Although impairment of humoral immunity is a well-recognized feature of HIV infection, the mechanisms behind this B-cell dysfunction are not well understood. Now, a study just published in Nature Immunology describes a novel mechanism by which HIV-1 directly inhibits B-cell function. Andrea Cerutti and colleagues report that the HIV-1 negative factor (Nef) protein crosses into bystander B cells and blocks the production of class-switched immunoglobulins such as IgA and IgG.

B cells generate IgA and IgG by a process known as class-switch recombination (CSR), which is initiated when activated CD4+ T cells interact with IgD+B cells. Signalling mediated by CD40 ligand (CD40L) interaction with CD40, together with secretion of the T-cell cytokines interleukin-10 (IL-10) and IL-4, induces the transcription of IgA, IgE or IgG heavy-chain genes. Compared to IgM, these class-switched immunoglobulins have different effector functions, including the ability to neutralize invading pathogens at sites of entry. In HIV-1 infection, T-cell-dependent IgA and IgG responses to specific antigens are suboptimal, which indicates an impairment of the class-switch programme. Although viral destruction of CD4+ T cells clearly has a role in impaired B-cell function, this does not explain all the features of humoral immune dysfunction in individuals infected with HIV-1.

HIV-1 does not infect B cells, so the authors looked for a soluble factor that might disrupt B-cell function. They focused on the immunosuppressive early HIV-1 protein Nef, which is released into the extracellular milieu from infected cells.

The authors first showed that Nef enters IgD+ B cells from the extracellular environment. Assays that detect molecular markers of CSR showed that exogenous Nef inhibits the induction of CSR in B cells that have been activated by CD40L, IL-4 and IL-10. Nef blocks the CD40 signalling pathway by increasing the amount of the regulatory protein IκBα (inhibitor of nuclear factor-κB (NF-κB) α. Increased IκBα concentrations prevent translocation of cytoplasmic NF-κB dimers into the B-cell nucleus, a step that is required for induction of the transcriptional programme that initiates CSR. Nef also upregulates the negative-feedback proteins suppressor of cytokine signalling 1 (SOCS1) and SOCS3, which inhibit the JAK (Janus kinase)–STAT (signal transducer and activator of transcription) pathways that are induced by IL-4 and IL-10. Inhibition of JAK–STAT signalling impairs CSR and blocks the differentiation of class-switched B cells into antibody-producing cells.

The inhibition of immunoglobulin class switching by HIV-1 Nef prevents the production of antibody classes that are most adept at neutralizing and clearing the virus. This is especially important for viral defence in the early stages of infection when the pool of CD4+ T cells is replete.