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Query: UMLS:C0021051 (immunodeficiency)
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Syncytia or multinucleated giant-cell formation is one of the major cytopathic effects induced by human immunodeficiency virus (HIV) infection. Cell fusion results from the strong interaction of CD4 molecules on the surface of the uninfected T cells and gp120, an external envelope glycoprotein of HIV on the infected T cells. We studied the production of HIV in fusion cells between MOLT-4 and virus-infected MOLT-4/HIV cells and found that HIV production was enhanced up to three- to fivefold, which showed a good correlation with the appearance and extent of syncytia formation. Blocking the fusion by monoclonal antibody against a binding epitope of CD4 molecule to gp120 decreased the HIV production significantly. Enhancement of HIV production was observed by more than five-fold in comparison with chronically infected cells, which were fusion free 20 hr postcocultivation. Electron microscopic observation also showed the presence of abundant HIV particles inside the fused cells and on the outer surface. AZT blocked the HIV augmentation of fused cells in coculture completely. Southern blot analysis revealed that both integrated and unintegrated HIV DNA were highly accumulated in fusion cells, as compared with fusion-free MOLT-4/HIV cells. Among unintegrated DNA, circular and linear DNA were accumulated to a similar degree. Northern blot hybridization showed that rapid enhancement of all three species of HIV-specific RNA containing genomic (9.2 kb) and subgenomic (4.3 and 1.9 kb) RNAs were found 20 hr postinfection in fusion cells. These data suggest that syncytia formation is an extremely active infection process of HIV, by which multiple rounds of reinfection might take place.
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PMID:Increased production of human immunodeficiency virus (HIV) in HIV-induced syncytia formation: an efficient infection process. 134 63

Incubation of the human T cell lymphotropic virus (HTLV)-IIIB and HTLV-RF strains of human immunodeficiency virus type 1 (HIV-1) with normal seronegative human serum under conditions that allow complement activation resulted in enhancement of infection of the MT2 human T cell line cultured in the presence of low amounts of virus. Infection of MT2 cells was assessed by measuring reverse transcriptase activity in supernatants at day 9 of culture. Complement activation by viral suspensions occurred through the alternative pathway. Opsonization of HTLV-RF viral particles with complement was sufficient to allow a productive infection to occur in cells exposed to suboptimal amounts of virus. Infection of MT2 cells with suboptimal amounts of serum-opsonized HIV-1 was suppressed by blocking the C3dg receptor (CR2, CD21) on MT2 cells with monoclonal anti-CR2 antibody and rabbit F(ab')2 anti-mouse immunoglobulin antibodies. Blocking of the gp120-binding site on CD4 under similar experimental conditions had no inhibitory effect on infection of MT2 cells with opsonized virus. Opsonization of HIV-1 with seronegative serum also resulted in a CR2-mediated enhancement of the infection of normal peripheral blood mononuclear cells and T lymphocytes. These results indicate that complement in the absence of antibody may enhance infection of C3 receptor-bearing T cells with HIV-1, and that the interaction of opsonized virus with the CR2 receptor may result by itself in the infection of target T cells in a CD4- and antibody-independent fashion.
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PMID:Complement mediates human immunodeficiency virus type 1 infection of a human T cell line in a CD4- and antibody-independent fashion. 182 39

A human Epstein-Barr virus-transformed B-cell line (IC.1) was characterized for cell surface antigen profile and permissivity to immunodeficiency virus (HIV) infection. According to cocultivation assay with MT2 cells, P24 release, and immunofluorescence assay, complement-sufficient serum enhanced in vitro infection of IC.1 cells. Enhancement occurs independently of the presence of HIV type 1-specific antibodies, although more efficiently when they are present. Blocking experiments with monoclonal antibodies demonstrated that complement receptor type 2 mediates this phenomenon and that the CD4 molecule is required for infection. Enhancement of in vitro infection on IC.1 cells appears closely related to previously described complement-mediated, antibody-dependent enhancement of HIV infection on the T-lymphoblastoid cell line MT2 (W. E. Robinson, Jr., D. C. Montefiori, and W. M. Mitchell, Lancet i:790-794, 1988).
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PMID:Antibody-dependent and antibody-independent complement-mediated enhancement of human immunodeficiency virus type 1 infection in a human, Epstein-Barr virus-transformed B-lymphocytic cell line. 184 8

Understanding the mode of replication of the human immunodeficiency virus (HIV) is necessary for explaining the natural history of HIV infection and for the development of therapeutic and prophylactic agents. The life cycle of HIV involves infective particles, the attachment of the virus to specific cell receptors, reverse transcription of the viral RNA into DNA by using viral encoded enzymes, integration of the viral DNA into the host genome, use of the host machinery to transcribe and translate viral genes, and the formation of budding particles. Viral encoded genes, regulated by a complex interaction of viral and host proteins with viral sequences, ultimately encode for the viral structural proteins, regulatory proteins, and enzymes necessary for the formation of mature infectious particles. Blocking one or more steps in the viral life cycle and preventing enhancement of virus production are important approaches in the control of HIV.
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PMID:Virology of the human immunodeficiency virus type 1. 219 58

