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PubMed2005

Role of thromboxane A2 in the induction of apoptosis of immature thymocytes by lipopolysaccharide.

Lipopolysaccharide (LPS) causes apoptotic deletion of CD4(+) CD8(+) thymocytes, a phenomenon that has been linked to immune dysfunction and poor survival during sepsis. Given the abundance of thromboxane-prostanoid (TP) receptors in CD4(+) CD8(+) thymocytes and in vitro evidence that thromboxane A(2) (TXA(2)) causes apoptosis of these cells, we tested whether enhanced generation of TXA(2) plays a role in LPS-induced thymocyte apoptosis. Mice injected with 50 micro LPS intraperitoneally displayed a marked increase in generation of TXA(2) and prostaglandin E(2) in the thymus as well as apoptotic deletion of CD4(+) CD8(+) thymocytes. Administration of indomethacin or rofecoxib inhibited prostanoid synthesis but did not affect thymocyte death. In contrast, thymocyte apoptosis in response to LPS was significantly attenuated in TP-deficient mice. These studies indicate that TXA(2) mediates a portion of apoptotic thymocyte death caused by LPS. The absence of an effect of global inhibition of prostanoid synthesis suggests a complex role for prostanoids in this model.

Animals↗
PubMed1995

Dysregulated production of interleukin-10 (IL-10) and IL-12 by peripheral blood lymphocytes from human immunodeficiency virus-infected individuals is associated with altered proliferative responses to recall antigens.

The loss of immune function following infection with human immunodeficiency virus (HIV) may result from altered production of immunoregulatory cytokines such as interleukin-10 (IL-10) and IL-12. In this study, we analyzed IL-10 and IL-12 production by mitogen-stimulated peripheral blood mononuclear cells (PBMC) from HIV+ individuals and correlated their levels with proliferative responses to the recall antigens HIV p25 and influenza virus. We report two distinct groups of HIV+ patients. One group produced small amounts of IL-10, had PBMC that proliferated in response to recall antigens, and demonstrated enhanced recall antigen-induced proliferation upon addition of anti-IL-10 antibodies and/or IL-12. Conversely, the second group produced high levels of IL-10, had PBMC that failed to proliferate to recall antigens, and did not demonstrate enhanced proliferation upon addition of anti-IL-10 antibodies and/or IL-12. Mitogen-stimulated PBMC from both groups produced significantly lower levels of IL-12 than did those from HIV- controls. Analysis of the source of the IL-10-producing cell subset in PBMC demonstrated that in HIV+ individuals, IL-10 is produced by monocytes, while in HIV- controls, it is produced by both T cells and monocytes. Taken together, our results suggest that monocytes from HIV+ individuals secrete decreased amounts of IL-12, a Th1-type cytokine, which may lead to the development of Th2-type responses characterized by high IL-10 secretion and immune dysfunction.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Induction of hypergammaglobulinemia and macrophage activation by silicone gels and oils in female A.SW mice.

Although most published epidemiological studies have found little evidence of systemic autoimmune disease associated with silicone breast implants, there still remains a question of whether silicones can cause local and/or systemic immune dysfunction. This study further investigates the effects of silicones on autoantibody and immunoglobulin production and macrophage activation in female A.SW mice. Sixty mice were divided among four treatment groups receiving a 0.5-ml intraperitoneal injection of either phosphate-buffered saline (PBS), pristane, silicone gel, or silicone oil. Test bleeds were taken periodically for 6 months. In contrast to pristane, neither silicone gel nor silicone oil induced lupus-associated antinuclear autoantibodies (immunoglobulin G [IgG] anti-nRNP/Sm, Su, and ribosomal P) or lupus nephritis. However, serum IgM became elevated persistently within 1 month of silicone gel or silicone oil administration. Also, the level of IgG3 was clearly elevated in silicone oil-treated mice. In contrast, IgG1, IgG2a, and IgG2b levels were not affected greatly by either silicone gel or oil. Furthermore, peritoneal macrophages from silicone- and pristane-treated mice produced higher levels of interleukin-1beta (IL-1beta) and IL-6 than those from PBS-treated mice after lipopolysaccharide stimulation. These results suggest that silicone gels and oils are capable of inducing hypergammaglobulinemia and activating macrophages in female A.SW mice.

Animals↗
PubMed1982

T and B lymphocyte function in response to a protein-free diet.

