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Anthony S Fauci

Publications and source records attributed to Anthony S Fauci.

At least 19 recordsLinked to original sources
PubMed2006

Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms.

Perturbations of B cells in HIV-infected individuals are associated with the overrepresentation of distinct B cell populations. Here we describe high extrinsic CD95 ligand (CD95L)-mediated apoptosis in CD10-/CD21lo mature/activated B cells that likely arise from HIV-induced immune activation. In addition, high intrinsic apoptosis was observed in CD10+ immature/transitional B cells that likely arise as a result of HIV-induced lymphopenia. CD10+ B cells expressed low levels of Bcl-2 and Bcl-xL, consistent with their high susceptibility to intrinsic apoptosis. Higher levels of activated Bax and Bak were induced in CD10+ B cells compared with CD95L-treated CD10- B cells, consistent with the greater involvement of mitochondria in intrinsic vs. extrinsic apoptosis. Of interest, both extrinsic apoptosis in CD95L-treated CD10- B cells and intrinsic apoptosis in CD10+ B cells were associated with caspase-8 activation. Our data suggest that two distinct mechanisms of apoptosis are associated with B cells of HIV-infected individuals, and both may contribute to the depletion and dysfunction of B cells in these individuals.

Apoptosis↗
PubMed2006

Seasonal and pandemic influenza preparedness: science and countermeasures.

Influenza has not been treated with the degree of medical attention that the disease warrants. As such, there is not an adequate baseline of preparedness in the United States to deal with the potential of pandemic influenza. The National Institute of Allergy and Infectious Diseases (NIAID) has been working to enact measures to deal more effectively with a potential influenza pandemic and also to assist in the management of seasonal influenza. The majority of the NIAID's efforts have been dedicated to basic research aimed ultimately at developing and testing, in clinical trials, countermeasures in the form of antiviral drugs and vaccines. Some of the NIAID's current and planned antiviral projects include the (1) assessment of oseltamivir therapy in infants, (2) conduct of clinical trials of higher doses of osteltamivir for avian influenza, (3) appraisal of combination therapies, and (4) evaluation of the next generation of neuraminidase inhibitors. In addition, the NIAID is screening potential new antiviral drugs and evaluating novel drug targets. Similarly, significant funding has been committed to vaccine preparedness, and numerous novel candidate influenza vaccines are in various stages of development. Importantly, there is an integral relationship between preparation for seasonal influenza and preparation for pandemic influenza. Until these approaches are firmly linked, the community will not have optimized its preparedness for a pandemic.

Academies and Institutes↗
PubMed2006

Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7.

Idiopathic CD4+ T lymphocytopenia (ICL) is a rare heterogeneous disorder defined by CD4+ T-cell counts below 300 cells/muL in the absence of human immunodeficiency virus (HIV) infection or other known immune deficiency disorders. Here, we report the expansion of immature/transitional B cells in patients with ICL, which is associated with elevated serum levels of IL-7. Both the percentage of immature/transitional B cells and levels of IL-7 were inversely correlated with levels of CD4+ T-cell counts and directly correlated to each other. Further analyses of B cells indicated that, in contrast to the activating effects of HIV disease on mature B cells, the expansion of immature/transitional B cells in patients with ICL occurred at the expense of memory B cells. These findings extend previous reports on primary immunodeficiencies as well as HIV disease by suggesting that CD4+ T-cell lymphopenia has an impact on human B-cell development either directly or indirectly via the associated elevation of IL-7 levels.

B-Lymphocytes↗
PubMed2006

Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection.

