transforming-growth-factor-beta and Acquired-Immunodeficiency-Syndrome

As we continue to explore the biology of TGF-beta in the network of cells and mediators contributing to host defense, the mechanisms controlling whether the pro- or antiinflammatory effects of this peptide prevail will be unraveled. Understanding these basic mechanisms may offer new approaches for identifying agonists and/or antagonists and in which circumstances their use might be appropriate. The striking differences between local and systemic administration of this cytokine reaffirm that the functional consequences of any biologic mediator must be considered in context (9) and, furthermore, suggest avenues of therapeutic application (Table III). In summary, the central role of TGF-beta in normal and aberrant host defense has become indisputable.

Topics: Acquired Immunodeficiency Syndrome; Animals; Disease Models, Animal; Fibrosis; Humans; Immune Tolerance; Immunosuppression Therapy; Inflammation; Monocytes; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Wound Healing

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Chronic Disease; Cryptosporidiosis; Cytokines; Humans; Interferon-gamma; Interleukin-15; Interleukin-4; Jejunum; Transforming Growth Factor beta; Viral Load

Gp120 is a critical component of the envelope of HIV-1. Its role in viral entry is well described. In view of its position on the viral envelope, gp120 is a part of the retrovirus that immune cells encounter first and has the potential to influence antiretroviral immune responses. We propose that high levels of gp120 are present in tissues and may contribute to the failure of the immune system to fully control and ultimately clear the virus. Herein, we show for the first time that lymphoid tissues from acutely HIV-1/SIV (SHIV)-KB9-infected macaques contain deposits of gp120 at concentrations that are high enough to induce suppressive effects on T cells, thus negatively regulating the antiviral CTL response and contributing to virus survival and persistence. We also demonstrate that SHIV-KB9 gp120 influences functional T cell responses during SHIV infection in a manner that suppresses degranulation and cytokine secretion by CTLs. Finally, we show that regulatory T cells accumulate in lymphoid tissues during acute infection and that they respond to gp120 by producing TGFbeta, a known suppressant of cytotoxic T cell activity. These findings have significant implications for our understanding of the contribution of non-entry-related functions of HIV-1 gp120 to the pathogenesis of HIV/AIDS.

Topics: Acquired Immunodeficiency Syndrome; Animals; CD8-Positive T-Lymphocytes; CHO Cells; Cricetinae; Cricetulus; HIV Envelope Protein gp120; HIV-1; Humans; Immunity, Cellular; Lymphoid Tissue; Macaca mulatta; Membrane Glycoproteins; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Viral Envelope Proteins

Peripheral blood CD16 (Fc receptor for immunoglobulin G III)-positive monocytes have been shown to expand in different pathological conditions, such as cancer, asthma, sepsis, human immunodeficiency virus infection, and AIDS progression, but data in leishmaniasis are lacking. We found that cutaneous leishmaniasis patients (n = 15) displayed a significant increase in the percentage (3.5 vs. 10.1) as well as mean fluorescent intensity (13.5 vs. 29.2) of ex vivo CD16 expression in monocytes as compared with healthy controls. We observed a significant positive correlation between the percentage of ex vivo CD16+ monocytes and lesion size (P = 0.0052, r = 0.75) or active transforming growth factor-beta plasma levels (P = 0.0017, r = 0.78). In addition, two patients with nonhealing lesions during a 3-year follow-up had high (9.1-19.4%) CD16 levels at diagnosis. Our data suggest a deleterious role for CD16 in human leishmaniasis, as well as its possible use as a marker for disease severity and/or adverse disease outcome.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antigens, CD; Biomarkers; Follow-Up Studies; Gene Expression Regulation; GPI-Linked Proteins; HIV; Humans; Leishmaniasis, Cutaneous; Male; Monocytes; Neoplasms; Receptors, IgG; Sepsis; Transforming Growth Factor beta