Groups of female adult rats were fed either isocaloric protein-free or 18% protein diets for various intervals. Four days before sacrifice, the animals were immunized either with sheep erythrocytes or with a trinitrophenyl-lipopolysaccharide (TNP-LPS) conjugate. Spleen lymphoid cell populations, spleen plaque-forming cells, and serum hemolysins were measured. A persistent diminution, proportional to the duration of protein deprivation, was observed in all parameters studied after immunization with the T-dependent antigen, sheep erythrocytes. The immune dysfunction was more pronounced for hemolysin titers, which became undetectable after 15 days of protein-free diet. The response of the protein-free group to the T-independent antigen (TNP-LPS) after 15 days of diet was only 34% of the control. When a T-cell lymphokine, macrophage migration inhibitory factor, was measured, a normal response was observed in the protein-free group. Feeding a normal diet rapidly restored the spleen plaque-forming cell populations to 60% of normal after 4 days and to 100% after 6 days. Protein starvation influenced the production of antibodies more than it did the number of antibody-forming cells. The nutritional impairment of immunoglobulin synthesis appears to be reversible.

Animals↗
PubMed1982

Effects of immunosuppression with cyclophosphamide on acute murine cytomegalovirus infection and virus-augmented natural killer cell activity.

The effects of cyclophosphamide (CY) treatment on acute murine cytomegalovirus (MCMV) infection were studied to explore the potential usefulness of MCMV as a means of detecting immune dysfunction and to identify host defense mechanisms important for protection against MCMV. Conditions found optimal for enhancing MCMV infection with CY included infecting adult mice with 2 X 10(5) PFU or more of virus and administering 80 mg or more of CY per kg 1 to 3 days later. In addition to enhanced mortality, virus titers in lung, liver, and spleen were elevated in CY-treated mice, and wet weights of liver, spleen, and thymus were depressed when compared with those of infected but untreated mice. Treatment with CY before MCMV challenge was not as efficient a means of enhancing mortality as treatment after virus challenge. The effect that the time of CY administration relative to infection had on mortality correlated with the effect of such timing on natural killer cell activity. Animals treated before infection exhibited depressed natural killer cell activity initially. However, they rapidly recovered this response, and by 5 days postinfection they had the same level of virus-augmented activity seen in untreated mice. In contrast, animals treated after infection did not recover natural killer cell activity and were more likely to die. A similar correlation was not obtained when the effects of CY on lymphocyte responses to B and T cell mitogens were examined, nor were there striking differences in pathology between the treatment groups. The data suggest an important role for natural killer cells in host defense against MCMV. Also, increased susceptibility to MCMV may provide a useful indicator of deficits in the natural killer cell response.

Animals↗
PubMed1983

Macrophage activation in murine African trypanosomiasis.

African trypanosomiasis is accompanied by a profound general immunosuppression in which both suppressive T cells and macrophages (M phi) have been implicated. The present studies define changes in the M phi surface, endocytic and secretory properties, during the infection of mice by Trypanosoma brucei. Peritoneal M phi obtained after the control of the first wave of parasitemia displayed characteristics similar to those activated by intracellular pathogens, such as Mycobacterium bovis bacillus Calmette-Guérin, e.g., the enhanced expression of Ia antigen, decreased M phi-specific antigens, receptors mediating the pinocytosis of mannose-terminal glycoproteins, and an increased ability to secrete plasminogen activator, superoxide anion, and H2O2. Some markers of macrophage activation persisted during the subpatent period before the recurrence of parasitemia, whereas others reverted to normal. Mature T cell function appears not to be essential for M phi activation by T. brucei since the infection of athymic nude mice also induced Ia antigens and plasminogen activator. These studies show that M phi activated by different pathways express common features which may contribute to immune dysfunction observed in trypanosomiasis, as well as in other infections.

Animals↗
PubMed2001

Detection of Mycobacterium tuberculosis group organisms in human and mouse joint tissue by reverse transcriptase PCR: prevalence in diseased synovial tissue suggests lack of specific association with rheumatoid arthritis.

