The rockefeller university

Many studies have documented how extensively HIV-1 and related viruses interact with host cells. Virus-host interactions are of two conceptual types. First, viruses have evolved to make use of numerous host-cell functions to facilitate their own replication. Second, hosts have evolved a number of activities to inhibit virus replication. Understanding the scope and details of HIV-host interactions has been an extraordinary rich scientific endeavor, and in addition to their biomedical importance, studies in this area have established HIV as a model system in virology. Here, I present an overview of how HIV-1 interacts with some key host cell factors during its replication cycle. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Voltage-gated sodium (Na-v) channels are essential for the rapid depolarization of nerve and muscle(1), and are important drug targets(2). Determination of the structures of Na-v channels will shed light on ion channel mechanisms and facilitate potential clinical applications. A family of bacterial Na-v channels, exemplified by the Na+-selective channel of bacteria (NaChBac)(3), provides a useful model system for structure-function analysis. Here we report the crystal structure of NavRh, a NaChBac orthologue from the marine alphaproteobacterium HIMB114 (Rickettsiales sp. HIMB114; denoted Rh), at 3.05 angstrom resolution. The channel comprises an asymmetric tetramer. The carbonyl oxygen atoms of Thr 178 and Leu 179 constitute an inner site within the selectivity filter where a hydrated Ca2+ resides in the crystal structure. The outer mouth of the Na+ selectivity filter, defined by Ser 181 and Glu 183, is closed, as is the activation gate at the intracellular side of the pore. The voltage sensors adopt a depolarized conformation in which all the gating charges are exposed to the extracellular environment. We propose that NavRh is in an 'inactivated' conformation. Comparison of NavRh with Na(v)Ab(4) reveals considerable conformational rearrangements that may underlie the electromechanical coupling mechanism of voltage-gated channels.

The interferon (IFN)-induced transmembrane protein 3 (IFITM3) is a cellular restriction factor that inhibits infection by influenza virus and many other pathogenic viruses. IFITM3 prevents endocytosed virus particles from accessing the host cytoplasm although little is known regarding its regulatory mechanisms. Here we demonstrate that IFITM3 localization to and antiviral remodeling of endolysosomes is differentially regulated by S-palmitoylation and lysine ubiquitination. Although S-palmitoylation enhances IFITM3 membrane affinity and antiviral activity, ubiquitination decreases localization with endolysosomes and decreases antiviral activity. Interestingly, autophagy reportedly induced by IFITM3 expression is also negatively regulated by ubiquitination. However, the canonical ATG5-dependent autophagy pathway is not required for IFITM3 activity, indicating that virus trafficking from endolysosomes to autophagosomes is not a pre-requisite for influenza virus restriction. Our characterization of IFITM3 ubiquitination sites also challenges the dual-pass membrane topology predicted for this protein family. We thus evaluated topology by N-linked glycosylation site insertion and protein lipidation mapping in conjunction with cellular fractionation and fluorescence imaging. Based on these studies, we propose that IFITM3 is predominantly an intramembrane protein where both the N and C termini face the cytoplasm. In sum, by characterizing S-palmitoylation and ubiquitination of IFITM3, we have gained a better understanding of the trafficking, activity, and intramembrane topology of this important IFN-induced effector protein.

Staphylococcus epidermidis is a harmless commensal, but it can become a human pathogen, mainly in the hospital environment. In order to clarify strategies used by these bacteria to adapt to the hospital environment, we compared the population structure and staphylococcal cassette chromosome mec (SCCmec) content of S. epidermidis from the community and hospital. S. epidermidis were collected from nasal swabs of both healthy military draftees (192 isolates) and patients (94 isolates) recovered in the same time period and geographical region. S. epidermidis were characterized by PFGE, multilocus sequence typing and SCCmec typing. Clonal complex 5 was predominant in the hospital (100) and the community (58), but some clonal types were specific to each environment and others were found in both (C/H clones). The methicillin-resistant S. epidermidis (MRSE) colonization rate in the community was very low (7) when compared with the hospital (30; P0.05). Community-associated MRSE carried mostly SCCmec IV and V [Simpsons index of diversity (SID)57.52; 95 CI 38.3576.69], whereas hospital-associated MRSE carried 17 SCCmec structures (SID82.67; 95 CI 77.3887.96). Isolates of the same PFGE type had a much higher number of different SCCmec types when collected in the hospital than in the community. Our data suggest that the S. epidermidis population is composed of hospital-associated clonal types, community-associated clonal types and types that are able to survive in both environments. Moreover, adaptation to the hospital environment in S. epidermidis appears to promote an increase in the frequency and diversification of SCCmec.

Mu opioid receptor (OPRM1) ligands may alter expression of chemokines and chemokine receptors involved in penetration of human immunodeficiency virus (HIV) type 1 into the cell. We suggest that OPRM1 variants may affect the pathophysiology of HIV infection. DNA samples from 1031 eligible African Americans, Hispanics, and whites from the Women's Interagency HIV Study (WIHS) who were alive as of April 2006 were analyzed. We performed regression analysis of association of 18 OPRM1 variants with a change of viral load and CD4 cell count during 2 periods: between admission to WIHS and the start of highly active antiretroviral therapy (HAART) (interval X) and between the start of HAART and the most recent WIHS visit (interval Y), and examined the association of these variants with HIV status. Regardless of genotype, a significant decrease in viral load during interval X was found for each ethnicity. Whites with allele G of the functional polymorphism 118A > G (reference sequence rs1799971) showed a smaller decrease in viral load; those bearing minor alleles IVS1 + 1050A, IVS1 + 14123A, and IVS2 + 31A showed a larger decrease in viral load over interval X (0.01 < P < .05). Hispanics with the same alleles showed a greater increase in CD4 cell count over interval Y (0.01 < P < .05). We found an association between OPRM1 variants and HIV status in African Americans and whites. OPRM1 polymorphisms may alter the severity of HIV infection before and after HAART.

