Cecil H. Fox

Tulane University, New Orleans, Louisiana, United States

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Publications (26)332.45 Total impact

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    ABSTRACT: Most human immunodeficiency virus (HIV)–infected individuals experience increases in peripheral CD4+ T cell counts with suppressive antiretroviral therapy (ART) that achieves plasma HIV RNA levels that are less than the limit of detection. However, some individuals experience decreasing CD4+ T cell counts despite suppression of plasma viremia. We evaluated 4 patients with a history of CD4+ T cell decline despite successfully suppressive ART, from a median of 719 cells/mm3 (range, 360–1141 cells/mm3) to 227 cells/mm3 (range, 174–311 cells/mm3) over a period of 18–24 months; 3 of the patients were receiving tenofovir and didanosine, which may have contributed to this decrease. There was no evidence of HIV replication, nor of antiretroviral drug resistance in the blood or lymphoid tissue, or increased proliferation or decreased thymic production of naive CD4+ T cells. All 4 patients had significant fibrosis of the T cell zone of lymphoid tissue, which appeared to be an important factor in the failure to reconstitute T cells
    Full-text · Article · Jul 2009 · The Journal of Infectious Diseases
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    ABSTRACT: Although continuous highly active antiretroviral therapy (HAART) is effective for many HIV-infected patients, it can be toxic and prohibitive in cost. By decreasing the total amount of time patients receive medications, intermittent HAART could reduce toxicity and cost. Therefore, we initiated a pilot study in which 10 HIV-infected individuals receiving effective therapy that resulted in levels of HIV RNA <50 copies per ml of plasma and CD4(+) T cell counts >300 cells per mm(3) of whole blood received repeated cycles of 7 days on HAART followed by 7 days off of HAART. Patients maintained suppression of plasma viremia for 32-68 weeks. There was no significant increase in HIV proviral DNA or replication-competent HIV in peripheral CD4(+) T cells or HIV RNA in peripheral blood or lymph node mononuclear cells. There was no significant change in CD4(+) T cell counts, no significant increase in CD4(+) or CD8(+) T cells expressing activation markers or producing IFN-gamma in response to HIV, no increase in CD4(+) T cell proliferation to p24 antigen, and no evidence for the development of resistance to HAART medications. There was a significant decrease in serum cholesterol and triglyceride levels. Thus, in this proof-of-concept study, short-cycle intermittent HAART maintained suppression of plasma viremia as well as HIV replication in reservoir sites while preserving CD4(+) T cell counts. In addition, there was a decrease in serum cholesterol and triglyceride levels. Intermittent therapy may be an important strategy to reduce cost and toxicity for HIV-infected individuals.
    Full-text · Article · Dec 2001 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Hybridization of labeled specific molecular probes to nucleic acids in tissues allows geometric and functional location of gene expression or of foreign genome sequences. Estimates of amounts and location of target nucleic acid sequence can be made with phosphor storage imaging and molecular controls.
    No preview · Article · Jun 2001 · Current protocols in molecular biology / edited by Frederick M. Ausubel ... [et al.]
  • Cecil H. Fox · Michele Cottler-Fox
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    ABSTRACT: In HIV studies, in situ hybridization can be used for identifying virion RNA, mRNA being produced for virion packaging, and proviral DNA in the cytoplasm or integrated in the nucleus. This unit focuses primarily on identifying virion RNA, because this is the most sensitive means by which in situ hybridization can be employed to detect HIV expression. In situ hybridization, as developed for HIV RNA detection, involves several protocols: (1) preparation of a radioactive or nonradioactive RNA probe; (2) in situ hybridization of probe to cells and paraffin sections of tissue; (3) detection of radiolabeled probe by emulsion autoradiography; (4) development, staining, and mounting of slides; and finally (5) examination of slides by bright-field, dark-field, specular reflectance, or laser-scanning confocal microscopy. The protocols presented in this unit describe a setup involving up to 150 slides.
