Recombinant Glycoprotein 120 of Human Immunodeficiency Virus is a Potent Interferon Inducer

Abstract

Cells infected with human immunodeficiency virus (HIV) induce antiviral activity in peripheral blood mononuclear cells (PBMC) from healthy donors. This activity is neutralized by anti-interferon-alpha antibody and partially destroyed at pH 2. Previous studies with enriched cell populations and monoclonal antibodies suggest that B lymphocytes are the main IFN-producing cells, and that both CD4 and HLA class II antigens are essential for IFN induction. Since the initial event of HIV infection of CD4+ cells is the interaction of the virus coat glycoprotein gp120 with CD4 molecule, we investigated whether gp120 is responsible for IFN induction. Using PBMC and recombinant gp120 obtained from a baculovirus expression system, dose-dependent induction of antiviral activity was observed with titers approaching 10(3) IU/ml. This induction was blocked in the presence of antibody to gp120. The antiviral activity was characterized as IFN-alpha by neutralization with IFN alpha-specific antibody. Preincubation of PBMC with anti-CD4 or the presence of soluble CD4 during incubation inhibited IFN induction, indicating that interaction of gp120 with cell-associated CD4 is responsible for this induction. Neither lymphoproliferation nor interleukin-2 (IL-2) production was observed during IFN induction. However, class G immunoglobulin secretion was enhanced by gp120, indicating that B cells are direct or indirect targets of gp120 stimulation in this experimental system. Since gp120 is shed from HIV-infected cells and occurs in the serum of acquired immunodeficiency syndrome (AIDS) patients, our data suggest that this glycoprotein is responsible for the induction of endogenous IFN and the polyclonal activation of B cells both of which are observed in AIDS patients.

In Vitro Treatment of Human Monocytes/Macrophages with Myristoylated Recombinant Nef of Human Immunodeficiency Virus Type 1 Leads to the Activation of Mitogen-Activated Protein Kinases, IκB Kinases, and Interferon Regulatory Factor 3 and to the Release of Beta Interferon

“…It has been shown that other HIV products, i.e., gp120, are able to induce the production of type I IFNs in MDMs, as well as in PBMC (3,20,21,42). Induction of both IFN-␣ and -␤ production as a consequence of the in vitro infection of MDM cultures has been reported (43,95).…”

Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor- viral RNA interactions

“…As retrotranscription can occur within cell-free HIV-1 virions (33), it is possible that HIV-1 DNA within viral particles could activate pDCs through TLR9 and fail to stimulate MDCs, which lack this receptor. Finally, a role played by interactions between viral envelope glycoproteins from Newcastle disease virus, HSV-1, CMV, and HIV-1 and components of the plasma membrane has been demonstrated in the induction of the type I IFN response (34)(35)(36)(37)(38). In human pDCs, HIV-1-induced IFN-α is inhibited with neutralizing anti-CD4 antibodies (39), implicating a role for viral envelope glycoprotein-CD4 contact in pDC activation.…”

Human immunodeficiency virus type 1 interaction with the membrane of CD4+ cells induces the synthesis and nuclear translocation of 70K heat shock protein

“…Besides the capacity to bind HIV-1 to CD4 receptor, gpl20 has been shown to possess intrinsic biological activities of its own (Capron & Ward, 1991) as shown, for instance, by its ability to induce neuronal cell injury in the mammalian central nervous system (Brennemann et al, 1988;Dreyer et al, 1990) and by its capacity to induce interferon (Capobianchi et al, 1992).…”