HIV-produced Protein Decreases Antibody Specificity

Pharmaceutical Executive

Pharmaceutical Executive, Pharmaceutical Executive-03-29-2006, Volume 0, Issue 0

A new study indicates that a protein produced by HIV invades uninfected B cells and inhibits a mechanism that makes certain antibodies very good at targeting invading agents.

New research reveals one of the HIV virus’s many complex mechanisms for evading the immune system. Published in the March issue of Nature Immunology, a study shows that a protein produced by HIV negative factor or Nef, could inhibit the way infected people’s bodies produce two specific antibodies necessary for fighting invading agents.

    Nef has long been known to have several roles in HIV infection, particularly the early stages, explained lead author Andrea Cerutti. But until now, most studies have focused on Nef’s effect on T cells. Cerutti and his lab look at Nef’s affect on B cells.

    Their research showed that Nef accumulates in germinal centers, which are clusters of B cells inside the lymph nodes. Even though HIV does not infect B cells, Nef still penetrates the B cells, Cerutti said. The mechanism by which the protein enters these B cells is unknown.

    All B cells produce antibodies, but the B cells in germinal centers are able to produce especially specific versions of antibodies called IgG and IgA, according to Cerutti. These highly specific antibodies are particularly effective at targeting infectious agents.

    “They work like molecular bullets,” Cerutti said.

    Antibody production is turned on when the B cells receives chemical signals from a T cell that has been activated by an invader. The germinal center’s B cells first produce less specific antibodies, called IgM, Cerutti said.

    Through a process called class switching, IgM is altered into the more specific IgG and IgA. B cells inside and outside of the germinal centers can produce IgG and IgA. But inside the germinal centers, the antibodies undergo a second step called somatic hypermutation, which allows them to more specifically target the foreign object they were designed to fight.

    HIV-positive people are less capable of producing specific antibodies than uninfected individuals, Cerutti explained. As a result they are not as capable of responding to pathogens, including the HIV virus, opportunistic infections, and vaccines. IgA is especially important for helping bodies fight the HIV virus, because it’s structure makes it especially capable of targeting foreign agents that enter the body through mucous membranes in the mouth, intestinal tract, and genital region.

    The Nature Immunology paper shows that after invading the germinal centers, Nef is able to inhibit the B cells ability to create IgG and IgA. So Nef works to inhibit class switching, at least in the laboratory, Cerutti explained. Based on his results, it looks like Nef accomplishes this by hijacking the body’s own mechanism for regulating class switching.

    Class switching is inhibited through a negative feedback loop at a certain point in the immune response, in order to prevent the body from reacting too strongly. When the immune response is too strong it can attack healthy cells, resulting in autoimmune disorders.

    Cerutti’s research demonstrated that Nef enhances molecular expression of two proteins that are involved in this negative feedback pathway for class switching. Eventually, this interference might prevent the class-switching process from ever getting turned on, he said.

    According to Cerutti, Nef is a good drug target, because it is involved in several aspects of HIV infection. If agents that block Nef were discovered, among other things, they could stop the class switching process from being shut down.

    “This could improve the quality and magnitude of antibody responses to the virus and other pathogens,” Cerutti said.

    Since Nef is known to be involved in the early stages of infection, a Nef blocker might someday be used to prevent infection in high-risk individuals, he speculated.