Contribution of B cells to tumorigenesis in HIV-1-infected patients

Kaposi’s sarcoma (KS) is the most common cancer in HIV-1-infected persons. It is caused by human herpesvirus 8 (HHV-8), one of only seven human cancer viruses. KS tumor cells are primarily of endothelial cell origin. HHV-8 infection of endothelial cells is mandatory for the development of KS but it is insufficient to drive the formation of KS lesions as these cells are not fully transformed. Extensive studies suggest that this oncogenic process is linked to the latent expression of HHV-8 oncoproteins and microRNAs to promote cell proliferation and prevent apoptosis. Accumulating evidence, however, has incriminated lytic HHV-8 infection in driving HHV-8-associated cancers with persistent latent HHV-8 infection being associated with ongoing lytic virus replication. Several HHV-8 lytic proteins with homology to human proteins are thought to contribute to endothelial cell survival and proliferation by mimicking host proteins that normally regulate the cell cycle and by having immuno-modulatory effects that favor virus replication.

An unsolved enigma of KS remains in that HHV-8 latency and lytic cycle encoded factors, while unique amongst human oncogenic viruses, are insufficient to really cause cancer. An emerging hypothesis is that KS is a paracrine neoplasia in which HHV-8-infected endothelial cells depend on an abnormal excess of host cytokines and chemokines for their outgrowth. B lymphocytes are hypothesized to fundamentally contribute to this process since early studies demonstrated the presence of HHV-8-infected B cells in a large proportion of KS lesions and HHV-8 DNA in circulating B cells in patients with KS. Researchers also showed that upon pre-activation of B cells with soluble CD40L and IL-4, HHV-8 can successfully replicate in B cells in vitro.

The tumor necrosis factor (TNF) receptor family member CD40 is a critical regulator of cellular and humoral immunity. It is broadly expressed on immune cells, although predominantly on antigen-presenting cells (APCs) such as B cells and dendritic cells. One of the main functions of the CD40L/CD40 system is to provide B cells with a signal to induce proliferation, immunoglobulin class switching, antibody secretion, and rescue from apoptosis. It also has a role in the development of germinal centers and the survival of memory B cells. Although normally induced by helper T cells, CD40 signaling on B cells and other APCs can also be effectively triggered using agonistic antibodies or CD40L, thus bypassing the need for surrogates in the shape of CD4+ T helper cells. Crucially, the efficacy of CD40 signaling is dependent on the clustering of CD40 within the membrane of the targeted cells and CD40-signaling induced by soluble CD40L (sCD40L) can be potentiated up to 100-fold upon secondary crosslinking of sCD40L into higher order multimers such as Enzo’s MegaCD40L® proteins.

In a recent study conducted by Dr. Knowlton and coworkers from the University of Pittsburgh, the role of B cells on the development of Kaposi’s sarcoma (KS) was investigated. Following pre-activation of B lymphocytes with Enzo’s recombinant human soluble MegaCD40L®, they assessed HHV-8 infection and production of cytokines and chemokines. Their results showed that naive and IgM memory B cells as well as plasma cell-like populations can be infected by HHV-8 both in vitro and in the blood of subjects with KS. Importantly, virus-infected B cells are highly poly-functional, producing two to five cytokines and chemokines (i.e. IL-6, IL-8, MIP-1α, MIP-1β and TNFα) that have been postulated to enhance endothelial cell outgrowth. Altogether, these data support the hypothesis that secretion of cytokines and chemokines by HHV-8-infected B cells is central to the development of Kaposi’s and that further work is required for a complete understanding of the process and the discovery of new drugs capable of blocking this phenomenon.

Enzo Life Sciences provides immunologists and virologists with a comprehensive product portfolio to assess the immune response such as antibodies, ELISA kits and recombinant proteins; some of which are described below:

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