New studies by National Institute of Allergy and Infectious Diseases (NIAID) scientists and grantees help fill in pieces of the AIDS vaccine research puzzle. In three separate reports published in the February 1999 issue of the journal Nature Medicine, researchers report new insights about the kind of immune responses needed to protect against HIV infection. In the same issue, another group presents important findings regarding the safety of live, attenuated HIV vaccines.
The Role of Neutralizing Antibodies
Defining the precise immune responses that a vaccine must induce to protect against infection with HIV will allow scientists to design tailor-made vaccines that elicit those responses. Two series of experiments led by Malcolm A. Martin, M.D., chief of NIAID's Laboratory of Molecular Microbiology, provide important new information about the role that antibodies can play in defending against HIV.
In one study, Dr. Martin and his colleagues showed that "neutralizing" antibodies against HIV can prevent infection in primates. As their name implies, neutralizing antibodies bind to the virus in a way that prevents it from infecting cells. Dr. Martin's team isolated high levels of very potent neutralizing antibodies from healthy but HIV-infected chimpanzees and transferred them to rhesus monkeys. The monkeys were then exposed to SHIV, a hybrid virus composed of a simian immunodeficiency virus (SIV) core surrounded by HIV envelope proteins. SHIV normally causes infection in primates. However, none of the monkeys that had been passively immunized with the neutralizing antibodies became infected with SHIV.
In a second study, conducted with scientists from the National Cancer Institute, Dr. Martin's research team investigated whether neutralizing antibodies to HIV can accelerate the removal of HIV from the blood of monkeys. The scientists measured HIV clearance after infusing large quantities of the virus into three groups of monkeys: animals that had been persistently infected with SHIV for several years (and therefore made antibodies that recognized the HIV proteins); uninfected animals that had received the anti-HIV antibodies as in the first study; and animals that had never been infected with HIV or SHIV.
The researchers found that HIV rapidly disappeared from the blood in each group of animals. However, in monkeys with neutralizing antibodies to HIV, virus clearance occurred more than twice as fast as in animals lacking these antibodies.
Dr. Martin acknowledges that scientists do not yet know how to elicit neutralizing antibodies to HIV in humans, nor can they produce antibodies that will cross-react broadly with different strains of HIV. He also notes that an effective preventive vaccine against HIV may have to elicit multiple immune responses that can interfere with different steps in the HIV life cycle. Still, Dr. Martin's demonstration that neutralizing antibodies can prevent HIV infection should be a boon to HIV vaccine research.
If we can learn how to raise sufficient quantities of neutralizing antibodies to a broad range of HIV strains, we will have made an important step towards an effective HIV vaccine."
Broad-Based Immunity Essential in Mice
A study by another team of NIAID researchers suggests that HIV vaccines must elicit responses in all three major immune cell subsets - antibody producing B cells, CD4+ (helper) T cells, and CD8+ (killer) T cells - to be effective.
Kim J. Hasenkrug, Ph.D., of NIAID's Rocky Mountain Laboratories in Hamilton, Mont., and his colleague Ulf Dittmer, Ph.D., immunized mice with a live, attenuated vaccine against Friend virus, a retrovirus that causes a fatal, immunosuppressive disease in mice. The vaccine they used is highly effective at preventing disease. To determine which immune responses confer protection, they transferred various combinations of all three major immune cell subsets from immunized mice to non-immunized mice, then exposed the mice to a pathogenic form of Friend virus.
The researchers found that mice that had received just one or two immune cell types became infected and developed disease. Only mice that received all three immune cell types were completely protected from infection with the virus.
"Each lymphocyte subset seems to have unique and necessary functions that act in concert to induce protection," notes Dr. Hasenkrug. "It remains possible that single or dual lymphocyte subsets might be protective if transferred in overwhelming numbers, but the efficacy of vaccination with live, attenuated Friend virus seems to be related to its ability to stimulate multiple arms of the immune system. The implication is that only broadly based HIV vaccines that are designed to elicit responses in all three types of immune cells will prove effective."
Live, Attenuated Vaccines - How Safe?
Some scientists believe that a live, attenuated HIV vaccine - composed of virus rendered non-pathogenic by removal of one or more essential genes - could be the best way to stimulate broad- based immunity to HIV. Other scientists, however, question whether concerns about the safety of using live, attenuated HIV vaccines can be adequately addressed. Given HIV's propensity to mutate, they fear that an attenuated strain of HIV could revert to a pathogenic form.
Researchers led by NIAID grantee Ruth Ruprecht, M.D., Ph.D., of the Dana-Farber Cancer Institute in Boston, in collaboration with scientists at the Yerkes Regional Primate Research Center in Atlanta, report that an experimental live, attenuated SIV vaccine can cause AIDS in infant and adult monkeys. The vaccine consisted of an SIV strain from which three different genetic elements, each involved in viral replication, had been removed.
"Our findings confirm that this triply deleted SIV candidate vaccine retains its ability to cause AIDS," says Dr. Ruprecht. "Given the genetic similarities between HIV and SIV, a live, attenuated virus vaccine based on attenuation of replicative capacity should not be considered as a candidate for a human AIDS vaccine." Rather, she adds, attenuation strategies should focus on identifying viral genes that control virulence.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
References: 1. R Shibata, et al. Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys. Nature Medicine 5:211-16 (1999). 2. T Igarashi, et al. Human immunodeficiency virus type 1 neutralizing antibodies accelerate clearance of cell-free virions from blood plasma. Nature Medicine 5:204-10 (1999). 3. U Dittmer, et al. Requirement for multiple lymphocyte subsets in protection by a live attenuated vaccine against retroviral infection. Nature Medicine 5:189-93 (1999). 4. T Baba, et al. Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques. Nature Medicine 5:194-203 (1999).
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