characteristics of cancer cells by downregulating genes related to the cell cycle and cell-matrix adhesion. Our data suggest that HERV activation in tumors drives the concerted expression of KZFP genes for tumor suppression.

The presence of an ORF6 gene distinguishes Sarbecoviruses such as SARS-CoV and SARS-CoV-2 from other Betacoronaviruses. Here, we show that ORF6 inhibits the induction of type I IFN upon viral infection, as well as IFN types I and III signaling. Intriguingly, the anti-IFN activity of ORF6 proteins of SARS-CoV-2 lineages is more potent than that of SARS-CoV lineages. Mutational analyses identified residues E46 and Q56 as determinants of the potent IFN-antagonistic activity of SARS-CoV-2 ORF6. Moreover, we show that ORF6 binds to RAE1 and NUP98 via its C-terminus, thereby inhibiting the nuclear export of IFNB1 mRNA. Finally, we identify natural occurring frameshift/nonsense mutations that result in an inactivating truncation of ORF6 in approximately 0.2% of SARS-CoV-2 isolates. Altogether, our findings suggest that ORF6 contributes to the poor IFN activation observed in COVID-19 patients. Furthermore, the emergence of SARS-CoV-2 variants without functional ORF6 may contribute to the attenuation of viral pathogenicity. Funding: This study was supported in part by AMED Research Program on Emerging and Re-emerging Infectious Diseases 20fk0108146 (to K.S.), 19fk0108171 (to S.N. and K.S.) and 20fk0108270 (to K.S.); AMED Research Program on HIV/AIDS 19fk0410019 (to K.S.) and 20fk0410014 (to K.S.); JST J-RAPID JPMJJR2007 (to K.S.); KAKENHI Grant-in-Aid for Scientific Research B 18H02662 (to K.S.), KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas 16H06429 (to S.N. and K.S.), 16K21723 (to S.N. and K.S.), 17H05823 (to S.N.), 17H05813 (to K.S.), 19H04843 (to S.N.) and 19H04826 (to K.S.), and Fund for the Promotion of Joint International Research (Fostering Joint International Research) 18KK0447 (to K.S.); JSPS Research Fellow DC1 19J20488 (to I.K.) and DC1 19J22914 (to Y.K.); ONO Medical Research Foundation (to K.S.); Ichiro Kanehara Foundation (to K.S.); Lotte Foundation (to K.S.); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.S.); Daiichi Sankyo Foundation of Life Science (to K.S.); Sumitomo Foundation (to K.S.); Uehara Foundation (to K.S.); Takeda Science Foundation (to K.S.); JSPS Core-to-Core program (A. Advanced Research Networks) (to K.S.); the Canon Foundation in Europe (to. D.S. and K.S.); a COVID19 Research Grant of the Federal Ministry of Education and Research (MWK) Baden-Wurttemberg (to. D.S.); 2020 Tokai University School of Medicine Research Aid (to S.N.); and International Joint Research Project of the Institute of Medical Science, the University of Tokyo 2020-K3003 (to D.S. and K.S.). Conflict of Interest: The authors declare that no competing interests exist.

Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity., Graphical abstract, Motozono and G2P-Japan Consortium et al. show that the emerging mutations L452R and Y453F in the SARS-CoV-2 spike receptor-binding motif evade HLA-A24-restricted cellular immunity. L452R increases spike stability, viral infectivity, and viral fusogenicity, thereby promoting viral replication. These data suggest that HLA-restricted cellular immunity potentially affects evolution of viral phenotypes.

