Human Immunodeficiency Virus Type 1-Associated CD40 Ligand Transactivates B Lymphocytes and Promotes Infection of CD4⁺T Cells

Abstract

Abnormal activation of B lymphocytes is a feature commonly seen in human immunodeficiency virus type 1 (HIV-1)-infected persons. However, the mechanism(s) responsible for this dysfunction is still poorly understood. Having recently shown that CD40L, the ligand for CD40, is inserted within emerging HIV-1 particles, we hypothesized that the contact between virus-anchored host CD40L and CD40 on the surface of B lymphocytes might result in the activation of this cell type. We report here that CD40L-bearing viruses, but not isogenic virions lacking host-derived CD40L, can induce immunoglobulin G and interleukin-6 production. Furthermore, such viral entities were found to induce B-cell homotypic adhesion. These effects were paralleled at the intracellular level by the nuclear translocation of the ubiquitous transcription factor NF-B. The presence of host-derived CD40L within virions resulted in an increased virus attachment to B cells and a more-efficient B-cell-mediated transfer of HIV-1 to autologous CD4 ؉ T lymphocytes. All the above processes were independent of the virus-encoded envelope glycoproteins. Altogether, the data gathered from this series of investigations suggest that the incorporation of host-encoded CD40L in HIV-1 is likely to play a role in the B-cell abnormalities that are seen in infected individuals.

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

“…Experiments were conducted with isogenic viral particles either lacking (NL4-3) or bearing hostderived CD40L (NL4-3/CD40L). The former virus preparation was used as a control based on previous work indicating that such virus stocks could not induce significant phenotypic changes in B cells (33). An agonistic antibody directed against human CD40 (clone G28.5) was used as a positive control (13,28,29).…”

“…Following the degradation of its inhibitor, the NF-B complex can translocate to the nucleus, bind specific DNA sequences, drive the assembly of RNA polymerase IIdependent transcription machinery, and further promote RNA polymerase II processivity. It already has been established that CD40L-bearing viruses can induce NF-B activation and nuclear translocation (33). While microarray studies may not directly monitor events occurring at the protein level, such as phosphorylation and ubiquitinylation, they can provide indirect insight into these processes, as numerous signaling pathways feature feedback loops that require the transcriptional regulation of some of their components.…”

“…Importantly, the attachment of CD40L-bearing virions onto primary human B cells is sufficient to induce potent cellular activation, which demonstrates the functionality of such host-derived molecules (33). The capacity of CD40L to interact with its natural cognate ligand CD40 on the surface of B cells was confirmed by showing that CD40L-bearing viruses induce homotypic cell aggregation, the nuclear translocation of NF-B, and IgG secretion (33). We report herein that CD40L incorporation is a physiological phenomenon, since this cell surface molecule is detected when using an in vivo source of virus (i.e., plasma virus from patients).…”

A lymphomagenic role for HIV beyond immune suppression?

“…1 T cells, 42 and CD40L-bearing HIV virions were shown to strongly activate B cells, thus mimicking a physiological stimulation. 42,43 As part of CD40L-triggered events, hyperactivated B cells express activation-induced cytidine deaminase (AID), a DNA editing enzyme mediating immunoglobulin class switch recombination and somatic hypermutation.…”

“…42,43 As part of CD40L-triggered events, hyperactivated B cells express activation-induced cytidine deaminase (AID), a DNA editing enzyme mediating immunoglobulin class switch recombination and somatic hypermutation. 44 In addition to introducing point mutations in both immunoglobulin and nonimmunoglobulin genes (ie, BCL-6), AID can also induce chromosome translocations involving oncogenes that are critical for the development of B-cell lymphomas.…”