    No preview · Article · Jun 2001 · Current protocols in immunology / edited by John E. Coligan ... [et al.]
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    ABSTRACT: Objective: To compare the architecture and HIV-1 RNA and Gag p24 protein expression in lymph nodes (LN) excised from individuals during chronic highly active antiretroviral therapy (HAART) with LN removed from the same patient after plasma virus rebound following the interruption of HAART. Materials and methods: Six HIV-1-infected patients on HAART, with CD4 cell counts greater than 350 cells/μl, and plasma HIV-1 RNA less than 50 copies/ml, underwent inguinal LN excision upon discontinuation of HAART, and again after rebound of plasma virus. Lymph nodes were evaluated by immunohistochemical staining for Gag p24 antigen and Ki67, in-situ hybridization for HIV-1 RNA and H3-histone, and transmission electron microscopy (TEM). Results: LN at baseline were quiescent to mildly hyperplastic and generally contained more primary than secondary follicles. Only one LN had detectable follicular dendritic cell (FDC)-associated p24 antigen, none had HIV RNA. Few mononuclear cells (MNC) expressed RNA or p24 antigen. Plasma virus at the second biopsy ranged from 329 to 3.2 × 106 copies/ml. CD4 cell count decline ranged from 5 to 51% during drug hiatus, and was greatest in patients with highest viral rebound. Four of six of the second LN were more hyperplastic than the initial LN, two showed paracortical hyperplasia. MNC expression of HIV RNA in the second LN paralleled the level of plasma viremia. Increased Ki67 and H3-histone signal occurred in the second LN. Conclusion: Quiescent LN from individuals on HAART rapidly become hyperplastic and activated within 1-2 months after treatment interruption. As in acute HIV infection, virus expression by LN MNC parallels the rebound in plasma viremia and fall in CD4 cell count.
    No preview · Article · Aug 2000 · AIDS
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    ABSTRACT: Although efavirenz-containing regimens effectively suppress plasma levels of human immunodeficiency virus (HIV) RNA, it is now clear that undetectable plasma viremia may not reflect a lack of viral replication. Because lymphoid tissue is an active site of HIV replication, the lymph node virus burden was analyzed in persons who received highly active antiretroviral therapy (HAART) containing either efavirenz or a protease inhibitor (PI). Testing with in situ hybridization revealed no detectable follicular dendritic cell—associated HIV RNA in either group, and only 2 of 8 persons in the efavirenz group and 1 of 4 in the PI group had detectable RNA in lymph node mononuclear cells (LNMC) when tested by use of nucleic acid sequence—based amplification. Low levels of replication-competent HIV were identified in both groups by use of quantitative coculture assays. There was no evidence of development of resistance to either regimen in virus isolated from LNMC. These data support the use of efavirenz as an alternative to a PI in initial HAART regimens.
    Full-text · Article · May 2000 · The Journal of Infectious Diseases
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    ABSTRACT: Objectives: To evaluate changes in architecture, viral RNA, and viral protein over 6 months in lymph nodes from retroviral-naïve HIV-infected persons before and after commencing highly active antiretroviral therapy (HAART). Methods: Nine antiretroviral-naïve HIV-infected persons had lymph nodes excised at baseline and at 2 and 6-8 months after beginning a four-drug combination regimen containing zidovudine, lamivudine, nevirapine, and indinavir. Two patients had AIDS. Lymph nodes were examined by immunohistochemical staining for Gag p24 HIV, CD3, CD21, CD20, HAM 56, and Ki67 antigens and by in-situ hybridization (ISH) for HIV RNA and H3-histone RNA. Results: Eight of nine baseline lymph nodes showed follicular hyperplasia and germinal center and paracortical mononuclear cell activation. At 2 months, the lymph nodes from seven patients, including the AIDS patients, showed more follicular hyperplasia and activation than their baseline specimens but with decreased mononuclear cell activation. By 6 months, seven lymph nodes were less hyperplastic and activated than their corresponding 2 month specimens. Combined ISH/immunohistochemical staining of baseline lymph nodes revealed productively infected T (CD3) and B (CD20) cells and macrophages (HAM56+). HIV RNA-positive mononuclear cells were infrequent at 2 months, and rare at 6 months. HIV RNA was still associated with follicular dendritic cells (FDC) at 2 months, but not at 6 months. HIV p24-positive antigen in germinal centers persisted through all 6, and the one 8 month specimens. The baseline lymph nodes from one of the AIDS patients was involuted and T cell depleted, whereas the follow-up lymph nodes were hyperplastic with normal T cell levels. Conclusion: Follicular hyperplasia and cell activation, possibly caused by persistent viral protein in germinal centers, may help explain why HIV viremia rebounds so rapidly after the interruption of HAART. Restoration of architecture may follow the treatment of patients with AIDS who initially had involuted and CD4 cell-depleted lymph nodes.
