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Christopher J. Miller

Bio: Christopher J. Miller is an academic researcher from University of Pennsylvania. The author has contributed to research in topics: Simian immunodeficiency virus & Medicine. The author has an hindex of 90, co-authored 648 publications receiving 30569 citations. Previous affiliations of Christopher J. Miller include University of Wisconsin-Madison & University of New South Wales.


Papers
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Journal ArticleDOI
28 Apr 2005-Nature
TL;DR: It is shown that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4+ T cells, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.
Abstract: In early simian immunodeficiency virus (SIV) and human immunodeficiency virus-1 (HIV-1) infections, gut-associated lymphatic tissue (GALT), the largest component of the lymphoid organ system, is a principal site of both virus production and depletion of primarily lamina propria memory CD4+ T cells; that is, CD4-expressing T cells that previously encountered antigens and microbes and homed to the lamina propria of GALT. Here, we show that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4+ T cells. Surprisingly, most of the initially infected memory cells were not, as expected, activated but were instead immunophenotypically 'resting' cells that, unlike truly resting cells, but like the first cells mainly infected at other mucosal sites and peripheral lymph nodes, are capable of supporting virus production. In addition to inducing immune activation and thereby providing activated CD4+ T-cell targets to sustain infection, virus production also triggered an immunopathologically limiting Fas-Fas-ligand-mediated apoptotic pathway in lamina propria CD4+ T cells, resulting in their preferential ablation. Thus, SIV exploits a large, resident population of resting memory CD4+ T cells in GALT to produce peak levels of virus that directly (through lytic infection) and indirectly (through apoptosis of infected and uninfected cells) deplete CD4+ T cells in the effector arm of GALT. The scale of this CD4+ T-cell depletion has adverse effects on the immune system of the host, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.

970 citations

Journal ArticleDOI
12 Nov 1999-Science
TL;DR: Both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues, and infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells.
Abstract: In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus-type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy. Latently and chronically infected cells that may be derived from this population pose challenges to eradicating infection and developing an effective vaccine.

904 citations

Journal ArticleDOI
15 Oct 1999-Science
TL;DR: In this article, an 18-residue macrocyclic, tridisulfide antibiotic peptide was found in granules of neutrophils and monocytes, which is termed rhesus theta defensin-1 (RTD-1).
Abstract: Analysis of rhesus macaque leukocytes disclosed the presence of an 18-residue macrocyclic, tridisulfide antibiotic peptide in granules of neutrophils and monocytes. The peptide, termed rhesus theta defensin-1 (RTD-1), is microbicidal for bacteria and fungi at low micromolar concentrations. Antibacterial activity of the cyclic peptide was threefold greater than that of an open-chain analog, and the cyclic conformation was required for antimicrobial activity in the presence of 150 millimolar sodium chloride. Biosynthesis of RTD-1 involves the head-to-tail ligation of two α-defensin–related nonapeptides, requiring the formation of two new peptide bonds. Thus, host defense cells possess mechanisms for synthesis and granular packaging of macrocyclic antibiotic peptides that are components of the phagocyte antimicrobial armamentarium.

669 citations

Journal ArticleDOI
TL;DR: Ion channels are integral membrane proteins spanning the lipid bilayer and necessarily communicating with both aqueous phases, and may be considered as enzymes, in that they reduce the energies of transmembrane ionic diffusion from the 250 kJ/mol above to values in the range of 20 kj/mol a rate enhancement of about 1039.
Abstract: A lipid bilayer membrane presents an enormous energy barrier to the movement of small ions. The electrostatic work required to transfer a K* ion, for example, from the aqueous medium of high dielectric constant to the interior of the low dielectric constant membrane is in the order of 250 kJ/ mol (60kcal/mol [119]). Because many cellular processes rely upon the passive diffusion of ions across biological membranes, a class of membrane proteins the \"ion channels\" has evolved to catalyze ion movements of this kind. Although the concept of the ion channel evolved from electrophysiological studies of ionic currents across the specialized membranes of nerve and muscle, it is now understood that these proteins are distributed widely throughout the biological world, appearing in membranes of prokaryotes, protozoa, and plant cells, as well as in nonexcitable animal cells of many types. Likewise, in addition to operating as the basis for the propagated electrical impulse of nerve and muscle membranes [69], ion channels are fundamentally involved in processes of hormone secretion [36, 37, 98], visual transduction [137], transepithelial electrolyte transport [90], contractile activation [54], and cell volume regulation [53]. Ion channels are integral membrane proteins spanning the lipid bilayer and necessarily communicating with both aqueous phases. Conceptually they may be considered as enzymes, in that they reduce the energies of transmembrane ionic diffusion from the 250 kJ/mol above to values in the range of 20 kJ/mol [44] a rate enhancement of about 1039. Hille [65] further pointed out that ion channels display the essential aspects of enzyme

