HIV Reveals Another Secret to Its Success

In HIV infection, a protein produced by infected cells penetrates immune B cells, preventing them from producing antibodies that could do the virus real harm.

That finding by Weill Cornell Medical College researchers could alter the way experts view HIV, helping to explain how the virus evades the immune system in the first days and weeks of infection.

It also helps unravel a longstanding paradox in HIV treatment: The fact that patients can have high blood levels of immune T cells and yet still be vulnerable to the virus.

"It's because the virus produces this protein, negative factor (Nef), which enters B cells to prevent antibodies being targeted to HIV. This process leaves other, less targeted immune responses intact - but since they pose little threat to the virus, HIV proliferates," explained lead researcher Dr. Andrea Cerutti, Assistant Professor of Pathology and Laboratory Medicine at Weill Medical College of Cornell University, in New York City.

The findings appear in this month's issue of Nature Immunology.

For years, scientists have associated Nef with HIV infection - in fact, it is found in all HIV-infected cells.

"But the common wisdom was that Nef never appeared in healthy immune cells," Dr. Cerutti said.

However, his lab's earlier in vivo studies using lymph nodes from HIV-positive patients revealed high concentrations of Nef in B cells located within the germinal centers of lymph nodal glands. Germinal centers are specialized structures that foster production of IgG and IgA antibodies capable of recognizing microbial targets with high affinity and specificity. These antibodies are extremely important to the human immune response as they can provide protection against infectious agents, including viruses.

Driven by signals from CD4+ T cells (which roam the body looking for threats), germinal center B cells produce immunoglobulin (Ig) antibodies that specifically target invading microorganisms. Maturing B cells initially produce a relatively nonspecific antibody, IgM, but through a process called "class switching," IgM transforms into more targeted antibodies that acquire novel functions, such as the capacity to reach mucosal surfaces. Then, a second process, called "somatic hypermutation," increases the specificity with which IgG and IgA antibodies bind to their targets.

"The end products of the germinal center reaction are highly specific IgG and IgA antibodies - they're like molecular bullets aimed at a particular target," Dr. Cerutti said.

One antibody, IgA, is HIV's most fearsome foe.

"It's specifically designed to fight pathogens like HIV that invade through the body's mucosa - those moist, semi-permeable tissues found in the urogenital tract, the intestinal tract, or the mouth and throat," Dr. Cerutti explained. Another "class-switched" antibody, IgG, enhances systemic immune cell responses against HIV and other infectious agents.