    No preview · Article · Nov 1999 · AIDS
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    ABSTRACT: At present, it is not known whether undetectable plasma viremia corresponds to an absence of human immunodeficiency virus type 1 (HIV-1) replication in lymphoid tissues. This issue has been explored in 11 subjects with primary HIV-1 infection treated with zidovudine plus didanosine by evaluating virologic markers in blood and lymphoid tissues 9–18 months after initiation of treatment. These markers include plasma viremia, measured with a sensitive assay with a detection limit of 20 HIV-1 RNA copies/mL, infectious virus titers and proviral DNA in lymph node mononuclear cells, and HIV-1 RNA in lymphoid tissue. Five subjects had plasma viremia < 20 copies/mL and showed no evidence of viral replication in lymphoid tissue. Six subjects had both detectable plasma viremia and evidence of HIV-1 RNA in lymphoid tissue. The results indicate that absence of detectable HIV RNA in lymphoid tissue is associated with viremia levels of HIV-1 RNA < 20 copies/mL.
    Full-text · Article · Jul 1998 · The Journal of Infectious Diseases
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    ABSTRACT: Evolutionary patterns of virus replication and distribution in lymphoid tissue during the early phases of HIV infection have not been delineated. Lymph node (LN) biopsies were excised from patients at different times after the estimated time of primary infection. Within 3 months of the acute viral syndrome, HIV was mostly present in individual virus-expressing cells in LNs; trapping of virions in the follicular dendritic cell (FDC) network was minimal or absent, but was the predominant form of HIV detected in LNs of subjects with chronic infection, either recent (4-20 months after primary infection) or long-term (>2-3 years after primary infection). Plasma viremia was significantly higher in patients during the first 3 months than in those recently infected; however, there were no significant differences in the number of virus-expressing cells per square millimeter of LN tissue in these two groups. Numbers of virus-expressing cells in lymphoid tissue were significantly lower in the subjects with long-term infection than in the other two groups. Therefore, during the transition from primary to chronic HIV infection, the level of HIV replication in lymphoid tissue remains elevated despite the fact that viremia is significantly downregulated. These findings have implications for therapeutic strategies in primary HIV infection and in recent seroconvertors.
    No preview · Article · Mar 1998 · Nature Medicine
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    ABSTRACT: Evolutionary patterns of virus replication and distribution in lymphoid tissue during the early phases of HIV infection have not been delineated. Lymph node (LN) biopsies were excised from patients at different times after the estimated time of primary infection. Within 3 months of the acute viral syndrome, HIV was mostly present in individual virus-expressing cells in LNs; trapping of virions in the follicular dendritic cell (FDC) network was minimal or absent, but was the predominant form of HIV detected in LNs of subjects with chronic infection, either recent (4−20 months after primary infection) or long-term (>2−3 years after primary infection). Plasma viremia was significantly higher in patients during the first 3 months than in those recently infected; however, there were no significant differences in the number of virus-expressing cells per square millimeter of LN tissue in these two groups. Numbers of virus-expressing cells in lymphoid tissue were significantly lower in the subjects with long-term infection than in the other two groups. Therefore, during the transition from primary to chronic HIV infection, the level of HIV replication in lymphoid tissue remains elevated despite the fact that viremia is significantly downregulated. These findings have implications for therapeutic strategies in primary HIV infection and in recent seroconvertors.
