B-Cells and HIV

B cells wage a losing battle against HIV   

By Alix Morris
When a virus enters the body, the immune system launches a barrage of antibodies to stop the infection. In the case of HIV, however, the B cells that make those antibodies fail to generate a normal response, even in the early stages of infection, when concentrations of the virus are at their peak. Research published in the October 27th edition of Nature Immunology sheds some light on a potentially major driver of this dysfunction.

The HIV glycoprotein gp120, a component of the HIV envelope, latches onto the CD4 molecule of T cells to initiate viral invasion. But this protein is also known to bind to a separate receptor on the surface of those cells known as α4β7. In the Nature Immunology paper, researchers led by Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID), show that gp120 also binds to α4β7 on B cells, starting a cascade of internal signaling that leads to the observed B-cell dysfunction. 

This finding, Fauci says, has been 30 years in the making. In 1983, before HIV had been isolated and identified, Fauci and his colleagues noted that B cells were aberrantly activated in patients with AIDS. Later, when they began to look at the effect of the HIV envelope on different types of cells, they focused primarily on T cells, as these were the immune cells most significantly affected by HIV infection.

As the field evolved, however, it became clear that in acute HIV infection, and even during chronic infection, the body did not produce normal levels of neutralizing antibodies against HIV. Researchers were stumped as to why this is the case. Part of the answer, it turned out, had to do with the structural complexity and extraordinary variability of the HIV envelope. But that did not account for the weird B-cell dysfunction.

Then, in 2008, Fauci and his team discovered that the integrin α4β7, expressed on T cells, is also a receptor for gp120. So he and his colleagues hypothesized that if the HIV envelope is inducing immune dysfunction in B cells, and B cells don’t express CD4 or the HIV co-receptor CCR5, the envelope might be inducing dysfunction in B cells through α4β7—which is found on B cells.

That, it appears, is indeed the case. Fauci and his colleagues also suggest how this interaction might disrupt B-cell responses. They find that α4β7 binding to gp120 induces the expression of the immunosuppressive cytokine TGF-β1 as well as an inhibitory B-cell receptor called FcRL4.

“We know that, particularly in acute HIV infection, when you have very high levels of virus and, therefore, high levels of envelope, you might be able to impair B-cell function,” says Fauci. This, he says, provides at least a partial explanation for why antibody responses are so tepid during acute HIV infection. 

The finding does not, however, have any implications for vaccines that seek to elicit antibody responses. “The amount of envelope that you expose the body to in a vaccine,” explains Fauci, “is orders of magnitude less than what you get when you get HIV viremia. I would not expect a vaccine that contains envelope to cause B-cell dysfunction at all.”

The key takeaway from the research, says Fauci, is that the virus has extraordinary capabilities of impairing the host response—and we can now add B-cell disruption through α4β7 to that already formidable list.

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