589 citations

Journal ArticleDOI
TL;DR: SIV enters the vaginal mucosa within 60 min of intravaginal exposure, infecting primarily intraepithelial DC and that SIV-infected cells are located in draining lymph nodes within 18 h of intrabaginal SIV exposure, posing a serious challenge to HIV vaccine development.
Abstract: Despite recent insights into mucosal human immunodeficiency virus (HIV) transmission, the route used by primate lentiviruses to traverse the stratified squamous epithelium of mucosal surfaces remains undefined. To determine if dendritic cells (DC) are used by primate lentiviruses to traverse the epithelial barrier of the genital tract, rhesus macaques were intravaginally exposed to cell-free simian immunodeficiency virus SIVmac251. We examined formalin-fixed tissues and HLA-DR(+)-enriched cell suspensions to identify the cells containing SIV RNA in the genital tract and draining lymph nodes within the first 24 h of infection. Using SIV-specific fluorescent in situ hybridization combined with immunofluorescent antibody labeling of lineage-specific cell markers, numerous SIV RNA(+) DC were documented in cell suspensions from the vaginal epithelium 18 h after vaginal inoculation. In addition, we determined the minimum time that the SIV inoculum must remain in contact with the genital mucosa for the virus to move from the vaginal lumen into the mucosa. We now show that SIV enters the vaginal mucosa within 60 min of intravaginal exposure, infecting primarily intraepithelial DC and that SIV-infected cells are located in draining lymph nodes within 18 h of intravaginal SIV exposure. The speed with which primate lentiviruses penetrate mucosal surfaces, infect DC, and disseminate to draining lymph nodes poses a serious challenge to HIV vaccine development.

557 citations


Cited by
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Journal ArticleDOI
24 Jan 2002-Nature
TL;DR: As the need for new antibiotics becomes more pressing, could the design of anti-infective drugs based on the design principles these molecules teach us?
Abstract: Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?

7,657 citations

Journal ArticleDOI

6,278 citations

Book ChapterDOI
01 Jan 2010

5,842 citations

Journal ArticleDOI
TL;DR: In this paper, the authors present cosmological parameter constraints based on the final nine-year WMAP data, in conjunction with a number of additional cosmology data sets.
Abstract: We present cosmological parameter constraints based on the final nine-year WMAP data, in conjunction with a number of additional cosmological data sets. The WMAP data alone, and in combination, continue to be remarkably well fit by a six-parameter CDM model. When WMAP data are combined with measurements of the high-l cosmic microwave background (CMB) anisotropy, the baryon acoustic oscillation (BAO) scale, and the Hubble constant, the matter and energy densities, bh 2 , ch 2 , and , are each determined to a precision of 1.5%. The amplitude of the primordial spectrum is measured to within 3%, and there is now evidence for a tilt in the primordial spectrum at the 5 level, confirming the first detection of tilt based on the five-year WMAP data. At the end of the WMAP mission, the nine-year data decrease the allowable volume of the six-dimensional CDM parameter space by a factor of 68,000 relative to pre-WMAP measurements. We investigate a number of data combinations and show that their CDM parameter fits are consistent. New limits on deviations from the six-parameter model are presented, for example: the fractional contribution of tensor modes is limited to r < 0.13 (95% CL); the spatial curvature parameter is limited to k = 0.0027 +0.0039 0.0038 ; the summed mass of neutrinos is limited to P m < 0.44 eV (95% CL); and the number of relativistic species is found to lie within Ne = 3.84±0.40, when the full data are analyzed. The joint constraint on Ne and the primordial helium abundance, YHe, agrees with the prediction of standard Big Bang nucleosynthesis. We compare recent Planck measurements of the Sunyaev‐Zel’dovich eect with our seven-year measurements, and show their mutual agreement. Our analysis of the polarization pattern around temperature extrema is updated. This confirms a fundamental prediction of the standard cosmological model and provides a striking illustration of acoustic oscillations and adiabatic initial conditions in the early universe. Subject headings: cosmic microwave background, cosmology: observations, early universe, dark matter, space vehicles, space vehicles: instruments, instrumentation: detectors, telescopes

5,488 citations