    No preview · Article · Feb 1998 · Nature Medicine
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    ABSTRACT: HIV-1-infected long-term nonprogressors are a heterogeneous group of individuals with regard to immunologic and virologic markers of HIV-1 disease. CC chemokine receptor 5 (CCR5) has recently been identified as an important coreceptor for HIV-1 entry into CD4+ T cells. A mutant allele of CCR5 confers a high degree of resistance to HIV-1 infection in homozygous individuals and partial protection against HIV disease progression in heterozygotes. The frequency of CCR5 heterozygotes is increased among HIV-1- infected long-term nonprogressors compared with progressors; however, the host defense mechanisms responsible for nonprogression in CCR5 heterozygotes are unknown. We hypothesized that nonprogressors who were heterozygous for the mutant CCR5 gene might define a subgroup of nonprogressors with higher CD4+ T cell counts and lower viral load compared with CCR5 wild-type nonprogressors. However, in a cohort of 33 HIV-1-infected long-term nonprogressors, those who were heterozygous for the mutant CCR5 gene were indistinguishable from CCR5 wild-type nonprogressors with regard to all measured immunologic and virologic parameters. Although epidemiologic data support a role for the mutant CCR5 allele in the determination of the state of long-term nonprogression in some HIV-1- infected individuals, it is not the only determinant. Furthermore, long-term nonprogressors with the wild-type CCR5 genotype are indistinguishable from heterozygotes from an immunologic and virologic standpoint.
    Full-text · Article · Oct 1997 · Journal of Clinical Investigation
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    ABSTRACT: Virologic and immunologic effects of immunomodulation during primary simian immunodeficiency virus (SIV) infection were examined in monkeys treated with cyclosporin or vehicle for 32 days beginning 5 days before SIV inoculation. Duration of antigenemia decreased in 5 of 7 treated monkeys, 2 having delayed onset and peak of antigenemia. Although proviral DNA levels in blood and lymph nodes and infected cell numbers in lymph nodes were transiently decreased, levels were similar to those in controls by day 14. The CD4:CD8 ratio and percentage of CD4+CD29+ cells decreased in controls 14 days after inoculation, but this decrease was delayed in treated monkeys. Two treated monkeys demonstrated rapid disease, with progressive antigenemia preceding early deaths 90–96 days after inoculation. Nevertheless, immunomodulation influenced the kinetics of primary SIV infection in some monkeys, supporting the rationale of careful exploration of the strategy of interference with the heightened state of cellular activation together with direct antiretroviral therapy in human immunodeficiency virus infection.
    Full-text · Article · Sep 1997 · The Journal of Infectious Diseases
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    ABSTRACT: Lymph nodes serve as reservoirs for the replication of human immunodeficiency virus (HIV) type 1. Comparison of serial measurements of virus burden in lymph nodes and peripheral blood after a change in antiretroviral therapy may provide insights into pathogenic mechanisms and permit a more accurate assessment of a therapeutic response. Nevirapine was added to the drug regiment of eight children with HIV infection treated with the combination of zidovudine and didanosine who had increasing levels of serum p24 antigen. Lymph node biopsies were performed at entry and after 12 weeks of therapy. Neither CD4 counts nor p24 antigen level correlated with the degree of viremia as measured by ribonucleic acid copy numbers in plasma. Correlations were found between HIV DNA copy number in peripheral blood mononuclear cells and HIV DNA copy number in lymph nodes (p = 0.02), as well as between peripheral blood CD4 counts and lymph node architecture. The HIV signals in the lymph nodes conformed to the anatomic organization of apical light zones in the germinal centers; however, in more advanced disease stages, organized germinal centers disappeared as evidence by a decline in the extent of the follicular dendritic network. Lymph node biopsies in this small number of HIV-infected children revealed a progressive loss of an organized architecture, especially of the follicular dendritic network. This correlated with a progressive loss of CD4+ cells but not with other measures of disease stage, including viral load, as measured by ribonucleic acid copy numbers.