Binding of glycoprotein gp120 to the T cell-surface receptor CD4 is a crucial step in CD4-dependent infection of a target cell by the human immunodeficiency virus (HIV). Blocking some or all gp120 molecules on the viral surface should therefore inhibit infection. Consequently, competitive receptor inhibitors, such as soluble synthetic CD4 (sCD4), synthetic CD4 peptides and immunoglobulins, have been investigated in vitro and in vivo, but little is known about the molecular mechanisms of these inhibitors. We have now quantitatively examined blocking by soluble CD4 in the hope of gaining insight into the complex process of viral binding, adsorption and penetration. At low sCD4 concentrations, the inhibition in three HIV strains is proportional to the binding of gp120. The biological association constant (gp120-sCD4 Kassoc) for HIV-2NIHZ is (8.5 +/- 0.5) x 10(7) M-1, whereas Kassoc for HIV-1HXB3 (1.4 +/- 0.2) and HIV-1MN (1.7 +/- 0.1) x 10(9) M-1 are 15-20-fold larger. For all three viral strains, the biological Kassoc from infectivity assays is comparable to the chemical Kassoc. The inhibitory action of sCD4 at high concentrations, however, is not fully explained by simple proportionality with the binding to gp120. Positive synergy in blocking of infection occurs after about half the viral gp120s molecules are occupied, and is identical for all three viral strains, despite the large differences in Kassoc. Our method of measuring the viral-cell receptor Kassoc directly from infectivity assays is applicable to immunoglobulins, to other viruses and to assays using primary or transformed cell lines.
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PMID:HIV requires multiple gp120 molecules for CD4-mediated infection. 237 93

The cellular receptor for HIV-1 is the leucocyte differentiation antigen, CD4. Blocking of HIV-1 infectivity can be achieved with monoclonal antibodies (MAbs) to some, but not all epitopes of this antigen. We demonstrate here, by inhibition of virus infection, blocking of syncytium formation and inhibition of pseudotype infection with a panel of CD4 MAbs, that HIV-1, HIV-2 and simian immunodeficiency virus (SIV) isolates share the same cellular receptor, the CD4 glycoprotein. It is also shown that very similar epitopes of this molecule are involved in virus binding. We infer from these data that the binding sites on these viruses are highly conserved regions, and may therefore make good targets for potential vaccines. In addition, we show that cell surface expression of CD4 is similarly modulated after infection of cell lines by all the viruses.
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PMID:The human and simian immunodeficiency viruses HIV-1, HIV-2 and SIV interact with similar epitopes on their cellular receptor, the CD4 molecule. 245 42

The expression of CD4 antigen on the surface of LeuM3-positive human blood monocytes was found to be variable with 65 to 90% of cells from 46 normal human volunteers being positive by dual staining flow cytometry. When monocytes adhered to plastic (but not when cultured on Teflon), a marked decrease in CD4 expression was observed between 1 and 24 h post-adherence. CD4 expression could not be detected in macrophages adhered to plastic for 5 days by using four anti-CD4 monoclonal antibodies in flow cytometry or direct immunofluorescence. Conversely an increasing proportion of adherent cells expressed LeuM3 and OKM5 surface antigens over the 5 days. CD4 mRNA levels were measured by slot-blot and Northern hybridization, and total cellular CD4 protein levels by immunoprecipitation. Both cellular mRNA and CD4 levels remained constant throughout the 5 day period but membrane CD4 protein levels were greatly reduced indicating that the down-regulation of CD4 was post-translational. Infection with two of six fresh human immunodeficiency virus (HIV) isolates showed different kinetic patterns when tested on purified monocytes recently adhered to plastic and macrophages adherent for 5 days. HIV antigen and reverse transcriptase levels in infected monocyte cultures remained high for 3 to 4 weeks before detachment and necrosis of the cells occurred. Infection of macrophages generated much lower levels of antigen and reverse transcriptase which declined to very low or undetectable levels over 2 weeks, leaving persisting viable macrophages. One week after infection HIV nucleic acid was detected in 69 +/- 7% of monocytes and 6 +/- 3% of macrophages by in situ hybridization. Blocking experiments with anti-Leu3a monoclonal antibody suggested that HIV infection of 5 day adherent macrophages occurred mainly by a mechanism other than binding to CD4.
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PMID:Variations in CD4 expression by human monocytes and macrophages and their relationships to infection with the human immunodeficiency virus. 267 36

Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) are important in normal immune processes. In this study, we demonstrate that human immunodeficiency virus type 1 (HIV-1) virions induce normal peripheral blood mononuclear phagocytes to produce both IL-1 and TNF within a few hours after their exposure to virus. The induction of these cytokines by HIV-1 does not require a productive infection. Blocking studies with soluble CD4 indicate that the effect is mediated through the CD4 molecule. In addition, the treatment of mononuclear phagocytes with OKT4A monoclonal antibody mimics the effects of HIV-1. Thus, these results indicate that induction of IL-1 and TNF alpha can occur via signals mediated through the CD4 molecule on mononuclear phagocytes. TNF has been shown by other investigators to induce HIV-1 expression. Therefore, TNF alpha may play a role in autocrine and paracrine regulation of HIV-1 expression. In addition, the induction of IL-1 and TNF by HIV-1 may also contribute to some of the neurologic and physiologic disorders associated with acquired immunodeficiency syndrome.
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PMID:Interleukin-1 and tumor necrosis factor alpha can be induced from mononuclear phagocytes by human immunodeficiency virus type 1 binding to the CD4 receptor. 278 93

Monocytes/macrophages (M/M) are the major host of human immunodeficiency virus (HIV) in solid tissues. However, blood monocytes are nonpermissive for HIV infection, indicating that M/M activation or differentiation is necessary for HIV replication. Since M/M are activated during immune responses, we investigated the effect of T-cell activation on HIV expression in M/M derived from peripheral blood of HIV-infected individuals. Previously, we reported that coculture of monocytes from HIV-infected donors with T cells and mitogens resulted in M/M differentiation and HIV expression. Production of HIV by M/M from infected donors required direct contact between monocytes and T cells (for the first 24 h), and the response to alloantigens, but not mitogens, was restricted to HLA-DR. In this study, we found that HIV was more readily recovered from M/M of asymptomatic HIV seropositive donors (69%) than from M/M of symptomatic donors (57%). Viral antigens (e.g., inactivated herpes simplex virus) could initiate the immune response and HIV expression. The ability of noninfected T cells to activate HIV expression in M/M and observations that treatments of M/M with antibodies to deplete T cells did not reduce HIV expression suggested that the monocytes were endogenously infected. To define the aspects of immune activation specifically involved in initiating HIV expression in M/M, interactions of M/M and T cells and participation of cytokines were investigated. The T cell which activated M/M was CD4+ CD8-. Fixed allogeneic cells are known to induce T-cell activation but were not able to serve as antigen for M/M differentiation, suggesting that M/M may need to function as antigen-presenting cells to receive the signal to differentiate and express HIV. Blocking of M/M-T-cell interaction with antibodies directed against LFA-1 or interleukin-1 prevented HIV expression. However, inhibition of later stages of T-cell activation, such as blocking of interleukin-2 receptors, did not diminish HIV expression in M/M. Consistent with the requirement for cell-cell contact between M/M and T cells, a variety of cytokines were unable to initiate HIV replication in M/M. The ability of T cells to induce cellular differentiation and HIV replication in M/M in vitro suggests that initiation of an immune response to an antigen, such as an opportunistic pathogen, could be a mechanism by which HIV disseminates to tissues in vivo.
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PMID:Mechanisms of immune activation of human immunodeficiency virus in monocytes/macrophages. 837 36

We tested the susceptibility of human purified, normal B lymphocytes to human immunodeficiency virus type 1 (HIV-1) infection, in the presence or absence of complement-sufficient serum and of virus-specific antibodies. Virus replication was detected when cells were infected in the presence of both complement and anti-HIV antibodies (C'-ADE conditions), by day 2 postinfection. Similar results were obtained when B lymphocytes were purified either from peripheral blood (three healthy donors) or from tonsils (four individuals with chronic tonsillitis). HIV infection was shown by polymerase chain reaction (PCR) detection of proviral sequences (gag and pol genes), by p24 antigen synthesis, and by cocultivation assay with MT2 cells. The higher p24 production was obtained when B cells were preactivated for 2 days by phorbol 12-myristate 13-acetate (PMA) before infection and then cultured in the presence of low-molecular weight B-cell growth factor (LMW-BCGF). Expression of virus envelope glycoprotein (gp) 120 could also be detected on a subpopulation of B cells (CD19+, CD22+) by flow cytometry. Blocking experiments with monoclonal antibodies (MoAbs) against CD4, CD21 (complement receptor 2 [CR2]), CD35 (CR1), CD19, and CD5 surface molecules indicated that infection of B cells involves CD4, CD21, and CD35 antigens. Indeed, blocking of CD4 receptor inhibited 10% of p24 production, and blocking of both CD21 and CD35 led to extinction of p24 signal. CR-dependent pathway is thus a major route for C'-ADE of HIV infection in normal B cells. Our results emphasize the importance of studying interactions between HIV and the complement system for better understanding infection mechanisms and the major dysfunctions of B cells in HIV-infected individuals.
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PMID:Complement and virus-specific antibody-dependent infection of normal B lymphocytes by human immunodeficiency virus type 1. 846 67

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