Eun Young Kim

Bio: Eun Young Kim is an academic researcher from Northwestern University. The author has contributed to research in topics: Virus & Viral replication. The author has an hindex of 25, co-authored 38 publications receiving 3340 citations. Previous affiliations of Eun Young Kim include Stanford University.

Persistent HIV-1 replication maintains the tissue reservoir during therapy

Abstract: Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.

Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients.

Abstract: Elevated plasma lipopolysaccharide (LPS), an indicator of microbial translocation from the gut, is a likely cause of systemic immune activation in chronic HIV infection. LPS induces monocyte activation and trafficking into brain, which are key mechanisms in the pathogenesis of HIV-associated dementia (HAD). To determine whether high LPS levels are associated with increased monocyte activation and HAD, we obtained peripheral blood samples from AIDS patients and examined plasma LPS by Limulus amebocyte lysate (LAL) assay, peripheral blood monocytes by FACS, and soluble markers of monocyte activation by ELISA. Purified monocytes were isolated by FACS sorting, and HIV DNA and RNA levels were quantified by real time PCR. Circulating monocytes expressed high levels of the activation markers CD69 and HLA-DR, and harbored low levels of HIV compared to CD4+ T-cells. High plasma LPS levels were associated with increased plasma sCD14 and LPS-binding protein (LBP) levels, and low endotoxin core antibody levels. LPS levels were higher in HAD patients compared to control groups, and were associated with HAD independently of plasma viral load and CD4 counts. LPS levels were higher in AIDS patients using intravenous heroin and/or ethanol, or with Hepatitis C virus (HCV) co-infection, compared to control groups. These results suggest a role for elevated LPS levels in driving monocyte activation in AIDS, thereby contributing to the pathogenesis of HAD, and provide evidence that cofactors linked to substance abuse and HCV co-infection influence these processes.

Propagation and Dissemination of Infection after Vaginal Transmission of Simian Immunodeficiency Virus

Abstract: In the current global AIDS pandemic, more than half of new human immunodeficiency virus type 1 (HIV-1) infections are acquired by women through intravaginal HIV exposure. For this study, we explored pathogenesis issues relevant to the development of effective vaccines to prevent infection by this route, using an animal model in which female rhesus macaques were exposed intravaginally to a high dose of simian immunodeficiency virus (SIV). We examined in detail the events that transpire from hours to a few days after intravaginal SIV exposure through week 4 to provide a framework for understanding the propagation, dissemination, and establishment of infection in lymphatic tissues (LTs) during the acute stage of infection. We show that the mucosal barrier greatly limits the infection of cervicovaginal tissues, and thus the initial founder populations of infected cells are small. While there was evidence of rapid dissemination to distal sites, we also show that continuous seeding from an expanding source of production at the portal of entry is likely critical for the later establishment of a productive infection throughout the systemic LTs. The initially small founder populations and dependence on continuous seeding to establish a productive infection in systemic LTs define a small window of maximum vulnerability for the virus in which there is an opportunity for the host, vaccines, or other interventions to prevent or control infection.

APOBEC3G Inhibits Elongation of HIV-1 Reverse Transcripts

Abstract: APOBEC3G (A3G) is a host cytidine deaminase that, in the absence of Vif, restricts HIV-1 replication and reduces the amount of viral DNA that accumulates in cells. Initial studies determined that A3G induces extensive mutation of nascent HIV-1 cDNA during reverse transcription. It has been proposed that this triggers the degradation of the viral DNA, but there is now mounting evidence that this mechanism may not be correct. Here, we use a natural endogenous reverse transcriptase assay to show that, in cell-free virus particles, A3G is able to inhibit HIV-1 cDNA accumulation not only in the absence of hypermutation but also without the apparent need for any target cell factors. We find that although reverse transcription initiates in the presence of A3G, elongation of the cDNA product is impeded. These data support the model that A3G reduces HIV-1 cDNA levels by inhibiting synthesis rather than by inducing degradation.