    No preview · Article · Oct 1996 · Journal of Pediatrics
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    ABSTRACT: In a small percentage of persons infected with human immunodeficiency virus type 1 (HIV-1), there is no progression of disease and CD4+ T-cell counts remain stable for many years. Studies of the histopathological, virologic, and immunologic characteristics of these persons may provide insight into the pathogenic mechanisms that lead to HIV disease and the protective mechanisms that prevent progression to overt disease. We studied 15 subjects with long-term nonprogressive HIV infection and 18 subjects with progressive HIV disease. Nonprogressive infection was defined as seven or more years of documented HIV infection, with more than 600 CD4+ T cells per cubic millimeter, no antiretroviral therapy, and no HIV-related disease. Lymph nodes from the subjects with nonprogressive infection had significantly fewer of the hyperplastic features, and none of the involuted features, characteristic of nodes from subjects with progressive disease. Plasma levels of HIV-1 RNA and the viral burden in peripheral-blood mononuclear cells were both significantly lower in the subjects with nonprogressive infection than in those with progressive disease (P = 0.003 and P = 0.015, respectively). HIV could not be isolated from the plasma of the former, who also had significantly higher titers of neutralizing antibodies than the latter. There was viral replication, however, in the subjects with nonprogressive infection, and virus was consistently cultured from mononuclear cells from the lymph nodes. In the lymph nodes virus "trapping" varied with the degree of formation of germinal centers, and few cells expressing virus were found by in situ hybridization. HIV-specific cytotoxic activity was detected in all seven subjects with nonprogressive infection who were tested. In persons who remain free of disease for many years despite HIV infection the viral load is low, but viral replication persists. Lymph-node architecture and immune function appear to remain intact.
    Full-text · Article · Feb 1995 · New England Journal of Medicine
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    Full-text · Article · Aug 1994 · Nature
  • Cecil H. Fox · M Cottler-Fox
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    ABSTRACT: In situ hybridization (ISH) for HIV is an arduous, demanding means of detecting viral genetic material in cells and tissues. Good ISH requires broad technical skills and devotion to controls for every step of the process as well as a critical eye when interpreting results. ISH may be used to detect HIV in three ways: by hybridizing to viral RNA, by hybridizing to proviral mRNA being produced for virion packaging, and by hybridizing to proviral DNA in the cytoplasm or integrated in the nucleus of an infected cell. Here we discuss the technical considerations involved and the problems encountered in using ISH to study the pathobiology of HIV infection.
    No preview · Article · May 1993 · Microscopy Research and Technique
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    ABSTRACT: Primary infection with the human immunodeficiency virus (HIV) is generally followed by a burst of viraemia with or without clinical symptoms. This in turn is followed by a prolonged period of clinical latency. During this period there is little, if any, detectable viraemia, the numbers of infected cells in the blood are very low, and it is extremely difficult to demonstrate virus expression in these cells. We have analysed viral burden and levels of virus replication simultaneously in the blood and lymphoid organs of the same individuals at various stages of HIV disease. Here we report that in early-stage disease there is a dichotomy between the levels of viral burden and virus replication in peripheral blood versus lymphoid organs. HIV disease is active in the lymphoid tissue throughout the period of clinical latency, even at times when minimal viral activity is demonstrated in blood.