Infection with mycobacterial species, including Mycobacterium tuberculosis, has long been implicated in the etiopathology of rheumatoid arthritis (RA) on the basis of clinical and pathological similarities between tuberculosis and RA. Despite evidence of immune responses to mycobacterial antigens in RA patient synovial fluid, cross-reactivity between these and host joint antigens, and the presence of M. tuberculosis protein antigen in RA synovial fluid, a definite causal association with RA has not been shown. Previous studies from our laboratory using reverse transcriptase PCR (RT-PCR) of bacterial rRNAs have shown RA synovium to be colonized by a diverse range of bacteria, most of commensal origin. However, M. tuberculosis group organism (MTG) RNA sequences were found in one RA patient tissue. Since this was considered of sufficient interest to warrant further investigation, we devised a M. tuberculosis-specific nested RT-PCR test which could be used for detection of MTG in a mixed pool of bacterial crDNAs. This test was used to investigate the distribution of MTG in RA synovial tissue and also non-RA arthritis and healthy control tissues and was also used to examine the tissue distribution of MTG in an acute and chronic model of M. tuberculosis infection in the BALB/c mouse. MTG sequences were found in a high proportion of RA patient synovial tissues but also in non-RA arthritis control tissues at lower frequency. This likely reflects trafficking of persistent M. bovis BCG to inflamed joint tissue, irrespective of cause. MTG were not found in healthy synovial tissue or the tissue of patients with undifferentiated arthritis. In both the acute and chronic models of infection in BALB/c mice, M. tuberculosis was also found to have trafficked to joint tissues, however, no signs of inflammation, arthritis, or pathology associated with M. tuberculosis infection was seen. These combined results would argue against a specific causal role of MTG in RA-like arthritis; however, their role as adjuvant in immune dysfunction in an innately susceptible host cannot be excluded.

Acute Disease↗
PubMed1987

Simian immunodeficiency virus induces expression of class II major histocompatibility complex structures on infected target cells in vitro.

The human immunodeficiency virus (HIV) and the closely related simian immunodeficiency virus (SIV) induce profound immune dysfunction in primate species. The present studies show that cell populations infected in vitro with SIV exhibit increases in major histocompatibility complex (MHC) class II antigen expression. Cell lines chronically infected with both the monkey and human viruses express substantially more MHC class II but not more lineage-restricted or activation antigens on their membranes than do uninfected cell lines. Furthermore, 2'-deoxy-5-iodouridine increased MHC class II antigen expression on SIV-infected cell lines in parallel with increased expression of viral antigens. MHC class II induction does not appear to be mediated through the production of a soluble factor, such as gamma interferon, by SIV-infected cells. Interestingly, studies of the kinetics of antigen expression by cell lines after SIV infection indicate that the induction of MHC class II structures is a late event. Immunoelectron microscopy revealed that MHC class II antigen is expressed not only on the surfaces of the SIV-infected cells but also on the envelope of virus particles derived from those cells. MHC antigen expression on virus-infected cells and the expression of those determinants by the virus may play a role in the pathogenesis of acquired immunodeficiency syndrome and the autoimmune abnormalities observed in HIV-infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Inhibition of lymphoproliferation by a synthetic peptide with sequence identity to gp41 of human immunodeficiency virus type 1.

Peptides were synthesized that contained sequences from two regions (env amino acids [aa] 581 to 597 and 655 to 671) of the transmembrane protein gp41 and one region of the external envelope glycoprotein gp120 (aa 457 to 464) of human immunodeficiency virus type 1. Selection of these sequences was based on their homology to the highly conserved and immunosuppressive sequence contained within the transmembrane proteins p15E and gp21 of animal and human retroviruses, respectively. Peptide aa581-597 was found to specifically inhibit human and murine lymphoproliferation, whereas peptides aa655-671 and aa457-464 had no activity. These results suggest a mechanism by which human immunodeficiency virus type 1 gp41 exerts a direct immunosuppressive effect in vivo, analogous to that postulated for p15E and gp21, which could contribute to the immune dysfunction observed in patients suffering from acquired immunodeficiency syndrome. It is of particular interest that the sequence aa 584 to 609, shown to contain B- and T-helper-cell epitopes, overlaps with the sequence aa 581 to 597 that is shown here to inhibit lymphoproliferation. The potential implications of this overlap of immunologic activities are discussed.

Cell Line↗
PubMed1992

Transcellular activation of the human immunodeficiency virus type 1 long terminal repeat in cocultured lymphocytes.

