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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transmittance of pathogenic viruses by the widespread administration of protein fractions such as F VIII prepared on a large scale from pooled human plasma has been of growing concern. We have now demonstrated that significant amounts of pathogenic viruses including LAV/HTLVIII may be removed by a new large scale fractionation process for the preparation of human F VIII (Monoclate) which employs immunoaffinity chromatography. Model viruses representative of different virus families and the LAV strain of HIV were added to cryoprecipitate and then the mixture was processed as for Monoclate manufacturing. Virus titers were determined at each step of the fractionation procedures. An overall reduction of at least 6 logs was obtained for the model viruses and the HIV due to the purification process. An added heating step further increased the safety margin for the product resulting in at least an overall reduction of 7-9 logs for HIV. Clinical experience with Monoclate in virgin hemophiliacs has confirmed its viral safety. Our laboratories are exploiting a similar strategy of immunoaffinity chromatography to ensure the viral safety of FIX and protein C preparations derived from plasma.
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PMID:Removal of viral contaminants by monoclonal antibody purification of plasma proteins. 249 83

CD4 (T4) is a 60 kD glycoprotein expressed on a subset of T lymphocytes. CD4 augments T cell responses to suboptimal Ag stimulation. In addition, the CD4 molecule is the receptor for HIV-1. CD4 is phosphorylated on serine residues within the cytoplasmic domain and its cell surface expression is decreased in response to PMA, APC bearing the appropriate Ag or HIV infection. The kinetics of CD4 phosphorylation and modulation are similar, suggesting that the two events may be related. L3T4, the murine CD4 equivalent, is not modulated from the surface of mature, peripheral T cells in response to PMA. The difference in the ability to modulate L3T4 and CD4 in response to PMA may be due to differences between the two molecules or to differences between the cells in which they are expressed. To further define the requirements for CD4 modulation, we used retroviral vectors to transfer the cDNA for CD4 and various mutants of CD4 into two murine T cell hybridomas that express L3T4. One of these hybridomas, By155.16, does not modulate L3T4 in response to PMA and the other, 5D5.63, does modulate L3T4 in response to PMA. When expressed by these hybridomas CD4 is not modulated from the surface of By155.16 and is modulated from the surface of 5D5.63 in response to PMA. In both of these hybridomas, CD4 is phosphorylated on serine residues in response to PMA. A mutant form of CD4, CD4 delta, was constructed in which the majority of the cytoplasmic domain was deleted. When expressed in 5D5.63, CD4 delta was not modulated in response to PMA. Replacing the cytoplasmic domain of CD4 with that of the human IL-2 receptor did not reconstitute the ability of CD4 to be modulated. These results suggest that the inability to modulate L3T4 from the surface of murine peripheral T cells is due to features of the cell and not the molecule. Furthermore, the cytoplasmic domain of CD4 is required for its modulation from the cell surface in response to PMA.
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PMID:Requirements for modulation of the CD4 molecule in response to phorbol myristate acetate. Role of the cytoplasmic domain. 278 43

We studied the effect of HIV infection on the human monocytic cell line U937. The cell line was infected with cellfree HIV, strain HTLV-IIIB. After 3 wk, a high reverse transcriptase activity was continuously detected in the supernatant of the cell line. Neither cytopathic effects nor changes in cell growth were observed. After infection, accessory cell function on T cell proliferation induced by anti-CD3 mAb of both IgG1 and IgG2a subclasses and Con A was tested. Accessory cell function provided by U937 cells started to decline 3 wk after inoculation with HIV. This correlated with detectable reverse transcriptase activity. The remaining accessory cell capacity varied between 10 and 60% of accessory cell function mediated by noninfected U937 cells. It was excluded that decreased FcR expression on U937/HIV cells contributed to the accessory cell defect in the anti-CD3-driven system. IL-2R expression on T cells, cocultivated with U937/HIV and anti-CD3, was minimal. The accessory cell defect could only be partly overcome by addition of rIL-2 or IL-1. Addition of high titer (10(4) TCID50) HIV or U937/HIV cells did not affect T cell proliferation, which rules out that the observed inhibition is caused by HIV infection of T cells or suppressive effects of U937/HIV cells. These results suggest that infection of APC may contribute to the induction of immunologic abnormalities in early HIV infection. Thus, monocytes/macrophages may not only serve as a reservoir for the dissemination of HIV, but may be an important target cell through which the immune system is affected.
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PMID:Decreased accessory cell function by human monocytic cells after infection with HIV. 296 77