T cell activation levels in HIV infection are predictive of AIDS progression. We searched for the immunological correlates of protection against disease progression by studying the early stages of nonpathogenic SIV infection in African green monkeys (SIVagm). The African green monkeys (AGMs) displayed high peak viremias and a transient decline in levels of blood CD4(+) and CD8(+) T cells between days 5 and 17 after infection. A concomitant increase in levels of CD4(+)DR(+), CD8(+)DR(+), and CD8(+)CD28(-) cells was detected. After the third week, T cell activation returned to baseline levels, which suggested a protective downregulation of T cell activation. A very early (24 hours after infection) and strong induction of TGF-beta1 and FoxP3 expression was detected and correlated with increases in levels of CD4(+)CD25(+) and CD8(+)CD25(+) T cells. This was followed by a significant increase in levels of IL-10, whereas IFN-gamma gene upregulation was more transient, and levels of TNF-alpha and MIP-1alpha/beta transcripts did not increase in either blood or tissues. The profiles were significantly different during primary SIV infection in macaques (SIVmac); that is, there was a delayed increase in IL-10 levels accompanied by moderate and persistent increases in TGF-beta levels. Together, our data show that SIVagm infection is associated with an immediate antiinflammatory environment and suggest that TGF-beta may participate in the generation of Tregs, which may prevent an aberrant chronic T cell hyperactivation.

Topics: Acquired Immunodeficiency Syndrome; Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chemokine CCL5; Chlorocebus aethiops; Disease Progression; DNA-Binding Proteins; Humans; Interferon-gamma; Interleukin-10; Lymphocyte Activation; Receptors, CCR1; Receptors, CCR5; Receptors, Chemokine; RNA, Viral; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; T-Lymphocyte Subsets; Transforming Growth Factor beta; Transforming Growth Factor beta1; Viremia

Originally identified as the gamma interferon-inducing factor, interleukin-18 (IL-18) was rediscovered as a proinflammatory cytokine related to the IL-1 family of cytokines that plays an important role in both innate and adaptive immune responses against viruses and intracellular pathogens. Despite its importance in inducing and regulating immune responses, relatively little is known about its production in HIV infection. We report here significantly (P < 0.05) elevated levels of this cytokine in the sera of human immunodeficiency virus (HIV)-infected/AIDS patients compared to those of HIV-seronegative healthy persons. Surprisingly, the peripheral blood mononuclear cells (PBMC) from HIV-infected/AIDS patients were compromised in the ability to upregulate IL-18 gene expression and produce this cytokine with and without lipopolysaccharide (LPS) stimulation. A significant positive correlation (P < 0.05) existed between the concentration of IL-18 in serum and its production from PBMC of HIV-seronegative healthy individuals but not those of HIV-infected/AIDS patients. Furthermore, the patients' PBMC expressed relatively reduced levels of activated caspase-1 constitutively as well as in response to LPS stimulation. Our data suggest the involvement of transforming growth factor beta (TGF-beta) in suppressing IL-18 production from the patients' PBMC for the following reasons. (i) In in vitro studies it suppressed the production of IL-18 from PBMC. (ii) Its levels were significantly higher in the plasma of patients compared to that of control subjects. (iii) A significant negative correlation existed between the concentrations of TGF-beta in plasma and of IL-18 in serum of the patients. The elevated levels of IL-18 in the serum of HIV-infected individuals may contribute to AIDS pathogenesis, whereas its compromised production from their PBMC in response to stimuli may reduce their innate defense to opportunistic intracellular pathogens.

Topics: Acquired Immunodeficiency Syndrome; Caspase 1; Cells, Cultured; Enzyme Activation; HIV Infections; Humans; Interleukin-18; Leukocytes, Mononuclear; Transforming Growth Factor beta

Kaposi's sarcoma (KS) is the most common neoplastic apoptosis manifestation of acquired immunodeficiency syndrome. Toremifene is known to upregulate transforming growth factor beta-1 (TGF-beta1), which is a growth-inhibitory factor for KS. We investigated the in vitro effect of toremifene on KS cells.. MTT assay was used to measure the growth of four KS cell lines and a human umbilical vein endothelial (HUVE) cell line after incubation with toremifene. Reverse transcription polymerase chain reaction and ELISA were used to measure the level of TGF-beta1.. The IC(50) for the KS cells ranged from 2.2 to 3.2 microM, and 80% of the growth inhibition occurred within 24 h. Toremifene enhanced TGF-beta1 mRNA expression, and the level of TGF-beta1 increased from 103 to 473 pg/ml after 48 h of incubation. Toremifene had no effect on the growth of HUVE cells.. Toremifene has a specific antiproliferative effect on KS cells. The stimulation of TGF-beta1 production may play a role in the antiproliferative process.

