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
"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," 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," Cerutti explained. Another "class-switched" antibody, IgG, enhances systemic immune cell responses against HIV and other infectious agents.
However, scientists have long known that HIV dampens B cell production of mucosal IgA specific for HIV. It was also known that HIV-1 weakens systemic IgG and IgA responses against opportunistic infections and vaccines early in the infection process. The question was, how?
Encouraged by their earlier discovery of Nef in uninfected B-cells, Cerutti's team followed up with in vitro studies in the lab. They found that Nef does penetrate B-cells.
"It's only a theory, but we believe the protein escapes from dying, infected cells nearby and then enters the 'bystander' B cell," Cerutti said.
Once inside, Nef disrupts critical signaling pathways essential to the class switching process.
The result: dramatic reductions in the production of "class-switched" IgA and IgG. In other words, by releasing Nef into B cells, HIV disarms the immune system of two of its most powerful antiviral weapons.
In the meantime, however, the production of non-specific and low affinity IgM, IgG, and IgA antibodies -- that pose little or no threat to HIV -- goes on unabated, causing a clinical manifestation known as hypergammaglobulinemia. Much of this production seems to take place outside the germinal centers and is triggered at least, in part, by a mechanism that does not require CD4+ T cells.
"That could explain why patients can have robust T cell counts and antibody levels early in the infection process but mount such a poor defense against HIV," said Dr. Daniel Knowles, a study co-author and chairman of Weill Cornell's Department of Pathology and Laboratory Medicine. "It's been a real puzzle to researchers and physicians alike."
Of course, any drug that could inhibit Nef could prove a potent new weapon against HIV/AIDS. "Many people are trying to come up with a Nef inhibitor, but, as far as I know, there's been no success yet," Cerutti said.
"That's the obvious goal here. Nef might not be the only reason HIV-infected people have impaired antibody responses, but it probably plays a big role," he said. "Our next step is to figure out how Nef penetrates B cells, with the hope that we can somehow stop that from happening. We are collaborating with Dr. John P. Moore here at Weill Cornell to address this and other important questions."
This work was funded by grants from the National Institutes of Health.
Co-researchers include lead researcher Dr. Xugang Qiao, now at Columbia University, New York City; and Dr. Bing He and Dr. Amy Chadburn, both of Weill Cornell Medical College.
Source: Weill Cornell Medical College