CD40 Ligand (CD154) Incorporated into HIV Virions Induces Activation-Induced Cytidine Deaminase (AID) Expression in Human B Lymphocytes

Abstract

Most AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL) arises from errors in immunoglobulin heavy-chain gene (IgH) class switch recombination (CSR) or somatic hypermutation (SHM), events that occur in germinal center (GC) B cells and require the activity of activation induced cytidine deaminase (AID). Several oncogenic viruses (EBV, HCV, HPV) can induce AID gene (AID) expression, and elevated AID expression is seen in circulating lymphocytes prior to AIDS-NHL diagnosis. Here, we report that HIV produced in peripheral blood mononuclear cells (PBMC) induced AID expression in normal human B cells. Since HIV produced in PBMC contains host cell CD40 ligand (CD40L) incorporated into the viral membrane, and CD40L is known to induce AID expression in human B cells, the role of virion-associated CD40L in HIV-induced AID expression was examined. Only viruses expressing functional CD40L were seen to induce AID expression; CD40L-negative HIV did not induce AID expression. The induction of AID expression by CD40L+ HIV was abrogated by addition of blocking anti-CD40L antibody. AID protein was detected in B cells exposed to CD40L+ HIV using intracellular multicolor flow cytometry, with most AID producing B cells expressing the CD71 activation marker on their surface. Therefore, HIV virions that express CD40L induce AID expression in B cells, and this induction appears to be due to a direct interaction between CD40L on these viruses and CD40 on B cells. These findings are consistent with a role for HIV in the direct stimulation of B cells, potentially leading to the accumulation of molecular lesions that have the potential to contribute to the development of NHL.

Acquisition of Host-Derived CD40L by HIV-1In Vivoand Its Functional Consequences in the B-Cell Compartment

“…be noted that a recent work by Epeldegui and colleagues reported the physical presence of host CD40L on the surface of virions circulating in the plasma from two out of three HIV-1-infected persons (18). Therefore, our observations validate this report and render experiments aimed at monitoring the biological activity of virus-associated CD40L highly important.…”

“…From crucial regulators of CD40/NF-B signal transduction and apoptosis, such as TRAF1 and A20, to adhesion molecules (ICAM-1), costimulation molecules (CD80), and cytokines (LTA and LTB) associated with B-cell immune functions, to negative-feedback-loop transcripts (IB␣) and essential components involved in antibody gene recombination and hypermutation (AID), the resulting portrait is unequivocally akin to an activated, proliferating, and/or differentiating B-cell phenotype. The present findings extend beyond the study made by Epeldegui and coworkers who have assessed the capacity of CD40L-bearing HIV-1 particles to induce the activation of a single gene in B cells, namely, AID (18).…”

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

“…Indeed, abnormal antibody responses and B cell phenotypes have been reported from aberrant gp120 and Nef signaling (24,25), and IL-10 and CD154 can be either helpful or deleterious in combination with different factors (26). Moreover, HIV exploits these interactions and hijacks the CD40 signaling pathway to induce alterations in B cell phenotype and function (27). Thus, the nature of the helper T cell response would be expected to influence antibody response to particular viral antigens.…”

Alterations of the B-Cell Response by HIV-1 Replication

“…Host cell derived CD40 ligand (CD40L) that are incorporated into HIV-1 virions are capable of binding to CD40 expressed on B cells and promoting class switch [15]. In a recent study, Epeldegui et al [16] investigated binding of host CD40L in HIV-1 virions to CD40 on B-cell surface and the effect on expression of AID in B cells. They demonstrated that HIV-1 virions produced in 293 T cells expressing CD40L, but not virions produced in 293 T cells without CD40L expression, stimulated AID transcription, resulting in elevated AID protein levels.…”