SummaryRestriction factors including APOBEC3 family proteins have the potential prevent cross-species lentivirus transmissions. Such events as well as ensuing pathogenesis require the viral Vif protein to overcome/neutralize/degrade the APOBEC3 enzymes of the new host species. Previous investigations have focused on the molecular interaction between human APOBEC3s and HIV-1 Vif. However, the evolutionary interplay between lentiviruses and great ape (including human, chimpanzee and gorilla) APOBEC3s has not been fully investigated. Here we demonstrate that gorilla APOBEC3G plays a pivotal role in restricting lentiviral transmission from chimpanzee to gorilla. We also reveal that a sole amino acid substitution in Vif is sufficient to overcome the gorilla APOBEC3G-mediated species barrier. Moreover, the antiviral effects of gorilla APOBEC3D and APOBEC3F are considerably weaker than those of human and chimpanzee counterparts, which can result in the skewed evolution of great ape lentiviruses leading to HIV-1.HighlightsSIVcpz requires M16E mutation in Vif to counteract gorilla A3GAcidic residue at position 16 of Vif is crucial to counteract gorilla A3GGorilla A3D and A3F poorly suppress lentiviral infectivitySIVgor and related HIV-1s counteract human A3D and A3F independently of DRMR motif

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) is a mammalian protein that restricts lentiviral replication. Various polymorphisms of mammalian APOBEC3 genes have been observed in humans, Old World monkeys and domestic cats; however, the genetic diversity of APOBEC3 genes in other mammals remains unaddressed. Here we identify a novel haplotype of the feline APOBEC3Z3 gene, an APOBEC3 gene that restricts feline immunodeficiency virus (FIV) replication, in a Eurasian lynx (Lynx lynx). Compared to the previously identified lynx APOBEC3Z3 (haplotype I), the new sequence (haplotype II) harbours two amino acid deletions (Q16 and H17) and a nonsynonymous substitution (R68Q). Interestingly, lynx APOBEC3Z3 haplotype II does not suppress FIV infectivity, whereas haplotype I does. Mutagenesis experiments further revealed that deleting two amino acids (Q16 and H17) causes anti-FIV activity loss. This report demonstrates that a naturally occurring APOBEC3 variant loses anti-lentiviral activity through the deletion of two amino acid residues.

Background The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) gene family appears only in mammalian genomes. Some A3 proteins can be incorporated into progeny virions and inhibit lentiviral replication. In turn, the lentiviral viral infectivity factor (Vif) counteracts the A3-mediated antiviral effect by degrading A3 proteins. Recent investigations have suggested that lentiviral vif genes evolved to combat mammalian APOBEC3 proteins, and have further proposed that the Vif-A3 interaction may help determine the co-evolutionary history of cross-species lentiviral transmission in mammals. Results Here we address the co-evolutionary relationship between two New World felids, the puma (Puma concolor) and the bobcat (Lynx rufus), and their lentiviruses, which are designated puma lentiviruses (PLVs). We demonstrate that PLV-A Vif counteracts the antiviral action of APOBEC3Z3 (A3Z3) of both puma and bobcat, whereas PLV-B Vif counteracts only puma A3Z3. The species specificity of PLV-B Vif is irrespective of the phylogenic relationships of feline species in the genera Puma, Lynx and Acinonyx. We reveal that the amino acid at position 178 in the puma and bobcat A3Z3 is exposed on the protein surface and determines the sensitivity to PLV-B Vif-mediated degradation. Moreover, although both the puma and bobcat A3Z3 genes are polymorphic, their sensitivity/resistance to PLV Vif-mediated degradation is conserved. Conclusions To the best of our knowledge, this is the first study suggesting that the host A3 protein potently controls inter-genus lentiviral transmission. Our findings provide the first evidence suggesting that the co-evolutionary arms race between lentiviruses and mammals has occurred in the New World. Electronic supplementary material The online version of this article (10.1186/s12977-018-0414-5) contains supplementary material, which is available to authorized users.

