145 research outputs found
Chemokines and Viruses: The Dearest Enemies
AbstractThe relation between viruses and the chemokine system is characterized by a complex blend of enmity and attraction. Chemokines are key regulators of innate and adaptive immune responses against invading microorganisms, including viruses. They act not only as immune system “traffic officers,” controlling leukocyte migration under both physiological and pathological conditions, but also as fine orchestrators that modulate the induction, amplification, and cytokine-secretion pattern of antiviral responses. However, viruses have succeeded in turning the chemokine system into an ally. During the course of a long parallel evolution, viruses have captured from their hosts the genetic information for encoding chemokines and chemokine receptors and have reprogrammed it for evading the control of the immune system. Moreover, selected viral agents, most notably primate immunodeficiency retroviruses, have adopted chemokine receptors as essential gateways for entry into their target cells. The endogenous secretion of chemokines is thus emerging as an important in vivo mechanism of viral control, which is potentially inducible by effective vaccines. The deepening knowledge of the interactions between viruses and chemokines may lead to novel therapeutic and preventive strategies for the control of viral and inflammatory diseases
Recent developments in animal models for human herpesvirus 6A and 6B
Progress in the identification of suitable animal models for human herpesvirus (HHV)-6A and HHV-6B infections has been slow. Recently, new models have been established, mainly for HHV-6A, which reproduce some pathological features seen in humans. Neuroinflammatory signs were observed in infected marmosets and CD46-transgenic mice; although viral replication was not prominent, persistence of viral DNA and specific immunologic responses were detected, suggesting an immune-mediated pathogenic mechanism. Pig-tailed macaques showed robust viral replication concomitant with acute-phase symptoms, and provided a model to study the effects of HHV-6A on AIDS progression. In humanized mice, viral replication was less evident, but infection led to T-cell alterations. Altogether, these recent developments have opened new perspectives for studying the pathogenic role of HHV-6A in humans. Addresse
Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46.
Human herpesvirus 6 (HHV-6) employs the complement regulator CD46 (membrane cofactor protein) as a receptor for fusion and entry into target cells. Like other known herpesviruses, HHV-6 encodes multiple glycoproteins, several of which have been implicated in the entry process. In this report, we present evidence that glycoprotein H (gH) is the viral component responsible for binding to CD46. Antibodies to CD46 co-immunoprecipitated an approximately 110-kDa protein band specifically associated with HHV-6-infected cells. This protein was identified as gH by selective depletion with an anti-gH monoclonal antibody, as well as by immunoblot analysis with a rabbit hyperimmune serum directed against a gH synthetic peptide. In reciprocal experiments, a monoclonal antibody against HHV-6 gH was found to co-immunoprecipitate CD46. Studies using monoclonal antibodies directed against specific CD46 domains, as well as engineered constructs lacking defined CD46 regions, demonstrated a close correspondence between the CD46 domains involved in the interaction with gH and those previously shown to be critical for HHV-6 fusion (i.e. short consensus repeats 2 and 3)
Human Herpesvirus 6 (HHV-6) Causes Severe Thymocyte Depletion in SCID-hu Thy/Liv Mice
Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that may act as a cofactor in the progression of AIDS. Here, we describe the first small animal model of HHV-6 infection. HHV-6 subgroup A, strain GS, efficiently infected the human thymic tissue implanted in SCID-hu Thy/Liv mice, leading to the destruction of the graft. Viral DNA was detected in Thy/Liv implants by quantitative polymerase chain reaction (PCR) as early as 4 d after inoculation and peaked at day 14. The productive nature of the infection was confirmed by electron microscopy and immunohistochemical staining. Atypical thymocytes with prominent nuclear inclusions were detected by histopathology. HHV-6 replication was associated with severe, progressive thymocyte depletion involving all major cellular subsets. However, intrathymic T progenitor cells (ITTPs) appeared to be more severely depleted than the other subpopulations, and a preferred tropism of HHV-6 for ITTPs was demonstrated by quantitative PCR on purified thymocyte subsets. These findings suggest that thymocyte depletion by HHV-6 may be due to infection and destruction of these immature T cell precursors. Similar results were obtained with strain PL-1, a primary isolate belonging to subgroup B. The severity of the lesions observed in this animal model underscores the possibility that HHV-6 may indeed be immunosuppressive in humans
Broad-Spectrum Inhibition of HIV-1 by a Monoclonal Antibody Directed against a gp120-Induced Epitope of CD4
To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1
X-ray Observations of a [C II]-bright, z=6.59 Quasar/Companion System
We present deep Chandra observations of PSO J231.657620.8335, a quasar at
redshift z=6.59 with a nearby ( proper kpc) companion galaxy. ALMA
observed both the quasar and companion to be bright in [C II], and the system
has significant extended Ly emission around the quasar, suggesting that
a galaxy merger is ongoing. Unlike previous studies of two similar systems, and
despite observing the system with Chandra for 140 ks, we do not detect the
companion in X-rays. The quasar itself is detected, but only
net counts are observed. From a basic spectral analysis,
the X-ray spectrum of the quasar is soft (hardness ratio of , power-law index of ), which
results in a rest-frame X-ray luminosity comparable to other bright quasars
($L_{2-10} = 1.09^{+2.20}_{-0.70}\times 10^{45}\ \textrm{erg}\
\textrm{s}^{-1}\Gamma\Gamma{\sim}2L_{2-10} \sim 0.6 \times 10^{45}\ \textrm{ erg}\ \textrm{ s}^{-1}$).Comment: 11 pages, 4 figures. Accepted for publication in Ap
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