One of the unexplained aspects of the progression of AIDS is that immunological abnormalities are detectable before CD4+ T-helper cell depletion occurs (A.R. Gruters, F.G. Terpstra, R. De Jong, C.J.M. Van Noesel, R.A.W. Van Lier, and F. Miedema, Eur. J. Immunol. 20:1039-1044, 1990; F. Miedema, A.J. Chantal-Petit, F.G. Terpstra, J.K.M.E. Schattenkerk, F. de Wolf, B.J.M. Al, M. Roos, J.M.A. Lang, S.A. Danner, J. Goudsmit, and P.T.A. Schellekens, J. Clin. Invest. 82:1908-1914, 1988; G.M. Shearer, D.C. Bernstein, K.S. Tung, C.S. Via, R. Redfield, S.Z. Salahuddin, and R.C. Gallo, J. Immunol. 137:2514-2521, 1986). In this report, we describe a mechanism by which human immunodeficiency virus type 1 (HIV-1)-infected cells can influence neighboring HIV-1-infected T lymphocytes and uninfected T cells as well. We have examined the interaction of T-cell and macrophage cell lines that are transfected with HIV-1 DNA by using cocultured lymphocytes. The HIV-1 constructs we used lack a functional pol gene and therefore do not produce infectious virus. Cocultivation results in the transcellular activation of the HIV long terminal repeat in the cocultured T cells. This transcellular activation is evident in as little as 3 h of cocultivation, at ratios of HIV-expressing cells to target cells as low as 1:1,000, and is dependent on the Tat-responsive element. The demonstration that a small number of HIV-expressing cells can affect a large number of uninfected bystander cells in a short period of time suggests a mechanism by which global immune dysfunction can precede the high prevalence of infected cells.

Cell Line↗
PubMed1994

Two subpopulations of human triple-negative thymic cells are susceptible to infection by human immunodeficiency virus type 1 in vitro.

Some infants infected with human immunodeficiency virus type 1 (HIV-1) rapidly develop a fatal disease characterized by a severe lymphopenia. To explain the immune dysfunction, we proposed a mechanism by which a nongeneration of CD4+ T cells is caused by HIV-1 infection of thymic cells. To examine this hypothesis, we infected primary triple-negative (TN; phenotypically CD3- CD4- CD8-), CD1a- TN, or CD1a+ TN thymic cell subsets. Our data indicate that by flow cytometry, TN, CD1a- TN, and CD1a+ TN cells remain CD4 negative throughout the culture period. We demonstrated that TN and CD1a+ TN thymic cell subsets are susceptible to HIV-1 as is the entire thymic cell population, whereas CD1a- TN cells are not. A limited number of infected TN cells are expressing HIV-1 but the level of transcription is very high in permissive cells, as detected by in situ hybridization. We then performed blocking experiments on TN cells to examine the mechanism of HIV-1 entry into these cells. CD4 (OKT4a) monoclonal antibody blocks their infection. Finally, infection experiments on two subpopulations of TN cells (CD2+ CD7+ and CD2- CD7-) indicate that infected TN cells may correspond to both immature thymocytes and thymic dendritic cells. These data are of particular interest since infection of thymic stromal cells might result in an impairment of T-cell differentiation, which may explain a nongeneration of functional CD4+ T-cell population in the thymus. This phenomenon may play a role in AIDS pathogenesis, in particular in infants born from seropositive mothers.

Antibodies, Monoclonal↗
PubMed1994

Myristylation of Pr60gag of the murine AIDS-defective virus is required to induce disease and notably for the expansion of its target cells.

Murine AIDS (MAIDS) is characterized by severe lymphadenopathy and splenomegaly. The proliferation of the infected target B cells is also an important manifestation of the disease (M. Huang, C. Simard, D. G. Kay, and P. Jolicoeur, J. Virol. 65:6562-6571, 1991). The etiologic agent of MAIDS is a defective murine leukemia virus that is deleted of most of its pol and env genes and appears to encode a single protein, the Gag precursor Pr60gag protein. Pr60gag is myristylated and attached to the plasma membrane. To study the role myristylation on the function of Pr60gag, we have generated a myristylation-negative (Myr-) mutant of the MAIDS defective virus. We found that Myr- Pr60gag interacted less tightly with the plasma membrane. In addition, the Myr- MAIDS defective virus mutant was unable to induce expansion of infected cells and was nonpathogenic. These results emphasize the essential role of Pr60gag in the disease process. Our data also suggest that Pr60gag, once recruited to the cell membrane through its myristylation, interacts with other membrane-bound effectors to send signals to induce proliferation of the infected cells and to initiate immune dysfunctions.