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Agents, Hormonal; Apoptosis; Cell Division; Enzyme-Linked Immunosorbent Assay; Humans; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sarcoma, Kaposi; Time Factors; Toremifene; Transforming Growth Factor beta; Tumor Cells, Cultured

This study focused on the role of the HIV-derived viral protein, tat, in activating central nervous system (CNS)-derived endothelial cells (EC) to produce interleukin-8 (IL-8), a stimulator and chemoattractant for neutrophils and lymphocytes. Human CNS-EC treated with tat (100 ng/ml) demonstrated a 2 to 3 fold upregulation in IL-8 mRNA and protein. Tumor necrosis factor-alpha (TNF) and tat were found to act additively in upregulating IL-8 production. In contrast, transforming growth factor beta (TGF beta), appeared to down modulate tat-induced IL-8 production. These data suggest that extracellular tat, especially in the presence of TNF, may be responsible for the local production of IL-8.

Topics: Acquired Immunodeficiency Syndrome; Brain; Cell Movement; Cells, Cultured; Chemotaxis; Endothelium; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Viral; Gene Products, tat; HIV-1; Humans; Interleukin-1; Interleukin-8; Male; Neutrophils; RNA, Messenger; tat Gene Products, Human Immunodeficiency Virus; Transforming Growth Factor beta

The T-cell stimulatory function of accessory cells isolated from peripheral blood lymphocytes of AIDS patients has been reported to be suppressed. These patients also have elevated levels of the immunosuppressive factor transforming growth factor (TGF)-beta1 in their serum and plasma.. To explore the role of TGF-beta1 in the loss of accessory cell function of peripheral blood lymphocytes from AIDS patients.. Fluorescent labeled anti-TGF-beta1 and confocal microscopy were used to detect the presence of TGF-beta1 on the cell membrane of dendritic cells. To assess the role of TGF-beta1 in the inhibition of accessory cell function in AIDS, antibodies against TGF-beta1 or the TGF-beta1 type III receptor, beta-glycan, were added to a mixed lymphocyte reaction.. TGF-beta1 was detected on the cell membrane of dendritic cells isolated from AIDS patients. The addition of blocking antibodies against either TGF-beta1 or beta-glycan restored the T-cell stimulatory function to accessory cells from these patients.. T-cell stimulatory function was not irreversibly lost in AIDS patients. Our data suggested that beta-glycan-TGF-beta1 immunosuppressive complexes may contribute to the suppression of accessory cell function in these patients.

Topics: Acquired Immunodeficiency Syndrome; Antibodies; Antigen-Presenting Cells; Dendritic Cells; Humans; Immune Tolerance; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Neutralization Tests; Proteoglycans; Receptors, Transforming Growth Factor beta; T-Lymphocytes; Transforming Growth Factor beta; Trypsin

Ameboid microglia express human immunodeficiency virus 1 (HIV-1) more frequently than do ramified microglia. These two microglial subtypes might also differ in the frequency with which they express transforming growth factor-beta1 (TGF-beta1), a cytokine that regulates HIV-1 expression in monocytes. Results described here show that ameboid and ramified microglia express TGF-beta1. In brain tissues from HIV-1-infected individuals as compared with seronegative controls, ameboid rather than ramified microglia more frequently expressed TGF-beta1. Ameboid microglia, isolated and cultured from postmortem adult human brain more frequently expressed TGF-beta1 in presence of interleukin-1(IL-1), a cytokine that is elevated in brains of HIV-1-infected individuals when compared with seronegative controls. The stimulation of TGF-beta1 by IL-1 was dose and time dependent, occurring with ameboid microglia isolated from either frontal cortex or globus pallidus but not midbrain pons. Ameboid microglia are similar to the RCA-1-positive cells that form clusters, called microglial nodules, in the brain of HIV-1-infected individuals. Pathologic conditions, such as disseminated microglial nodules, are associated with HIV-1 encephalitis, direct infection of the brain, and moderate to severe neurologic impairment. TGF-beta1 expression in ameboid microglia may play a role in HIV-1 neuropathogenesis.

Topics: Acquired Immunodeficiency Syndrome; Adult; Brain; Case-Control Studies; Cells, Cultured; Female; HIV-1; Humans; Interleukin-1; Male; Microglia; Middle Aged; RNA Processing, Post-Transcriptional; Stimulation, Chemical; Transforming Growth Factor beta

Topics: Acquired Immunodeficiency Syndrome; Animals; Cytokines; Female; HIV-1; Interferon-gamma; Interleukin-1; Interleukin-10; Interleukin-2; Interleukin-4; Lung Diseases, Interstitial; Lymphocyte Activation; Mice; Mice, Inbred C57BL; RNA, Messenger; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Virus Replication