One mechanism of the immune suppression in HIV infection has been postulated as being caused by the interaction of HIV envelope glycoprotein gp120 with CD4 molecules. Thus, pretreatment of purified peripheral blood T cells or CD4+ T cell clones with gp120 (or an anti-CD4 mAb) results in inhibition of anti-CD3 mAb-induced proliferative responses. In this study, we have analyzed the role of the interacting pairs of costimulatory molecules, CD28-B71 (CD80) and CD40 ligand (CD40L)-CD40, to elucidate further the mechanism of HIV gp120-induced inhibitory effects on T cell functions. Interactions between CD28-B71 and CD40L-CD40 were found to be essential for the anti-CD3 mAb-induced T cell proliferation, as demonstrated by up-regulation of B71 and CD40L and the ability of anti-B71 and anti-CD40L mAbs to inhibit this response. Pretreatment of CD4+ T cells with gp120 before CD3 ligation with anti-CD3 mAb resulted in failure of up-regulation of CD40L on T cells and B71 on APC. Exogenous addition of anti-CD28 mAb overcame the inhibitory effect of gp120 on anti-CD3 mAb-induced T cell proliferation. We conclude that binding of gp120 to CD4 molecules on T cells may interrupt the sequential cascade of intercellular interaction involving 1) Ag/MHC class II-TCR/CD4, 2) CD40L-CD40, and 3) B71-CD28. These studies indicate that the CD4-gp120 interaction results in dysregulation of expression of costimulatory molecules, CD40L, and B71 expression on T cells and APC, respectively, thereby contributing to the T cell hyporesponsiveness in HIV infection.
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PMID:HIV gp120 inhibits T cell activation by interfering with expression of costimulatory molecules CD40 ligand and CD80 (B71). 754 27

Dendritic cells (DC) are the principle APC involved in primary immune responses; their major function is to obtain Ag in tissues, migrate to lymphoid organs, and activate T cells. DC are also the first immune cells to arrive at sites of inflammation on mucous membranes, the major site of sexual transmission of HIV. We have demonstrated previously that three populations of cells that can develop a dendritic morphology are present in peripheral blood. Two of these populations can express CD83, a marker of DC, and appear to be at different stages of maturation: 1) a precursor population and 2) a mature immunostimulatory DC. Precursor-derived DC express high levels of CD86 (B7-2) and HLA-DR but no CD80 (B7-1), whereas mature DC have high levels of expression of all three markers. Mature DC in peripheral blood bind HIV to their surface and induce infection when added to autologous CD4+ T cells in the absence of added stimuli, such as mitogens. These mature DC, when isolated directly from peripheral blood, appear to be conjugated to T cells, and these conjugates are infected easily and productively with HIV. These findings suggest a role for DC in early HIV infection in which they bind virus and interact with T cells locally or after migrating to a lymphoid organ, thus establishing a productive infection. Furthermore, they likely play a role in the propagation of HIV infection by activating T cells in the presence of HIV, which leads to viral replication and immune cell destruction.
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PMID:Both a precursor and a mature population of dendritic cells can bind HIV. However, only the mature population that expresses CD80 can pass infection to unstimulated CD4+ T cells. 756 Nov 24