Defining APOBEC3 Expression Patterns in Human Tissues and Hematopoietic Cell Subsets

Abstract: Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins are polynucleotide cytidine deaminases that can edit and/or inhibit the replication of a range of retroviruses, retrotransposons, and DNA viruses (15, 30, 42). Most notable among susceptible substrates is human immunodeficiency virus type 1 (HIV-1), whose infectivity is profoundly inhibited by APOBEC3G (A3G) and APOBEC3F (A3F) in the absence of the viral Vif protein (6, 43, 69, 82, 87). In addition, APOBEC3B (A3B) and APOBEC3DE (A3DE) can suppress HIV-1 infectivity to comparatively modest extents, although A3B appears not to be regulated by Vif (6, 20, 23, 64). Most recently, one particular allelic variant of APOBEC3H, haplotype II, has also been shown to inhibit HIV-1, although uncertainty exists concerning this protein's sensitivity to Vif (19, 58). APOBEC3 proteins, and especially A3G, are effective mutators of HIV-1 sequences (6, 15, 30, 46, 47, 49, 86). Mutation of HIV-1 sequences occurs through the encapsidation of APOBEC3 proteins into assembling virus particles and the ensuing deamination of cytidine residues to uridines in nascent (mostly) minus-strand reverse transcripts. When fixed in viral DNA, these mutations register as guanosine-to-adenosine (G-to-A) changes in the viral plus strand and are often termed hypermutations when occurring at excessive levels. In addition to these editing effects, a growing amount of literature indicates that APOBEC3 proteins also diminish the accumulation of HIV-1 reverse transcripts in infected cells, most likely by interfering with the process of reverse transcription (3, 5, 8, 26, 29, 31, 45, 47, 49, 51). The relative contributions of these functions to viral suppression under differing infection conditions remain to be determined (40). HIV-1 Vif overcomes the activity of APOBEC3 proteins by recruiting them to a cullin 5-elongin B/C-Rbx ubiquitin ligase complex and inducing polyubiquitylation, proteasomal degradation, and exclusion from viral particles (18, 44, 50, 52, 70, 73, 85). There is persuasive evidence indicating that the APOBEC3 proteins, in particular A3G and A3F, encounter and influence HIV-1 during the course of natural infection in humans: first, all primate immunodeficiency viruses carry vif genes, which counteract their relevant A3G and A3F proteins (9, 25, 48, 68, 83); second, Vif expression is essential for pathogenic simian immunodeficiency virus infection (21) and is implicated as an important factor governing cross-species transmission of primate immunodeficiency viruses (25, 27, 71); and third, G-to-A hypermutated sequences are found frequently in HIV-1-infected individuals, with the targeted sequences matching the consensus substrate sequences for A3G, predominantly, and A3F (24, 32, 37, 38, 41, 59, 81). In addition to the inhibitory effects of the APOBEC3 proteins, it is also possible that low levels of activity could be beneficial to HIV-1 by providing an additional mechanism for acquiring sequence variation through sublethal levels of editing. Such mutations could facilitate immune evasion, drive phenotypic changes, or accelerate the development of drug resistance (34, 36, 54). Accordingly, it has been anticipated that fluctuation in the balance between A3G and/or A3F and Vif expression or function could influence the course of natural HIV-1 infection or the rate of viral transmission. Such variation could be provided through differences in A3G and/or A3F or Vif protein sequences, expression levels, or regulation of protein function. Indeed, a single nucleotide polymorphism in A3G that encodes the H186R change has been associated with an accelerated progression of HIV-1 disease in African Americans (1), a noncoding polymorphism in intron 4 of A3G has been associated with an increased risk of infection in Caucasians (79), and a polymorphism in CUL5 (which encodes cullin 5) has been linked to more rapid disease progression (2). Conversely, another study was unable to find an association between the H186R or other A3G polymorphisms and disease progression (22). Furthermore, HIV-1-exposed seronegative individuals were previously reported to show higher A3G mRNA expression levels than HIV-1-infected or uninfected controls, suggesting that A3G can modulate susceptibility to HIV-1 infection (4). More recently, it was reported that HIV-1-seropositive individuals with low viral set points have higher A3G and A3F mRNA expression levels than HIV-1-seropositive individuals with high viral set points (35, 78), yet others have been unable to discern a relationship between A3G and A3F mRNA expression levels and viral load (17). Finally, Vif sequence variability has been documented in vivo and was shown in cultured cells to significantly impact its neutralizing activity against A3G and/or A3F (72). In sum, although several studies indicated that variation in A3G and/or A3F expression levels can influence disease progression after infection by HIV-1, data from previously published reports in this area are not in good general agreement with each other. To investigate such issues with precision, it is important to define the cell types and tissues in which APOBEC3 proteins are naturally expressed, to understand the factors that regulate expression (transcriptionally and posttranscriptionally), to assign levels of expression of the different APOBEC3 proteins in different cell types and tissues, and to appreciate variations in expression levels both between individuals and within individuals at different points in time. A number of analyses that address the expression and posttranslational regulation of APOBEC3 genes have already been reported. There is general agreement that several APOBEC3 genes are expressed in lymphocyte populations and that A3G and A3F are expressed in monocytes, dendritic cells (DCs), and hepatocytes (33, 60, 62, 74, 84). Furthermore, A3A is expressed in monocytes (60), and A3B and A3C are expressed in hepatocytes (12). As factors involved in resistance to infection, there is much interest in examining APOBEC3 protein expression in the context of the innate and inflammatory response to infection and, in particular, in response to type I interferon (IFN). Indeed, alpha IFN (IFN-α) was previously reported to induce A3G and A3A in monocytes (60, 61, 67, 74) and A3G, A3F, and A3B in hepatocytes (12, 67, 75), whereas the effect of IFN-α on A3G expression in CD4+ T cells is controversial, as induction has (14) or has not (65, 67, 74, 84) been observed. In fact, in vitro studies with panels of cytokines have revealed relatively little in terms of A3G regulation in T cells, with the exception of a modest induction with interleukin-2 (IL-2) or IL-15 over 5 days of treatment (74). It was also previously reported that the stimulation of the cell surface molecules CCR5 and CD40 can upregulate A3G expression in CD4+ T cells and DCs (62). More recently, a poly(I:C)-induced type I IFN response in DCs was reported to induce the expression of a lower-molecular-mass A3G protein without changes in A3G mRNA levels (77). The targeting of A3G to high-molecular-mass (HMM) ribonucleoprotein complexes, and, hence, the masking of catalytic and postentry antiviral activity, has also been associated with T-cell activation, which is indicative of further levels of functional regulation (16, 76). In an effort to provide baseline information for future analyses addressing the effects of APOBEC3 expression phenotypes on HIV-1 pathogenesis, transmission, and sequence evolution, we have addressed the tissue and cell type expression profiles of human APOBEC3 genes, the variation in APOBEC3 mRNA expression levels between and within individuals, and alterations in expression in primary CD4+ T cells, macrophages, and DCs in response to extracellular stimuli, particularly IFN-α.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Nanostructures in Biodiagnostics