Four phototropin genes (PHOTA1, PHOTA2, PHOTB1, PHOTB2) have been isolated in the moss Physcomitrella patens. These genes encode phototropins that mediate blue-light–induced chloroplast movement. However, the individual functions of these phototropins, including the function of mediating blue-light–induced phototropism, remain unclear. To elucidate the individual functions of P. patens phototropins, each of these phototropin genes was expressed in a phototropin-deficient mutant of Arabidopsis (phot1-5 phot2-1). In addition, fluorescence of GFP fused to these phototropins was examined to determine the subcellular localization of each phototropin. Our results demonstrate that all four P. patens phototropins mediate blue-light–induced phototropism and are associated with the plasma membrane in Arabidopsis. Abbreviations GFP: green fluorescent protein; Pp_phot: Physcomitrella patens phototropin

Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, originated from simian immunodeficiency virus from chimpanzees (SIVcpz), the precursor of the human virus, approximately 100 years ago. This indicates that HIV-1 has emerged through the cross-species transmission of SIVcpz from chimpanzees to humans. However, it remains unclear how SIVcpz has evolved into pandemic HIV-1 in humans. To address this question, we inoculated three SIVcpz strains (MB897, EK505, and MT145), four pandemic HIV-1 strains (NL4-3, NLCSFV3, JRCSF, and AD8), and two nonpandemic HIV-1 strains (YBF30 and DJO0131). Humanized mice infected with SIVcpz strain MB897, a virus phylogenetically similar to pandemic HIV-1, exhibited a peak viral load comparable to that of mice infected with pandemic HIV-1, while peak viral loads of mice infected with SIVcpz strain EK505 or MT145 as well as nonpandemic HIV-1 strains were significantly lower. These results suggest that SIVcpz strain MB897 is preadapted to humans, unlike the other SIVcpz strains. Moreover, viral RNA sequencing of MB897-infected humanized mice identified a nonsynonymous mutation in env , a G413R substitution in gp120. The infectivity of the gp120 G413R mutant of MB897 was significantly higher than that of parental MB897. Furthermore, we demonstrated that the gp120 G413R mutant of MB897 augments the capacity for viral replication in both in vitro cell cultures and humanized mice. Taken together, this is the first experimental investigation to use an animal model to demonstrate a gain-of-function evolution of SIVcpz into pandemic HIV-1. IMPORTANCE From the mid-20th century, humans have been exposed to the menace of infectious viral diseases, such as severe acute respiratory syndrome coronavirus, Ebola virus, and Zika virus. These outbreaks of emerging/reemerging viruses can be triggered by cross-species viral transmission from wild animals to humans, or zoonoses. HIV-1, the causative agent of AIDS, emerged by the cross-species transmission of SIVcpz, the HIV-1 precursor in chimpanzees, around 100 years ago. However, the process by which SIVcpz evolved to become HIV-1 in humans remains unclear. Here, by using a hematopoietic stem cell-transplanted humanized-mouse model, we experimentally recapitulate the evolutionary process of SIVcpz to become HIV-1. We provide evidence suggesting that a strain of SIVcpz, MB897, preadapted to infect humans over other SIVcpz strains. We further demonstrate a gain-of-function evolution of SIVcpz in infected humanized mice. Our study reveals that pandemic HIV-1 has emerged through at least two steps: preadaptation and subsequent gain-of-function mutations.

In the fern Adiantum capillus-veneris, the phototropic response of the protonemal cells is induced by blue light and partially inhibited by subsequent irradiation with far-red light. This observation strongly suggests the existence of a phytochrome that mediates this blue/far-red reversible response; however, the phytochrome responsible for this response has not been identified. PHY3/NEO1, one of the three phytochrome genes identified in Adiantum, encodes a chimeric photoreceptor composed of both a phytochrome and a phototropin domain. It was demonstrated that phy3 mediates the red light-dependent phototropic response of Adiantum, and that phy3 potentially functions as a phototropin. These findings suggest that phy3 is the phytochrome that mediates the blue/far-red response in Adiantum protonemata. In the present study, we expressed Adiantum phy3 in a phot1 phot2 phototropin-deficient Arabidopsis line, and investigated the ability of phy3 to induce phototropic responses under various light conditions. Blue light irradiation clearly induced a phototropic response in the phy3-expressing transgenic seedlings, and this effect was fully inhibited by simultaneous irradiation with far-red light. In addition, experiments using amino acid-substituted phy3 indicated that FMN-cysteinyl adduct formation in the light, oxygen, voltage (LOV) domain was not necessary for the induction of blue light-dependent phototropism by phy3. We thus demonstrate that phy3 is the phytochrome that mediates the blue/far-red reversible phototropic response in Adiantum. Furthermore, our results imply that phy3 can function as a phototropin, but that it acts principally as a phytochrome that mediates both the red/far-red and blue/far-red light responses.