In this study, we demonstrate that the in vitro interactions between a CD56(neg)/CD16(pos) (CD56(neg)) subset of natural killer (NK) cells and autologous dendritic cells (DCs) from HIV-1-infected viremic but not aviremic individuals are markedly impaired and likely interfere with the development of an effective immune response. Among the defective interactions are abnormalities in the process of reciprocal NK-DC activation and maturation as well as a defect in the NK cell-mediated editing or elimination of immature DCs (iDCs). Notably, the lysis of mature DCs (mDCs) by autologous NK cells was highly impaired even after the complete masking of major histocompatibility complex I molecules, suggesting that the defective elimination of autologous iDCs is at the level of activating NK cell receptors. In this regard, the markedly impaired expression/secretion and function of NKp30 and TNF-related apoptosis-inducing ligand, particularly among the CD56(neg) NK cell subset, largely accounts for the highly defective NK cell-mediated lysis of autologous iDCs. Moreover, mDCs generated from HIV-1 viremic but not aviremic patients are substantially impaired in their ability to secrete interleukin (IL)-10 and -12 and to prime the proliferation of neighboring autologous NK cells, which, in turn, fail to secrete adequate amounts of interferon-gamma.

Adult↗
PubMed2006

Fluorodeoxyglucose imaging in healthy subjects with HIV infection: impact of disease stage and therapy on pattern of nodal activation.

OBJECTIVES: Nodal uptake in areas of lymphocyte activation can be visualized using fluorodeoxyglucose. Various patterns of fluorodeoxyglucose accumulation in HIV-positive patients have been described previously and hypothesized potentially to represent regions of active HIV replication or nodal activation. We evaluated the utility of fluorodeoxyglucose scanning as a tool to study HIV pathogenesis. DESIGN: We evaluated fluorodeoxyglucose biodistribution visually and quantitatively in HIV-negative individuals and various groups of HIV-infected patients to determine the impact on the pattern of nodal activation of HIV infection, the stage of HIV infection and degree of viremia, and HAART. In addition, we attempted to image anatomical site(s) of ongoing HIV replication in patients with suppressed HIV viremia on HAART, but subsequently discontinued HAART. METHOD: We performed fluorodeoxyglucose imaging on five groups: HIV-negative, HIV-positive individuals with early infection, HIV-positive patients with advanced disease, HIV-positive patients with suppressed viral loads, and HIV-positive patients who stopped HAART. RESULTS: Healthy HIV patients with suppressed viral loads and HIV-negative individuals had no or little fluorodeoxyglucose nodal accumulation or any other hypermetabolic areas, whereas viremic individuals with early and advanced HIV had increased fluorodeoxyglucose in the peripheral nodes, indicating that fluorodeoxyglucose potentially identifies areas of HIV replication. Fluorodeoxyglucose biodistribution was similar between early and advanced-stage disease. Four of five patients taken off HAART had negative baseline scans but developed nodal uptake and increases in viral loads. CONCLUSION: Abnormal fluorodeoxyglucose accumulation occurs in the nodes of individuals with detectable viral loads. Interruption of effective HAART results in the activation of previously quiescent nodal areas.

Adult↗
PubMed2006

Fluorodeoxyglucose imaging in healthy subjects with HIV infection: impact of disease stage and therapy on pattern of nodal activation.

OBJECTIVES: Nodal uptake in areas of lymphocyte activation can be visualized using fluorodeoxyglucose (FDG). Various patterns of FDG accumulation in HIV-positive subjects have been described previously and hypothesized to potentially represent regions of active HIV replication and or nodal activation. We evaluated the utility of FDG scanning as a tool to study HIV pathogenesis. DESIGN: We evaluated FDG biodistribution visually and quantitatively in HIV-negative individuals and various groups of HIV-infected subjects to determine the impact on pattern of nodal activation of: HIV infection; stage of HIV infection and degree of viremia; and HAART. In addition, we attempted to image anatomical site(s) of on-going HIV replication in subjects with suppressed HIV viremia on ART, but who subsequently discontinued ART. METHOD: We performed FDG imaging on five groups: HIV-negative, HIV-positive with early infection, HIV-positive with advanced disease, HIV-positive with suppressed viral loads, and HIV-positive who stopped ART. RESULTS: Healthy HIV subjects with suppressed viral loads and HIV-negative individuals had no or little FDG nodal accumulation or any other hypermetabolic areas, whereas viremic subjects with early and advanced HIV had increased FDG in peripheral nodes, indicating that FDG potentially identifies areas of HIV replication. FDG biodistribution was similar between early and advanced-stage. Four of five subjects taken off ART had negative baseline scans but developed nodal uptake and increases in viral load. CONCLUSIONS: Abnormal FDG accumulation occurs in nodes of subjects with detectable viral loads. Interruption of effective ART results in activation of previously quiescent nodal areas.

