Research findings suggest new course against HIV
Nef protein plays major role
New research provides some answers to long-standing questions about how HIV proliferates despite the initial strong immune response. Investigators have discovered evidence that HIV-1 evades some immune cell responses by hijacking physiological feedback inhibitors in B cells via the negative factor (Nef) protein, an HIV-1 protein that is expressed by infected cells.1
"Nef is a viral protein known to be involved in the development of AIDS, and it has a profound effect in viral replication," says Andrea Cerutti, MD, an assistant professor of pathology and laboratory medicine at Weill Medical College of Cornell University in New York, NY.
"Previous studies have shown that this viral protein is important in the development of immune deficiency in primates," Cerutti says. Among humans, there are long-term HIV survivors who lack the Nef protein and never progress with their disease, Cerutti notes.
"We know there are people who are exposed to HIV and yet do not develop the disease, and this can happen for several reasons: First, they lack CCR5, the receptor for HIV," Cerutti says. "Another reason is that they lack the viral protein Nef and were infected by viruses that for some reason lack function of the Nef protein."
The latter cases involve people who have developed an attenuated form of the disease or who have not developed the disease at all. "The role of Nef in antibody production was not known, and that’s why we wanted to do this study," Cerutti says. "Antibodies play an important role in HIV infection."
The immune system’s two arms include T cells that recognize infected cells and destroy them and the B cells which make antibodies, which work like molecular bullets, neutralizing targets, Cerutti explains. "So Nef is known to play an important role in the T cell response, but nothing was known about the response of the B cells, which make antibodies," Cerutti says.
Also, immunologists have been puzzled for years by the way HIV-infected people are unable to make effective antibody responses against the virus and opportunistic agents despite having high blood levels of immune T cells, he adds.
While HIV enhances nonspecific IgG and IgA production on one hand (this phenomenon is known as hypergammaglobulinemia), it decreases protective IgG and IgA responses against invading microorganisms and prevents patients from responding to vaccines on the other, Cerutti says.
"They cannot make effective antibodies of IgA and IgG types, particularly IgA against HIV itself," Cerutti says. "There is a lack of HIV-1-specific IgA at the level of intestinal and urogenital mucosa surfaces, which are an important site of entry for HIV in general," Cerutti explains.
"IgA plays an important role in blocking infections at those mucosal sites because the IgA can be secreted at those sites," Cerutti adds. "The reason why there is a lack of virus-specific IgA at mucosal sites during HIV-1 infection has long puzzled immunologists.?
Also, it’s unclear why HIV-1 prevents infected patients from mounting effective IgG and IgA responses to vaccines, even at the early stage of the disease, when T cells are relatively normal, Cerutti says.
This conundrum prompted scientists to hypoth- esize that the process involved in generating IgA and IgG antibodies somehow was defective or impaired in HIV patients, Cerutti says.
"So we started looking at the presence of Nef in the areas of lymph nodes where IgG and IgA antibodies are made and found an increased concentration of Nef," he says. "We hypothesized that since Nef was present there it has a role in inactivation of the process, and we found that Nef is able to penetrate B cells even though B cells are not infected."
By studying the lymph nodes where the B cells make antibodies, investigators found that in HIV patients Nef is present in the B cells, Cerutti says.
"We don’t know the mechanism by which Nef goes from infected cells to B cells," Cerutti notes. "It’s present in the B cells, although B cells are not infected by HIV, so future research will focus on the mechanisms by which Nef penetrates B cells."
The implications of the findings involving Nef’s important role in HIV infection could lead to new antiretroviral agents. "If Nef is so important in general for the impairment of the immune system, then one possibility is to utilize synthetic inhibitors of Nef to attenuate the immune deficiency of people already infected," Cerutti says. "This could be used, also, to prevent infection in subjects at risk for infection."
For example, there could be a vaccine that attenuates Nef, Cerutti suggests.
"Some investigators are testing the ability of an attenuated HIV virus that lacks Nef to stimulate the immune system of non-infected primates," Cerutti says. "An attenuated virus would be able to stimulate a robust immune response, generate memory, and create a potential for protection against subsequent infection."
Because of the lack of Nef, the attenuated virus would not generate any disease, Cerutti adds.
Another possibility is the development of a chemical agent, a small compound, that would neutralize the activity of Nef, and that could be used to improve the immune response and decrease the spread of HIV throughout the body, Cerutti says.
Scientists have been aware of how crucial Nef is because Nef has very profound effects on T cells and macrophages, two cell types central for the initiation of protective immune responses, Cerutti says.
"Nef seems to disrupt the immune response in several ways, and one of the ways is to impair the ability of T cells to orchestrate the immune response and kill cells infected by HIV-1," he says.
"Our study suggests Nef is also important in the impairment of the B cell response, which is essential because it leads to production of IgG and IgA antibodies against HIV and opportunistic agents."
The role of Nef in HIV infection is very interesting and should be further studied, Cerutti suggests.
- Qiao X, et al. Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nat Immunol 2006;7:302-310.