Immunohistochemical localization of transforming growth factor beta 1 (TGF-beta 1) was studied in Kaposi's sarcoma (KS) tissues obtained from autopsy and biopsy materials of patients with and without acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV) infection. There was no difference in the localization and distribution of TGF-beta 1 in KS tissues regardless of the HIV-1 status of the patients. Rabbit polyclonal antibodies to synthetic peptides, corresponding to the first 30 amino acids of mature TGF-beta 1, anti-LC(1-30), and anti-CC(1-30), were used for localization of intracellular and extracellular TGF-beta 1. An antibody to a peptide corresponding to amino acids 266 to 278 of the TGF-beta 1 precursor sequence anti-Pre(266 to 278) was used to detect the TGF-beta 1 precursor and the latency-associated peptide. Intracellular mature TGF-beta 1 was demonstrated in mononuclear cells, presumably macrophages, within KS tumors but not in spindle-shaped KS cells. Extracellular mature TGF-beta 1 was localized in the basement membranes of blood vessels and fibrous capsules of KS tumors. Intracellular reactivity to anti-Pre was localized in vascular smooth muscle cells and pericytes within the tumor, in variable proportions of spindle-shaped KS cells, and also in macrophage-like cells. These cells appear to be the production sites of TGF-beta 1, which may exert paracrine as well as autocrine proliferative effects.

Topics: Acquired Immunodeficiency Syndrome; HIV Seropositivity; HIV-1; Humans; Immunohistochemistry; Sarcoma, Kaposi; Tissue Distribution; Transforming Growth Factor beta

Myeloid cells are important reservoirs of HIV-1 infection. In response to pathogenic agents, macrophages secrete inflammatory cytokines that can modulate viral replication and contribute to AIDS pathogenesis. Because HIV replication is dependent on cellular activation, immunosuppressive cytokines that deactivate macrophages and T cells may be important modulators of an antiviral effect. We tested the anti-HIV potential of the immunosuppressive cytokine-transforming growth factor beta (TGF-beta 1) alone and in combination with AZT in a new monomyeloblastic model of HIV-1 infection. The PLB-985 cell model was infected with HIV IIIB strain, and the course of HIV-1 infection and replication was monitored by reverse transcriptase assay, p24 immunofluorescence, and northern blot analysis of HIV-1-specific mRNA. TGF-beta 1 as a single agent had no effect on the multiplication of HIV-IIIB in de novo-infected PLB 985 monomyeloblastic cells. However, cotreatment with TGF-beta 1 and AZT synergistically slowed virus multiplication within the first week following infection, as determined by reverse transcriptase measurement, p24 antigen detection, and northern blot analysis of viral RNA. The synergistic actions of TGF-beta 1 and AZT were also observed in PLB 985 cells infected with an AZT-resistant strain of HIV-1 (HIV 1393). Synergism between nucleoside analogs and cytokines may be an important therapeutic approach to HIV-1 infection. Elucidation of the role of cytokines in controlling the degree of HIV multiplication may have an impact on both clinical treatments and understanding the progression to AIDS.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Cell Line; Drug Therapy, Combination; HIV-1; Humans; Immunosuppressive Agents; Leukemia, Myelomonocytic, Acute; Leukocytes, Mononuclear; Transforming Growth Factor beta; Tumor Cells, Cultured; Zidovudine

Several humoral growth factors may contribute to the development and growth of AIDS-associated Kaposi's sarcoma (KS). They are either provided by chronically activated cells of the immune system or in an autocrine/paracrine manner by the neoplastic cells themselves. Transforming growth factor beta(TGF-beta) may directly enhance the growth of KS cells and tumor matrix formation. To mediate a signal both TGF-beta receptors type I and type II (TbetaR-I and TbetaR-II) have to be expressed. We investigated the expression of TGF-beta, TGF-beta receptors types I and II, and endoglin, a nonsignaling-type TbetaR-III, by means of immunohistochemistry on skin biopsies from patients with AIDS-related KS. We found that the TGF-beta ligand was expressed by KS cells in 9 of 11 samples. TbetaR-II was strongly expressed in 10 of 12 samples, but none of the investigated tumor samples stained for TbetaR-I. Endoglin was weakly expressed on all KS lesions and stained the endothelium of tumor-associated vessels in 92% of the samples. These findings show that most KS lesions have the ability to produce TGF-beta and that KS cells maintain a high expression of TbetaR-II in the absence of TbetaR-I, which may allow KS to escape growth inhibitory effects of endocrine or paracrine TGF-beta.