Animals↗
PubMed1995

The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle.

Human immunodeficiency virus type 1 (HIV-1) infection causes profound immunological defects in afflicted patients. Various mechanisms have been proposed to account for the immune dysfunction in AIDS ultimately leading to loss of CD4+ T cells, including HIV-1 envelope-mediated syncytium formation, apoptosis, and cytokine modulation. Here we present results which suggest a novel hypothesis for T-cell dysfunction. We show, using HIV-1 bearing a novel cell surface reporter gene, that infected cells are unable to progress normally through the cell cycle and became arrested in the G2 + M phase. Furthermore, we identify the HIV-1 vpr gene product as being both necessary and sufficient for eliciting this cell cycle arrest. Cell cycle arrest induced by Vpr correlates with an increase in the hyperphosphorylated (inactive) form of the cyclin-dependent serine/threonine kinase CDC2, consistent with an arrest of cells at the boundary of G2 and M.

Acquired Immunodeficiency Syndrome↗
PubMed1998

A lymph node-derived cytopathic simian immunodeficiency virus Mne variant replicates in nonstimulated peripheral blood mononuclear cells.

Lymph nodes (LNs) are sites of active human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) replication and disease at both early and late stages of infection. Consequently, variant viruses that replicate efficiently and subsequently cause immune dysfunction may be harbored in this tissue. To determine whether LN-associated SIVs have an increased capacity to replicate and induce cytopathology, a molecular clone of SIV was isolated directly from DNA extracted from unpassaged LN tissue of a pig-tailed macaque (Macaca nemestrina) infected with SIVMne. The animal had declining CD4+ T-lymphocyte counts at the time of the LN biopsy. In human CD4+ T-cell lines, the LN-derived virus, SIVMne027, replicated with relatively slow kinetics and was minimally cytopathic and non-syncytium inducing compared to other SIVMne clones. However, in phytohemagglutinin-stimulated pig-tailed macaque peripheral blood mononuclear cells (PBMCs), SIVMne027 replicated efficiently and was highly cytopathic for the CD4+ T-cell population. Interestingly, unlike other SIVMne clones, SIVMne027 also replicated to a high level in nonstimulated macaque PBMCs. High-level replication depended on the presence of both the T-cell and monocyte/macrophage populations and could be enhanced by interleukin-2 (IL-2). Finally, the primary determinant governing the ability of SIVMne027 to replicate in nonstimulated and IL-2-stimulated PBMCs mapped to gag-pol-vif. Together, these data demonstrate that LNs may harbor non-syncytium-inducing, cytopathic viruses that replicate efficiently and are highly responsive to the effects of cytokines such as IL-2.

Amino Acid Sequence↗
PubMed2002

Rev-independent simian immunodeficiency virus strains are nonpathogenic in neonatal macaques.

The viral protein Rev is essential for the export of the subset of unspliced and partially spliced lentiviral mRNAs and the production of structural proteins. Rev and its RNA binding site RRE can be replaced in both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) by the constitutive RNA transport element CTE of the simian type D retroviruses. We used neonatal macaques as a sensitive animal model to evaluate the pathogenicity of a pair of SIV mutant strains generated from Rev-independent molecular clones of SIVmac239 which differ only in the presence of the nef open reading frame. After high primary viremia, all animals remained persistently infected at levels below the threshold of detection. All macaques infected as neonates developed normally, and none showed any signs of immune dysfunction or disease during follow-up ranging from 2.3 to 4 years. Therefore, the Rev-RRE regulatory mechanism plays a key role in the maintenance of high levels of virus propagation, which is independent of the presence of nef. These data demonstrate that Rev regulation plays an important role in the pathogenicity of SIV. Replacement of Rev-RRE by the CTE provides a novel approach to dramatically lower the virulence of a pathogenic lentivirus. These data further suggest that antiretroviral strategies leading to even a partial block of Rev function may modulate disease progression in HIV-infected individuals.

Animals↗
PubMed2003

Human immunodeficiency virus type 1 infection inhibits granulocyte-macrophage colony-stimulating factor-induced activation of STAT5A in human monocyte-derived macrophages.

