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Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections. We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests. more...

The primary structures of four bovine clathrin light chains have been determined. Light chains LCaand LCbare homologous proteins encoded by different genes. In the brain the messenger RNA from these genes undergoes differential splicing to yield proteins having centrally inserted brain-specific sequences. A potentially α-helical region of the clathrin light chains shows homology with intermediate filament proteins. more...

Major histocompatibility complex (MHC) glycoproteins bind processed fragments of proteins and present them to the receptors of T lymphocytes1,2. The extraordinary polymorphism of class I MHC molecules in man (HLA-A, B and C) and mouse (H–2 K, D and L) poses many questions concerning their diversification and evolution. Comparison of allelic sequences within a species suggests diversity is generated by the assortment of point mutations into varied combinations by mechanisms of recombination and gene conversion3–5. We have now compared class I MHC alleles in two closely related species: humans (Homo sapiens) and chimpanzees (Pan troglodytes). Chimpanzee homologues of HLA-A, HLA-B and a non-classical gene have been identified. No features distinguishing human and chimpanzee alleles could be found. Individual HLA-A or B alleles are more closely related to individual chimpanzee alleles than to other HLA-A or B alleles. These results show that a considerable proportion of contemporary HLA-A and B polymorphism existed before divergence of the chimpanzee and human lines6,7. The stability of the polymorphism indicates that hyper-mutational mechanisms are not necessary to account for HLA-A, B and C diversity. more...

Class I major histocompatibility complex (MHC) molecules function in the recognition of antigens by cytotoxic T lymphocytes (CTL)1,2. Although this biological role is firmly established and much has been learnt about their structure and polymorphic variation3–6, little is known of the regions of class I molecules that are involved in functional interactions with components of the T-cell surface. Here we show that peptides derived from residues 98–113 of the α2 domain of HLA–A2 specifically inhibit the recognition of target cells by many HLA–A2-specific CTL. In addition to identifying a region that is probably involved in binding the T-cell receptor these results raise the possibility that alloreactive CTL may recognize degraded fragments of class I histocompatibility antigens. more...

Letter to the Editor

The class-I and class-II molecules encoded by the major histocompatibility complex (MHC) are homologous proteins which allow cytotoxic and helper T cells to recognize foreign antigens1,2. Recent studies have shown that the form of the antigen recognized by T cells is generally not a native protein but rather a short peptide fragment3,4and that class-II molecules specifically bind antigenic peptides5,6. Furthermore, the three-dimensional structure of the human MHC class-I molecule, HLA-A2, is consistent with a peptide-binding function for MHC class-I molecules7,8. An outstanding question concerns the molecular nature and involvement of MHC-bound peptides in antigens recognized by alloreactive T cells. In this study the effects of peptides derived from HLA-A2 on cytolysis of alloreactive cytotoxic T cells (Tc) cells are presented. Peptides can inhibit lysis by binding to the T cell or sensitize to lysis by binding an HLA-A2-related class-I molecule (HLA-Aw69) on the target cell. Thus, allospecific Tccells can recognize HLA-derived peptides in the context of the MHC. more...

CD4 and CDS are cell-surface glycoproteins expressed on mutually exclusive subsets of peripheral T cells. T cells that express CD4 have T-cell antigen receptors that are specific for antigens presented by major histocompatibility complex class II molecules, whereas T cells that express CDS have receptors specific for antigens presented by MHC class I molecules (reviewed in ref. 1). Based on this correlation and on the observation that anti-CD4 and anti-CDS antibodies inhibit T-cell function, it has been suggested that CD4 and CDS increase the avidity of T cells for their targets by binding to MHC class II or MHC class I molecules respectively2,3. Also, CD4 and CDS may become physically associated with the T-cell antigen receptor, forming a higher-affinity complex for antigen and MHC molecules4–8, and could be involved in signal transduction5,6,9,10. Cell-cell adhesion dependent CD4 and MHC II molecules has recently been demonstrated11. To determine whether CDS can interact with MHC class I molecules in the absence of the T-cell antigen receptor, we have developed a cell-cell binding assay that measures adhesion of human B-cell lines expressing MHC class I molecules to transfected cells expressing high levels of human CDS. In this system, CDS and class I molecules mediate cell-cell adhesion, showing that CDS directly binds to MHC class I molecules. more...

ANTIGENS of the HLA-A, -B, -C and -DR series have been defined mainly using sera from multiparous women1, which generally are comparatively weak, serologically complex and available in only limited quantities. Furthermore, large screening programmes are required to find usable sera, especially for rare specificities. Although antisera to HLA determinants can be produced in high titres by immunising animals of various species with purified HLA-A, -B, -C, -D antigens2–5, they usually require extensive absorption to reveal polymorphic specificity and so have not so far been used as routine tissue-typing reagents. The development of techniques for producing hybrid cell lines secreting monoclonal antibodies of defined specificity6,7, provides a way of circumventing the problems of generating human polymorphic antisera by heteroimmunisation and has already been used to produce a monoclonal antibody against the human blood group A determinant8. Here we describe the production of a cell line secreting an anti-HLA-A2 antibody. more...

At least four distinct forms of clathrin light chains are found in mammalian cells1–5. This molecular variability derives from tissue-specific patterns of expression of LCaand LCbgenes6. Sequence analysis shows an overall homology of 60% between LCaand LCband the presence of brain-specific insertion sequences. These findings suggest that the different light chains have both shared and specialized functions6. To address this question we have used a panel of monoclonal antibodies to identify two structurally and functionally distinct regions in the clathrin light-chain sequences. One region (residues 158–208) is exposed in native clathrin structures (triskelions7,8and coated vesicles) and includes the brain-specific insertion sequences. The second region (residues 93–157), which is cryptic in native clathrin structures, is involved in binding the clathrin heavy chain and contains the region of strongest homology with intermediate filament proteins6. more...

THE study of evolutionary relationships by immunological comparison of homologous proteins from different species has been limited by the complexity and variability of conventional heteroantisera1. These problems can be avoided by using selected panels of monoclonal antibodies, specific for single antigenic determinants, which would enable detailed immunochemical descriptions of homologous proteins to be made2. The human HLA-A,B,C antigens and their homologues provide a particularly interesting system for this type of analysis3. Although they are extraordinarily polymorphic within species, many features of their structure, including association with β-microglobulin, have been highly conserved during evolution4–6. A preliminary survey showed that monoclonal antibodies with specificity for the HLA-A,B,C–β2-microglobulin complex reacted with primate species but not with non-primates7. We have therefore concentrated on comparing primate species with a panel of anti-A,B,C monoclonal antibodies. We report here the finding that two different anti-HLA-A,B,C monoclonal antibodies with no demonstrable polymorphic specificity in humans define polymorphisms in owl and spider monkeys, thus demonstrating the potential of these reagents for fine structure antigenic mapping. more...