Topics: Acquired Immunodeficiency Syndrome; Antigens, CD; Endoglin; Humans; Male; Neoplasm Proteins; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; Sarcoma, Kaposi; Skin Neoplasms; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

To determine whether the early-acting hematopoietic growth factors stem-cell factor (SCF) or interleukin-3 (IL-3), are able to overcome the bone-marrow suppressive effects of cytokines or drugs involved in the hematologic abnormalities that accompany HIV-1 infection.. In vitro colony formation assays of normal human bone-marrow cells exposed to the myelosuppressive drugs, zidovudine, interferon-alpha (IFN-alpha) and ganciclovir, or the myelosuppressive cytokines, tumor necrosis factor-alpha (TNF-alpha) or transforming growth factor-beta (TGF-beta), implicated in HIV dysmyelopoiesis.. SCF (10 ng/ml) enhanced the numbers of erythroid (BFU-E) colonies in the presence of zidovudine or ganciclovir (P < 0.05) and myeloid [colony-forming unit granulocyte macrophage (CFU-GM)] colonies in the presence of ganciclovir or IFN-alpha (P < 0.05) relative to controls. IL-3 (10 ng/ml) also improved erythroid colony numbers in the presence of zidovudine (P < 0.05) and CFU-GM in the presence of IFN-alpha (P < 0.05). Neither factor consistently altered the inhibition of TGF-beta or TNF-alpha. The 50% inhibitory concentration (IC50) of the myelosuppressive agents was altered in only one setting, using IL-3 in the presence of zidovudine.. These data suggest that SCF or IL-3 may have a therapeutic application in overcoming hematopoietic abnormalities associated with drugs commonly used in the care of AIDS patients. However, they may have less capacity to overcome the bone-marrow inhibitory effects of the endogenous cytokines TNF-alpha and TGF-beta.

Topics: Acquired Immunodeficiency Syndrome; Bone Marrow Diseases; Cell Division; Colony-Forming Units Assay; Erythroid Precursor Cells; Ganciclovir; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Interferon alpha-2; Interferon-alpha; Interleukin-3; Macrophages; Recombinant Proteins; Stem Cell Factor; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Zidovudine

We examined the interaction between HIV-1 Tat protein and the opportunistic pathogen Mycobacterium avium. AIDS-associated strains of M. avium were shown to bind Tat protein quite avidly in an attachment assay. The attachment of M. avium to Tat was shown to occur via the integrin alpha 5 beta 1 present on the mycobacterial cell surface. M. avium strains were shown to bind the viral Tat protein with high affinity in a specific fashion (600 binding sites with a Kd of 1 to 5 nM). M. avium coated with Tat protein were shown to be more infective for human alveolar macrophages than untreated M. avium. Other HIV-1 Ags had no such effects (e.g., p24, p17). Examination of the cytokine profile of infected macrophages showed that M. avium-Tat complexes induced higher levels of TGF beta-1 (TGF beta 1) than M. avium alone or M. avium that had been in contact with other viral proteins. Conditioned media from HIV-1-infected H9 cells released a factor that enhanced M. avium intramacrophage growth, and was partially neutralized by an anti-Tat Ab. Finally, Tat protein (purified or present in conditioned media from infected cells) moderately enhanced the growth of M. avium strains in extracellular media, and exposure of M. avium to Tat protein in the presence of IL-6 enhanced the growth of AIDS-associated strains. These data argue for an interaction between the Tat viral product and the opportunistic pathogen M. avium which may contribute to the exquisite susceptibility of AIDS subjects to this pathogen.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Bacterial Adhesion; Gene Products, tat; HIV-1; Humans; Integrins; Interleukin-6; Macrophages, Alveolar; Monokines; Mycobacterium avium; tat Gene Products, Human Immunodeficiency Virus; Transforming Growth Factor beta

We investigated whether reduction of the phytohemagglutinin (PHA)-induced proliferative response of lymphocytes from HIV type-1 (HIV-1)-infected (HIV+) individuals could be explained by overproduction of transforming growth factor-beta 1 (TGF-beta 1), a strong inhibitor of T cell proliferation. PHA-stimulated PBMC from 40 HIV- and 42 HIV+ homosexual men from the Baltimore Center of the Multicenter AIDS Cohort Study (MACS) were studied using Northern blot analysis of expression of TGF-beta 1 mRNA and determining the effects of anti-TGF-beta 1 neutralizing antibody on PHA-induced proliferative responses. Compared to the HIV- donors, HIV+ donors did not show increased expression of TGF-beta 1 mRNA in unstimulated or PHA-stimulated PBMC. Furthermore, a neutralizing antibody to TGF-beta 1 did not reverse the decreased proliferative response of PBMC from HIV+ individuals to PHA or interleukin-2. These results indicate that TGF-beta 1 is not involved in T cell proliferation defects seen in HIV+ donors.

