The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression

Abstract

The humoral immune response following acute HIV-1 infection is delayed and ineffective. The HIV-1 envelope protein gp120 binds to and signals through α4β7 on T cells. We show that gp120 also binds and signals through α4β7 on naïve B cells, resulting in an abortive proliferative response. In primary B cells gp120 signaling through α4β7 resulted in increased expression of the immunosuppressive cytokine TGF-β1 and the B cell inhibitory receptor FcRL4. Co-culture of B cells with HIV-1-infected autologous CD4+ T cells also increased B cell FcRL4 expression. These findings indicate that, in addition to mediating chronic immune activation, viral proteins can contribute directly to HIV-1-associated B cell dysfunction. Our studies provide a mechanism whereby the virus may subvert the early HIV-1-specific humoral immune response.

Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals

“…However, the technique of directly evaluating HIV-specific B cell responses by HIV envelope probes also presents certain challenges and limitations, the most important being the fact that the HIV envelope can bind to non-BCR elements expressed on the surface of B cells or to nonconventional sites of the BCR itself (24)(25)(26)29). While such binding cannot be completely eliminated, non-BCRmediated binding of the HIV envelope to B cells can be minimized by a combination of costaining for IgG that creates a diagonal pattern of staining and by using B cells from HIV-uninfected individuals to determine where to set the gate between negative and likely positive BCR-mediated staining.…”

“…Analyses were restricted to B cells that expressed IgG in order to maximize BCR-binding measurements and minimize low-affinity non-BCR binding of the HIV envelope to B cells that can occur via various cell surface receptors, including several lectins and integrins (24,26,29). As shown by the representative profile in Figure 1A and consistent with published observations (15,30), a low yet clearly discernible frequency of IgG + B cells in the peripheral blood of HIV-infected, but not uninfected, individuals bound the gp140-WT probe with high affinity.…”

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…TGF-b produced in the mucosal lymph nodes during HIV infection can also induce apoptosis of activated CD8 þ T cells (Cumont et al 2007), whereas promoting the generation of NKT cells, which share properties of both T cells and NK cells, which produce IL-17 (Campillo-Gimenez et al 2010). Furthermore, the HIV envelope protein gp120 can bind to a4b7 integrins on naïve B cells to induce TGF-b and Fc receptor-like 4 (FcRL4) expression, which causes B-cell dysfunction and inhibits their proliferation (Jelicic et al 2013). Furthermore, TGF-b is an important mediator of pathological fibrosis, and promotes collagen deposition in lymphoid organs in response to HIV-or SIV (simian immunodeficiency virus)-induced inflammation.…”

Binding of HIV-1 virions to α4β7 expressing cells and impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells

“…HIV-1 gp120 has been reported to interact with integrin α 4 β 7 expressed on primary lymphocytes and such interaction has been well studied (Arthos J, et al, 2008;Cicala C, et al, 2009;Darc M, et al, 2011;Jelicic K, et al, 2013;Li H, et al, 2011). However, whether gp120-α 4 β 7 interaction mediates the binding of HIV-1 virions to target cells remains to be further clarifi ed (Arthos J, et al, 2008;Etemad B, et al, 2012).…”