CD4+ T cell clones specific for the HIV-1 envelope (env) protein are able to recognize not only uninfected APC that have taken up and processed exogenous env protein, but also virally infected cells expressing the env protein. We have evaluated the hypothesis that endocytosis of endogenously synthesized env protein from the plasma membrane of infected cells permits entry of the protein into the MHC class II-restricted Ag processing pathway. We show here that the env protein of HIV-1 is internalized at a surprisingly high rate through a mechanism that is dependent upon a tyrosine-containing motif located in the cytoplasmic domain of the gp41 subunit. Mutation of a critical cytoplasmic tyrosine residue or truncation of the C-terminal portion of the cytoplasmic domain resulted in forms of the env protein that did not undergo rapid internalization. However, by a variety of assays, these poorly internalized forms of the env protein were processed for class II-restricted Ag presentation as efficiently as wild-type env protein, indicating that internalization by this pathway is not essential for class II-restricted presentation. In addition, a secreted form of the env protein was presented efficiently by class II MHC under conditions that prevented re-uptake by endocytosis. Taken together, these results suggest that although rapid endocytosis from the cell surface is likely to be a major mechanism by which endogenously synthesized env protein is processed for association with class II MHC, an internal pathway may also be used.
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PMID:Endocytosis of endogenously synthesized HIV-1 envelope protein. Mechanism and role in processing for association with class II MHC. 760 19

A subset of endogenously synthesized Ags can be processed for class II-restricted presentation, probably through multiple mechanisms. Processing of exogenous Ags for class II-restricted presentation appears to occur in unique endosomal processing compartments with lysosomal characteristics including the presence of the lysosomal membrane protein LAMP-1. Therefore, we attempted to enhance the efficiency of class II-restricted presentation of an endogenous Ag, the HIV-1 envelope (env) protein, by specifically targeting the Ag to class II processing compartments through the pathway followed by LAMP-1. Because the env protein associates tightly with CD4 shortly after synthesis, we first targeted the env protein using a chimeric CD4 protein consisting of the extracellular domain of CD4 and the transmembrane and cytoplasmic domains of LAMP-1. When co-expressed with this chimeric protein, the env protein was efficiently localized to lysosome-like compartments. Enhanced stimulation of env-specific CD4+ T cell clones by APC expressing the env protein and the CD4-LAMP-1 chimera was readily demonstrated in both cytotoxicity assays and proliferation assays. We also targeted the env protein directly as a chimeric protein consisting of the extracellular domain of the env protein and the transmembrane and cytoplasmic domains of LAMP-1. The proliferative response of env-specific CD4+ T cell clones to the env-LAMP-1 chimera was greatly enhanced compared with wild-type env protein, especially when limiting numbers of stimulator cells were used. The enhanced stimulatory capacity of APC expressing LAMP-1-targeted Ags has important implications for vaccine design.
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PMID:Lysosome-associated membrane protein-1-mediated targeting of the HIV-1 envelope protein to an endosomal/lysosomal compartment enhances its presentation to MHC class II-restricted T cells. 763 36

APC dysfunction may be important in immune dysregulation associated with HIV disease. Langerhans cells, epidermal APC, can be infected with HIV, although their function in HIV-infected persons has not been studied. Therefore, we studied the immunologic function of Langerhans cells, in parallel with blood APC (enriched for monocytes/macrophages (M phi) function, in 21 HIV-seropositive (HIV+) and 21 HIV-seronegative volunteers, including three monozygotic twin pairs discordant for HIV serology. Langerhans cells from HIV+ patients were quantitatively normal and expressed normal levels of HLA-DR. However, Langerhans cells from AIDS patients and M phi from both AIDS and HIV+ non-AIDS patients stimulated allogeneic T cells less well compared with control APC. In addition, decreased recall Ag- and mitogen-induced T cell responsiveness was observed in HIV+ patients using either autologous Langerhans cells or autologous M phi as APC/accessory cells. Interestingly, Langerhans cells and M phi isolated from HIV+ twins (CD4+ cell counts of 181, 271, and 562/mm3) were able to present recall Ag normally to HIV-uninfected syngeneic T cells. In summary, APC from HIV+ patients were impaired in their ability to generate a primary immune response (i.e., alloantigen-induced T cell stimulation), but they retained the ability to generate a secondary immune response (i.e., recall Ag-induced syngeneic T cell stimulation). Thus, these findings suggest that defects in secondary immune responses commonly observed in HIV disease are dependent on T cell dysfunction alone, whereas defective primary immune responses may be secondary to both T cell and APC dysfunction.
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PMID:Functional studies of epidermal Langerhans cells and blood monocytes in HIV-infected persons. 789 31