Spontaneous clearance of hepatitis C virus (HCV) occurs in similar to 30% of acute infections. Host genetics play a major role in HCV clearance, with a strong effect of single nucleotide polymorphisms (SNPs) of the IL28B gene already found in different populations, mostly infected with viral genotypes 1 and 3. Egypt has the highest prevalence of HCV infection in the world, which is mostly due to viral genotype 4. We investigated the role of several IL28B SNPs in HCV spontaneous clearance in an Egyptian population. We selected nine SNPs within the IL28B genomic region covering the linkage disequilibrium (LD) block known to be associated with HCV clearance in European populations. These SNPs were genotyped in 261 HCV-infected Egyptian subjects (130 with spontaneous clearance and 131 with chronic infection). The most associated SNPs were rs12979860 (P = 1.6x10(-7)) and the non-synonymous IL28B SNP, rs8103142 (P = 1.6x10(-7)). Interestingly, three SNPs at the two bounds of the region were monomorphic, reducing the size of the LD block in which the causal variants are potentially located to similar to 20 kilobases. HCV clearance in Egypt was associated with a region of IL28B smaller than that identified in European populations, and involved the non-synonymous IL28B SNP, rs8103142.

Biology presents many examples of planar distribution and structural networks having dense sets of closed loops. An archetype of this form of network organization is the vasculature of dicotyledonous leaves, which showcases a hierarchicallynested architecture containing closed loops at many different levels. Although a number of approaches have been proposed to measure aspects of the structure of such networks, a robust metric to quantify their hierarchical organization is still lacking. We present an algorithmic framework, the hierarchical loop decomposition, that allows mapping loopy networks to binary trees, preserving in the connectivity of the trees the architecture of the original graph. We apply this framework to investigate computer generated graphs, such as artificial models and optimal distribution networks, as well as natural graphs extracted from digitized images of dicotyledonous leaves and vasculature of rat cerebral neocortex. We calculate various metrics based on the asymmetry, the cumulative size distribution and the Strahler bifurcation ratios of the corresponding trees and discuss the relationship of these quantities to the architectural organization of the original graphs. This algorithmic framework decouples the geometric information (exact location of edges and nodes) from the metric topology (connectivity and edge weight) and it ultimately allows us to perform a quantitative statistical comparison between predictions of theoretical models and naturally occurring loopy graphs.

Addiction to drugs is a chronic, relapsing brain disease that has major medical, social, and economic complications. It has been established that genetic factors contribute to the vulnerability to develop drug addiction and to the effectiveness of its treatment. Identification of these factors may increase our understanding of the disorders, help in the development of new treatments and advance personalized medicine. In this review, we will describe the genetics of the major genes of the opioid system (opioid receptors and their endogenous ligands) in connection to addiction to opioids, cocaine, alcohol and methamphetamines. Particular emphasis is given to association and functional studies of specific variants. We will provide information on the sample populations and the size of each study, as well as a list of the variants implicated in association with addiction-related phenotypes, and with the effectiveness of pharmacotherapy for addiction.

Powerful ultrastructural tools are providing new insights into neuronal circuits, revealing a wealth of anatomically-defined synaptic connections. These wiring diagrams are incomplete, however, because functional connectivity is actively shaped by neuromodulators that modify neuronal dynamics, excitability, and synaptic function. Studies of defined neural circuits in crustaceans, C. elegans, Drosophila, and the vertebrate retina have revealed the ability of modulators and sensory context to reconfigure information processing by changing the composition and activity of functional circuits. Each ultrastructural connectivity map encodes multiple circuits, some of which are active and some of which are latent at any given time.

Langerhans cells (LCs) are dendritic cells (DCs) localized to the epidermis. They should be the first antigen-presenting cells to encounter squamous cell carcinoma (SCC). The aim of this study was to investigate the ability of LCs isolated from human SCC to induce T-cell proliferation and polarization. We investigated the ability of LCs from SCC and peritumoral skin to induce T-cell proliferation and polarization. We also studied the effect of SCC supernatant on the ability of LCs from normal skin, in vitro-generated LCs, and DCs to activate and polarize T cells. LCs from SCC were stronger inducers of allogeneic CD4(+) and CD8(+) T-cell proliferation and IFN-gamma production than LCs from peritumoral skin. We found that tumor supernatants (TSNs) were rich in immunosuppressive cytokines; despite this, allogeneic CD4(+) and CD8(+) T-cell proliferation and IFN-gamma induction by LCs were augmented by TSN. Moreover, TSN facilitated IFN-gamma induction by in vitro-generated LCs, but suppressed the ability of in vitro-generated DCs to expand allogeneic CD4(+) and CD8(+) T cells. We have demonstrated that LCs from SCC can induce type 1 immunity. TSN induces IFN-gamma induction by in vitro-generated LCs. This contrasts greatly with prior studies showing that DCs from SCC cannot stimulate T cells. These data indicate that LCs may be superior to DCs for SCC immunotherapy and may provide a new rationale for harnessing LCs for the treatment of cancer patients.