The aim of this study was to review the role of MRI in the assessment of heart neoplasm, 25 cases with heart neoplasm (10 myxoma, 6 rhabdomyoma, 5 angiosarcoma, 2 mesothelioma, 1 lymphoma, and 1 fibroma) were examined with MRI and echocardiography. Multislice T1- and T2-weighted spin-echo images and static gradient-echo images were taken in appropriate directions with electrocardiogram gating. Gadolinium enhancement was performed in 21 cases. Transthoracic echocardiography was performed in all cases. Except for the 5 patients with rhabdomyoma, the pathological diagnosis was obtained. MRI proved to be useful for tissue characterization of myxoma, angiosarcoma, mesothelioma, and fibroma in cases with tuberous sclerosis. MRI also proved to be useful for detection of the tumor, depiction of contour, relation with other cardiac structures, in cases with myxoma, angiosarcoma, mesothelioma, lymphoma, and fibroma. In the differential diagnosis, MRI provided important information in cases with myxoma, rhabdomyoma, angiosarcoma, and fibroma. In cases with tumors expanding into the mediastinum, such as mesothelioma and fibroma in this report, MRI was useful in determining the location and border. In cases with tumors adjacent to pericardium, MRI was useful in detecting pericardial invasion. Gadolinium enhancement added useful information in cases with myxoma, rhabdomyoma, angiosarcoma, and mesothelioma. The role of MRI with and without Gd enhancement differs somewhat in individual types of heart neoplasm, and adaptation must be considered in each kind of neoplasm. On the other hand, MRI is an essential examination in all cases with a cardiac mass, which has not been diagnosed, since it may provide useful information for the differential diagnosis.

Determination of electron density distribution in the plasmasphere has been attempted using wave normal directions and delay time of Omega signals, and in-situ electron density observed on the Akebono satellite /1/, /2/. The present study is based on the assumption that the plasma model is represented by a diffusive equilibrium (DE) model with a vertical temperature gradient, and the electron density at a reference altitude (1000km) being dependent on the L value. The parameters related to these models were determined by non-linear least square fitting of the in-situ electron density, the wave normal direction and delay time of Omega signals observed by Akebono. Relative concentrations of ion constituents of H + , He + , O + at the reference altitude are determined by fitting as either L independent or L dependent. Connecting the global plasmaspheric density model with IRI in the ionospheric altitude is also tried.

The main scientific objectives of GEOTAIL Plasma Wave Instrument (PWI) are to investigate the characteristic features of wave phenomena which are generated by a variety of plasma processes occurring within the Earth's magnetosphere. The PWI measures plasma waves in the frequency range from 5.62 Hz to 800 kHz for the electric components and from 5.62 Hz to 12.5 kHz for the magnetic components. The instrument is composed of three distinct sets of receivers: (1) the Sweep Frequency Analyzer (SFA), (2) the Multi-Channel Analyzer (MCA) and (3) the Wave-Form Capture (WFC). The first two receivers are dedicated to wave spectra measurement, while the last one is used to capture actual wave forms of two electric and three magnetic field components for the measured plasma wave emissions. The present paper describes the PWI subsystems and their functions. We also report some results from initial observations made during the traversal of the geomagnetic tail and a skimming pass of the dayside magnetopause. These observational results are useful in providing a good overview of the PWI capabilities as well as elucidating the characteristic features of the wave spectra in these regions.