Antiretroviral Therapy, Highly Active↗
PubMed2006

R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells.

HIV envelope binds to and signals through its primary cellular receptor, CD4, and through a coreceptor, either CC chemokine receptor 5 (CCR5) or CXC chemokine receptor 4 (CXCR4). Here, we evaluate the response of peripheral blood mononuclear cells to a panel of genetically diverse R5 and X4 envelope proteins. Modulation of gene expression was evaluated by using oligonucleotide microarrays. Activation of transcription factors was evaluated by using an array of oligonucleotides encoding transcription factor binding sites. Responses were strongly influenced by coreceptor specificity. Treatment of cells from CCR5delta32 homozygous donors with glycoprotein (gp)120 derived from an R5 virus demonstrated that the majority of responses elicited by R5 envelopes required engagement of CCR5. R5 envelopes, to a greater extent than X4 envelopes, induced the expression of genes belonging to mitogen-activated protein kinase signal transduction pathways and genes regulating the cell cycle. A number of genes induced by R5, but not X4, envelopes were also up-regulated in the resting CD4+ T cell population of HIV-infected individuals. These results suggest that R5 envelope facilitates replication of HIV in the pool of resting CD4+ T cells. Additionally, signaling by R5 gp120 may facilitate the transmission of R5 viruses by inducing a permissive environment for HIV replication.

CD4-Positive T-Lymphocytes↗
PubMed2006

Emerging and re-emerging infectious diseases: influenza as a prototype of the host-pathogen balancing act.

To respond to emerging and re-emerging infections, it is necessary to understand the interactions between microbial pathogens and their hosts and the impact of environmental and social factors on these interactions. The importance of understanding host-pathogen interactions is underscored by the emergence of virulent H5N1 avian influenza viruses and their transmission to humans, and the potential pandemic threat they pose.

Animals↗
PubMed2006

Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: correlation with increased IL-7.

Progression of HIV disease is associated with the appearance of numerous B cell defects. We describe herein a population of immature/transitional B cells that is overly represented in the peripheral blood of individuals with advancing HIV disease. These B cells, identified by the expression of CD10, were unresponsive by proliferation to B cell receptor triggering and possessed a phenotype and an Ig diversity profile that confirmed their immature/transitional stage of differentiation. Consistent with an immature status, their lack of proliferation to B cell receptor triggering was reversed with CD40 ligand, but not B cell activation factor. Finally, levels of CD10 expression on B cells were directly correlated with serum levels of IL-7, suggesting that increased levels of IL-7 modulate human B cell maturation either directly or indirectly by means of a homeostatic effect on lymphopenia. Taken together, these data offer insight into human B cell development as well as B cell dysfunction in advanced HIV disease that may be linked to IL-7-dependent homeostatic events.

B-Lymphocytes↗
PubMed2006

Innate immune dysfunction in HIV infection: effect of HIV envelope-NK cell interactions.

We have previously described a number of NK cell dysfunctions in HIV-viremic individuals. In the present study, we performed DNA microarray analysis followed by phenotypic and functional characterization in an effort to investigate which HIV envelope glycoproteins (gp120) affect the physiologic functions of NK cells. Upon treatment of NK cells with HIV gp120, DNA microarray analyses indicated up-regulation of several categories of genes that are associated with apoptosis, suppression of both cellular proliferation and survival, as well as down-regulation of genes that play a vital role in cell proliferation, innate immune defense mechanism, and cell survival. Both subtypes of gp120 suppressed NK cell cytotoxicity, proliferation, and the ability to secrete IFN-gamma. NK cells exposed to X4-subtype HIV gp120 showed a significant decrease in the levels of CC chemokines, while exposure to R5-subtype HIV gp120 had minimal effect. Extended exposure to HIV gp120 resulted in apoptosis of NK cells, further validating the microarray data. Our data demonstrate that exposure of NK cells to HIV envelope proteins results in profound cellular abnormalities at the level of gene expression as well as generic cell functions. These findings are likely to be a consequence of a direct HIV gp120-mediated effect on NK cells. Identification of specific surface receptors on NK cells that interact with HIV envelope proteins might explain how HIV is capable of circumventing innate immune defense mechanisms and establishing infection in susceptible individuals.