Human immunodeficiency virus type 1 (HIV-1) infects cells of the monocyte/macrophage lineage. While infection of macrophages by HIV-1 is generally not cytopathic, it does impair macrophage function. In this study, we examined the effect of HIV-1 infection on intracellular signaling in human monocyte-derived macrophages (MDM) stimulated with the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is an important growth factor for cells of both the macrophage and granulocyte lineages and enhances effector functions of these cells via the heterodimeric GM-CSF receptor (GM-CSFR). A major pathway which mediates the effects of GM-CSF on macrophages involves activation of the latent transcription factor STAT5A via a Janus kinase 2 (JAK2)-dependent pathway. We demonstrate that GM-CSF-induced activation of STAT5A is inhibited in MDM after infection in vitro with the laboratory-adapted R5 strain of HIV-1, HIV-1(Ba-L), but not after infection with adenovirus. HIV-1 infection of MDM did not decrease the STAT5A or JAK2 mRNA level or STAT5A protein level or result in increased constitutive activation of STAT5A. Surface expression of either the alpha-chain or common beta(c)-chain of GM-CSFR was also unaffected. We conclude that HIV-1 inhibits GM-CSF activation of STAT5A without affecting expression of the known components of the signaling pathway. These data provide further evidence of disruption of cellular signaling pathways after HIV-1 infection, which may contribute to immune dysfunction and HIV-1 pathogenesis.

Base Sequence↗
PubMed2003

Differential impairment of lytic and cytokine functions in senescent human immunodeficiency virus type 1-specific cytotoxic T lymphocytes.

Telomere length is abnormally short in the CD8(+) T-cell compartment of human immunodeficiency virus type 1 (HIV-1)-infected persons, likely because of chronic cell turnover. Although clonal exhaustion of CD8(+) cytotoxic T lymphocytes (CTL) has been proposed as a mechanism for loss of antigen-specific responses, the functional consequences of exhaustion are poorly understood. Here we used telomerase transduction to evaluate the impact of senescence on CTL effector functions. Constitutive expression of telomerase in an HIV-1-specific CTL clone results in enhanced proliferative capacity, in agreement with prior studies of other human cell types. Whereas the CTL remain phenotypically normal in terms of antigenic specificity and requirements for proliferation, their cytolytic and antiviral capabilities are superior to those of control CTL. In contrast, their ability to produce gamma interferon and RANTES is essentially unchanged. The selective enhancement of cytolytic function in memory CTL by ectopic telomerase expression implies that loss of this function (but not cytokine production) is a specific consequence of replicative senescence. These data suggest a unifying mechanism for the in vivo observations that telomere lengths are shortened in the CD8(+) cells of HIV-1-infected persons and that HIV-1-specific CTL are deficient in perforin. Telomerase transduction could therefore be a tool with which to explore a potential therapeutic approach to an important pathophysiologic process of immune dysfunction in chronic viral infection.

Cytokines↗
PubMed2004

Human immunodeficiency virus type 1 gp120 induces abnormal maturation and functional alterations of dendritic cells: a novel mechanism for AIDS pathogenesis.

Dendritic cells (DCs) play a crucial role in bridging innate and acquired immune responses to pathogens. In human immunodeficiency virus type 1 (HIV-1) infection, immature DCs (iDCs) are also main targets for HIV-1 at the mucosal level. In this study, we evaluated the effects of HIV-1-DC interactions on the maturation and functional activity of these cells. Exposure of human monocyte-derived iDCs to either aldrithiol-2-inactivated HIV-1 or gp120 led to an upmodulation of activation markers indicative of functional maturation. Despite their phenotype, these cells retained antigen uptake capacity and showed an impaired ability to secrete cytokines or chemokines and to induce T-cell proliferation. Although gp120 did not interfere with DC differentiation, the capacity of these cells to produce interleukin-12 (IL-12) upon maturation was markedly reduced. Likewise, iDCs stimulated by classical maturation factors in the presence of gp120 lacked allostimulatory capacity and did not produce IL-12, in spite of their phenotype typical of activated DCs. Exogenous addition of IL-12 restores the allostimulatory capacity of gp120-exposed DCs. The finding that gp120 induces abnormal maturation of DCs linked to profound suppression of their activities unravels a novel mechanism by which HIV can lead to immune dysfunction in AIDS patients.

Acquired Immunodeficiency Syndrome↗