[1] The mechanism for formation of the Earth's radiation belts has been an outstanding issue for utilization of the geospace environment. We present a magnetic storm recovery phase that occurred from 10 to 19 October 1990, in which there is a clear correlation among continuous injection of hot electrons, generation of chorus, geomagnetic AE activity (all for ∼8 days) and the acceleration of electrons to relativistic energies. We propose a following scenario to explain the observations: the continuous injection of hot electrons associated with the continuous AE activity. The hot electrons with Tperp/Tpara > 1 temperature anisotropies excite whistler-mode chorus waves. The chorus interacts with energetic electrons accelerating them to MeV energies forming a flux of “killer electrons” in the outer radiation belt.

Triaxial search coil measurements of ELF waves in the frequency range below 50 Hz have been made with the polar orbiting satellite, EXOS-D (AKEBONO), in the plasmasphere. Single component electric field measurements were also obtained along with measurements of the magnetic field. A survey of realtime telemetry data received for the period of March - October, 1989 reveals the existence of variety of plasma waves in the frequency range around ion gyrofrequencies near the equatorial region of the plasmasphere. Electromagnetic noises with a multi-band structure were observed mostly above the local helium gyro-frequency (f{sub He{sup +}}), in the region of L values of 1.5{approximately}2.5. Multi-band ELF emission are common in the daytime and were observed in 49 out of 250 orbits examined here. Another type of electromagnetic ELF waves with a broad-band spectrum are also observed in the frequency range above the helium gyrofrequency in 10 orbits. Both types of wave spectra extend above the local proton gyrofrequency, but no absorption effect is observed at the local proton gyrofrequency. The electric field measurements clearly show spectral cut-off for both of these two types of waves near f {equals} (1.3{approximately}2.5) f{sub He{sup +}}. On the other hand, several spectral bands sometimesmore » appear between the helium and oxygen gyrofrequencies in magnetic field components of multi-band emissions.« less

The loss of haemolytic activity in sera during storage at low temperature (the cold activation of complement) was observed in 136 of 184 (74%) patients with chronic liver disease associated with hepatitis C virus (HCV) infection. This was more frequent than observed in the three of 40 (8%) patients with chronic hepatitis B (P < 0.001) or none in 43 normal controls (P < 0.001). Of 103 patients with chronic hepatitis C who had completed a full course of recombinant interferon-alpha 2a therapy (total dose: 516 x 10(6) U), 40 responded completely and 21 responded partially, as judged by the normalization or decrease of alanine aminotransferase levels 6 months after the completion of therapy; 42 patients did not respond at all. The cold activation of complement persisted in five (13%) complete responders, less often than in 33 (79%) non-responders (P < 0.001). At the completion of interferon therapy, the cold activation of complement persisted in 12 of 54 patients despite the normalization of alanine aminotransferase. Spontaneous exacerbation of hepatitis occurred in seven of 12 (58%) patients with cold activation, which was more frequent than in the four of 42 patients (10%) without it (P < 0.01). The cold activation of complement disappeared along with the loss of HCV-RNA in five of six responders during the 6 month period after the completion of interferon therapy, while both cold activation and HCV-RNA persisted in all eight non-responders. These results indicate that the cold activation of complement may be useful as a marker of HCV viraemia for monitoring the response to interferon in patients with HCV infection.

Determination of electron density distribution in the plasmasphere has been attempted using wave normal directions and delay time of Omega signals observed on the Akebono satellite as well as the electron density along the satellite trajectory.

We describe the first midlatitude F-region VHF radar observations of small-scale Field-Aligned Irregularities (FAI). Looking northward at ∼ 34° elevation the locus of perpendicularity with the geomagnetic field B remains inside the radar beam, such that FAI can be observed, at radar ranges from 350 to over 800 km or F region altitudes from 200 to 500 km, approximately. The preliminary results presented here show the large-scale (> 20 km) configuration of small-scale (322.6 cm, half the radar wavelength) F-region irregularities as well as typical spectral results. Our most important finding is that at least on some occasions there is a quasi-periodic variation in time and space, on scales of approximately 12 minutes and 50 km, of the observed plasma instabilities.