Abstract: In the last 10 years the field of molecular diagnostics has witnessed an explosion of interest in the use of nanomaterials in assays for gases, metal ions, and DNA and protein markers for many diseases. Intense research has been fueled by the need for practical, robust, and highly sensitive and selective detection agents that can address the deficiencies of conventional technologies. Chemists are playing an important role in designing and fabricating new materials for application in diagnostic assays. In certain cases assays based upon nanomaterials have offered significant advantages over conventional diagnostic systems with regard to assay sensitivity, selectivity, and practicality. Some of these new methods have recently been reviewed elsewhere with a focus on the materials themselves or as subclassifications in more generalized overviews of biological applications of nanomaterials.1-7 We intend to review some of the major advances and milestones in the field of detection systems based upon nanomaterials and their roles in biodiagnostic screening for nucleic acids, * To whom correspondence should be addressed. Phone: 847-4913907. Fax: 847-467-5123. E-mail: chadnano@northwestern.edu. Nathaniel L. Rosi earned his B.A. degree at Grinnell College (1999) and his Ph.D. degree from the University of Michigan (2003), where he studied the design, synthesis, and gas storage applications of metal−organic frameworks under the guidance of Professor Omar M. Yaghi. In 2003 he began postdoctoral studies as a member of Professor Mirkin’s group at Northwestern University. His current research focuses on the rational assembly of DNA-modified nanostructures into larger-scale materials.

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications.

Abstract: Biocompatibility, Pharmaceutical and Biomedical Applications L. Harivardhan Reddy,†,‡ Jose ́ L. Arias, Julien Nicolas,† and Patrick Couvreur*,† †Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, Universite ́ Paris-Sud XI, UMR CNRS 8612, Faculte ́ de Pharmacie, IFR 141, 5 rue Jean-Baptiste Cleḿent, F-92296 Chat̂enay-Malabry, France Departamento de Farmacia y Tecnología Farmaceútica, Facultad de Farmacia, Campus Universitario de Cartuja s/n, Universidad de Granada, 18071 Granada, Spain ‡Pharmaceutical Sciences Department, Sanofi, 13 Quai Jules Guesdes, F-94403 Vitry-sur-Seine, France