The AIDS-associated lymphomas represent a heterogeneous set of disease processes. The largest histologic subset of lymphomas is the large-cell lymphomas, which represent a spectrum of disease processes ranging from monomorphic monoclonal B-cell proliferations to very polymorphic and polyclonal mixtures of B cells, T cells and macrophages. The next most frequent class of systemic lymphoma are the small non-cleaved cell or Burkitt's-like lymphomas. These are relatively monomorphic, monoclonal malignant B-cell proliferations. The final subset of lymphomas, which are likely to become more common as the AIDS epidemic progresses, are the primary CNS lymphomas, which are expansions of EBV-immortalized B cells. The high incidence of tumor-associated EBV in the CNS lymphomas makes these lesions somewhat analogous to an opportunistic EBV infection. In HIV disease there is a long lag after infection before the appearance of clinical manifestations of impaired T-cell immunity. During this period, both appropriate B-cell proliferation in response to antigen (including the ubiquitous HIV) and abnormal B-cell proliferation (autoimmune, dysregulated) occur as the follicular architecture is disrupted by the virus and potential APC are exposed and/or infected with HIV. The destruction of FDC or the involution of their processes could interfere with the elimination by apoptosis of low-avidity B-cell clones. Antigen-competent B cells with pre-existing chromosomal translocations such as the t(8;14) (c-myc, IgH) would have a selective growth advantage in this setting. Figure 9 shows a schematic representation of prelymphomatous and lymphomagenic events as they are projected to occur. A similar pathogenetic scheme has been postulated for follicular B-cell lymphomas: PCR studies have demonstrated that a pool of t(14;18) (IgH;bcl-2) B-cells are present in lymph nodes featuring follicular hyperplasia. In response to antigen (the evidence favoring antigen drive is extensive hypersomatic mutation in sequences related to binding sites), B cells with the t(14;18) translocation have a selective advantage because the bcl-2 oncogene confers a resistance to apoptosis. Burkitt's lymphomas, particularly sporadic or HIV variants, fulfill at least the key criteria for antigen competence, mainly the presence of surface Ig. The c-myc-associated chromosomal translocational events are likely to occur early during the enzymatic machinations of gene rearrangement. Such B cells would be in the dysregulated cytokine and antigen milieu of HIV disease and ultimately could have a selective advantage. EBV infection of B cells probably requires activation and expression of the CD21 receptor. Furthermore, CD5+ B cells of CLL are refractory to EBV infection.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pathogenesis of AIDS lymphomas. 798 99

In the last few years, plasma fractionation has been subjected to major technological changes which have contributed to improve the viral safety and overall purity of plasma derivatives. New viral inactivation treatments, primarily solvent-detergent and pasteurization, have been introduced in the manufacturing processes of plasma derivatives to ensure the inactivation of major plasma-borne viruses, including HIV and hepatitis B and C viruses. Concurrently, new highly purified products obtained by chromatographic methods (mainly ion exchange and/or immunopurification) have been developed in the last five years and have replaced former preparations, providing a significantly higher safety level in terms of purity and viral risks. For an example, the new generation of Factor VIII and Factor IX concentrates (to treat hemophilia A and hemophilia B, respectively), which have been introduced in the last five years, are purified over 10,000- to 20,000-fold from plasma, as compared to only 50- to 100-fold for the former products. Similarly, new, standardized, clotting factor or protease inhibitor concentrates have been made available, thus permitting to carry out selective hemotherapy of specific diseases. Examples include the development of von Willebrand factor, factor XI, protein C, or alpha 1-antitrypsin concentrates for the substitutive therapy of congenital or acquired deficiencies. In addition, the concept of good manufacturing practices has been implemented, whereas carefully controlled, validated processes are contributing to the consistency in the quality of those products. Current major problems in plasma fractionation relate to the potential occurrence of new pathogenic agents that could resist present viral inactivation treatments and to the potential effect of given purification technologies on the development of immunogenic properties of proteins. Current trends indicate that significant progress in viral safety of plasma derivatives (for example through the introduction of new concept such as viral filtration) are to be expected very soon. Further research in this very important field is mandatory as plasma should remain the starting material of important therapeutic products in the coming years.
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PMID:[Plasma fractionation. Progress, problems and perspectives]. 799 59


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