Apoptosis↗
PubMed2006

Response to: "Rescuing the NIH before it is too late".

We, the directors of the 27 NIH institutes and centers, wanted to respond to the points made by Andrew Marks in his recent editorial. While we appreciate that the scientific community has concerns, the current initiatives and directions of the NIH have been developed through planning processes that reflect openness and continued constituency input, all aimed at assessing scientific opportunities and addressing public health needs.

Humans↗
PubMed2006

Pandemic influenza threat and preparedness.

The threat of a human influenza pandemic has greatly increased over the past several years with the emergence of highly virulent avian influenza viruses, notably H5N1 viruses, which have infected humans in several Asian and European countries. Previous influenza pandemics have arrived with little or no warning, but the current widespread circulation of H5N1 viruses among avian populations and their potential for increased transmission to humans and other mammalian species may afford us an unprecedented opportunity to prepare for the next pandemic threat. The US Department of Health and Human Services is coordinating a national strategy to respond to an influenza pandemic that involves multiple agencies, including the Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health (NIH). Within NIH, the National Institute of Allergy and Infectious Diseases (NIAID) conducts basic and clinical research to develop new vaccine technologies and antiviral drugs against influenza viruses. We describe recent research progress in preparing for pandemic influenza.

Animals↗
PubMed2005

HIV-1 gp120 induces NFAT nuclear translocation in resting CD4+ T-cells.

The replication of human immunodeficiency virus (HIV) in CD4+ T-cells is strongly dependent upon the state of activation of infected cells. Infection of sub-optimally activated cells is believed to play a critical role in both the transmission of virus and the persistence of CD4+ T-cell reservoirs. There is accumulating evidence that HIV can modulate signal-transduction pathways in a manner that may facilitate replication in such cells. We previously demonstrated that HIV gp120 induces virus replication in resting CD4+ T cells isolated from HIV-infected individuals. Here, we show that in resting CD4+ T-cells, gp120 activates NFATs and induces their translocation into the nucleus. The HIV LTR encodes NFAT recognition sites, and NFATs may play a critical role in promoting viral replication in sub-optimally activated cells. These observations provide insight into a potential mechanism by which HIV is able to establish infection in resting cells, which may have implications for both transmission of HIV and the persistence of viral reservoirs.

Active Transport, Cell Nucleus↗
PubMed2005

Identification of NKG2A and NKp80 as specific natural killer cell markers in rhesus and pigtailed monkeys.

Investigations of natural killer (NK) cells in simian models of disease have been hampered by a lack of appropriate phenotypic markers and by an inadequate understanding of the regulation of NK cell activities. In the present study, a panel of monoclonal antibodies (mAbs) specific for various human NK receptors was screened for cross-reactivity with NK cells from rhesus macaques and pigtailed macaques. Flow cytometric analyses using anti-human NKG2A and anti-human NKp80 mAbs individually, and particularly in combination with anti-CD16 mAb, allowed for the identification of the entire NK cell population in both species. NK cells in monkeys were generally identified by negative selection of peripheral blood mononuclear cells (PBMCs) for the absence of T-cell, B-cell, and monocyte markers. mAb-mediated ligation of NKp80 induced NK cell cytotoxicity, while in the case of NKG2A it displayed a clear capability to inhibit the lysis of target cells by NK cells from macaques, as well as from humans. This new phenotypic and functional characterization of NKG2A and NKp80 in rhesus and pigtailed macaque NK cells provides a new approach in the analysis of their innate immune system.

Animals↗