Topics: Acquired Immunodeficiency Syndrome; Antibodies; Gene Expression; HIV Seropositivity; HIV-1; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Phytohemagglutinins; RNA, Messenger; T-Lymphocytes; Transforming Growth Factor beta

The development of Candida meningitis in a patient following partial resection of a glioblastoma raised suspicion that transforming growth factor (TGF-beta), an immunosuppressive cytokine known to be produced by this tumor, would be elevated in his cerebrospinal fluid (CSF). By using a highly specific bioassay, the concentration of TGF-beta was found to be 609 pg/mL, which was 10-fold greater than the mean CSF TGF-beta value in control subjects with no neurologic disease. Increased CSF TGF-beta levels were also detected in patients with other central nervous system (CNS) diseases: malignancies and AIDS dementia complex. These findings suggest that TGF-beta may play an immunopathogenetic role in the CNS.

Topics: Acquired Immunodeficiency Syndrome; Brain Neoplasms; Candidiasis; Glioblastoma; Humans; Immunity, Cellular; Immunocompromised Host; Male; Meningitis, Fungal; Middle Aged; Postoperative Complications; Transforming Growth Factor beta

Monocytes in the circulation of normal individuals express two receptors for the constant region of immunoglobulin, Fc gamma RI and Fc gamma RII. In contrast, we have observed that AIDS monocytes express significant levels of a third Fc gamma R, Fc gamma RIII (CD16), which is normally associated with activation or maturation of the monocyte population. By dual-fluorescence analysis using a monoclonal antibody specific for Fc gamma RIII (MAb 3G8), 38.5 +/- 3.2% of the LeuM3 (CD14)-positive monocytes in AIDS patients were CD16 positive as compared to 10.4 +/- 1.0% for healthy individuals (n = 29; P less than 0.005). Furthermore, AIDS monocytes expressed Fc gamma RIII-specific mRNA which is expressed minimally or not at all in control monocytes. As a recently identified inducer of Fc gamma RIII expression on blood monocytes, transforming growth factor-beta (TGF-beta) was found to be elevated in the serum and/or plasma of AIDS patients. Moreover, incubation of normal monocytes with AIDS serum or plasma induced CD16 expression which correlated with serum TGF-beta levels (r = 0.74, P less than 0.001) and was inhibited with a neutralizing antibody to TGF-beta. Thus, the increased CD16 expression on peripheral blood monocytes in AIDS patients may be the consequence of elevated circulating levels of the polypeptide hormone TGF-beta.

Topics: Acquired Immunodeficiency Syndrome; Antigens, CD; Antigens, Differentiation; Antigens, Differentiation, Myelomonocytic; Humans; Lipopolysaccharide Receptors; Male; Monocytes; Receptors, Fc; Receptors, IgG; RNA, Messenger; Transforming Growth Factor beta

This study examines the contribution of transforming growth factor beta (TGF beta), one of the most potent endogenous immunosuppressive factors, to the development of immunodeficiency in human immunodeficiency virus (HIV) infection. Increased titers of TGF beta were found in supernatants of peripheral blood mononuclear cells (PBMCs) from HIV-infected donors as compared to uninfected controls (P less than 0.001). This correlated closely with defective responses of CD4+ lymphocytes to the recall antigens tuberculin purified protein derivative or tetanus toxoid. The addition of TGF beta-neutralizing antibody to PBMCs partially restored these defective T-cell responses. Furthermore, purified TGF beta or HIV+ PBMC culture supernatants preferentially inhibited proliferation of CD4+ lymphocytes as compared to CD8+ cells. The increased expression of the TGF beta protein was associated with increased TGF beta mRNA as determined by a polymerase chain reaction assay. This increase in TGF beta protein and mRNA was due to a selective upregulation of the TGF beta 1 isoform. These results indicate that overexpression of TGF beta 1 occurs in HIV-infected individuals and that this cytokine can contribute to impaired immune functions and to depletion of CD4+ T lymphocytes.

Topics: Acquired Immunodeficiency Syndrome; Base Sequence; CD4 Antigens; Cell Division; Cells, Cultured; HIV Infections; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Molecular Sequence Data; Oligonucleotide Probes; Polymerase Chain Reaction; RNA; T-Lymphocytes; Transforming Growth Factor beta