    No preview · Article · Apr 1993 · Nature
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    ABSTRACT: Dendritic cells (DC) were purified from human peripheral blood using a rapid and simple method based on magnetic depletion of phagocytes with carbonyl iron, followed by centrifugation of nonphagocytic cells on a Percoll density gradient and depletion of lymphocytes and macrophages/monocytes with a panel of MoAbs and immunomagnetic beads. Enriched DC were obtained with > 99% purity as judged by non-specific esterase (NSE) staining. After isolation, these cells, representing 0.4% of the starting mononuclear cell population, still function as potent antigen-presenting cells for purified T lymphocytes. The present results confirm the ability of human peripheral blood DC to present soluble antigens to T cells including microbial antigens and show, further, that DC are more potent soluble antigen-presenting cells than monocytes. The method was successfully applied to the purification of DC from the blood of HIV-infected individuals. We could not detect decreased numbers of DC in four individuals with early HIV infection and no replicating HIV was detected by in situ hybridization in the DC.
    Full-text · Article · Mar 1993 · Clinical & Experimental Immunology
  • D P Kotler · S Reka · J M Orenstein · C H Fox
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    ABSTRACT: Study objectives were to characterize the clinical syndrome of chronic idiopathic esophageal ulceration in patients with acquired immunodeficiency syndrome (AIDS), to determine the extent of local human immunodeficiency virus (HIV) infection, and to evaluate the effect of corticosteroid therapy upon symptoms and healing. Twelve AIDS patients with chronic esophageal ulcers whose etiology remained unknown after clinical evaluation were the subjects. All patients complained of severe odynophagia, chest pain, and weight loss. Barium radiography and endoscopy demonstrated large, undermined ulcers with severe acute inflammation. No evidence of herpes simplex viruses I or II, cytomegalovirus, fungi, or tumors were found histologically. Evidence of HIV was found in all ulcers using a combination of RNA in situ hybridization, immunohistochemistry, and quantitative antigen capture enzyme-linked immunosorbent assay of tissue homogenates. Steroid therapy by the oral or intravenous routes or by direct intralesional injection resulted in pain relief, weight gain in 10 patients, and ulcer healing in five patients. A characteristic clinical syndrome of chronic idiopathic esophageal ulceration may occur in patients with AIDS, related to local HIV infection in the esophagus. Corticosteroids relieve symptoms and may promote healing of the ulcer.
    No preview · Article · Jan 1993 · Journal of Clinical Gastroenterology
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    ABSTRACT: Study objectives were to characterize the clinical syndrome of chronic idiopathic esophageal ulceration in patients with acquired immunodeficiency syndrome (AIDS), to determine the extent of local human immunodeficiency virus (HIV) infection, and to evaluate the effect of corticosteroid therapy upon symptoms and healing. Twelve AIDS patients with chronic esophageal ulcers whose etiology remained unknown after clinical evaluation were the subjects. All patients complained of severe odynophagia, chest pain, and weight loss. Barium radiography and endoscopy demonstrated large, undermined ulcers with severe acute inflammation. No evidence of herpes simplex viruses I or II, cytomegalovirus, fungi, or tumors were found histologically. Evidence of HIV was found in all ulcers using a combination of RNA in situ hybridization, immunohistochemistry, and quantitative antigen capture enzyme-linked immunosorbent assay of tissue homogenates. Steroid therapy by the oral or intravenous routes or by direct intralesional injection resulted in pain relief, weight gain in 10 patients, and ulcer healing in five patients. A characteristic clinical syndrome of chronic idiopathic esophageal ulceration may occur in patients with AIDS, related to local HIV infection in the esophagus. Corticosteroids relieve symptoms and may promote healing of the ulcer.
    No preview · Article · Dec 1992 · Journal of Clinical Gastroenterology

Publication Stats

3k Citations
332.45 Total Impact Points

Institutions

  • 1997
    • Tulane University
      New Orleans, Louisiana, United States
  • 1996
    • National Cancer Institute (USA)
      • Pediatric Oncology Branch
      베서스다, Maryland, United States
  • 1993
    • Yale University
      New Haven, Connecticut, United States
  • 1991-1993
    • National Institutes of Health
      • Laboratory of Immunoregulation
      베서스다, Maryland, United States
  • 1992
    • George Washington University
      Washington, Washington, D.C., United States
  • 1989
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      베서스다, Maryland, United States