By David N. Leff
Africa south of the Sahara desert is a killing field for the AIDS virus. Across that continent, from the Indian Ocean to the Atlantic, upwards of 22 million men, women and children are fatally infected with HIV, and still counting. Two million of them died of AIDS in 1998 - five times the death rate in the U.S. Africa's standard of living is too low to qualify for the sophisticated multidrug therapy that has put the HIV infection on hold in advanced industrial countries. By 2001, the U.N. estimates, there will be 13 million AIDS orphans in Africa.
"The HIV envelope glycoprotein is like a stealth bomber," pointed out retrovirologist and clinician Ruth Ruprecht, at the Dana-Farber Cancer Institute in Boston. "The virus has this outer coating, which is covered with so many sugar molecules that antibodies have a hard time finding its important epitopes, and blocking virus entry into its target cell. Most of the antibodies that infected people make are directed against this outermost sugar layer, so they tend to be weak and ineffective.
"But every once in a while," Ruprecht continued, "a rare person makes an antibody that recognizes hidden inner structural components, which the virus absolutely needs. For instance, it needs to bind to the CD4 receptor on the surface of its target T cell. That CD4-binding site is the epitope on the viral envelope that matches the counterpart of the CD4 receptor."
Ruprecht is senior author of a paper in the February issue of Nature Medicine. It's title: "Human neutralizing monoclonal antibodies of the Ig G1 subtype protect against mucosal simian-human immunodeficiency virus infection." Her article reports the therapeutic use of "three such rare antibodies," she told BioWorld Today, "obtained from people whose blood, for unexplained reasons, contained powerful neutralizing antibodies. These led colleagues in other labs to isolate and immortalize the immune system's B cells that make these antibodies. That then allowed them to grow those cells in tissue culture in perpetuity, while still secreting antibodies."
Using three of these potent human monoclonal antibodies as passive immunization, she and her co-authors were able to protect monkeys from infection with an AIDS-like virus.
To see if their blue-ribbon, triple-antibody combination could prevent mother-to-child transmission of SIV - the simian equivalent of HIV - the researchers injected the antibodies into the veins of four healthy pregnant macaque monkeys, four days before delivery and three afterward. An hour later, the dams received intravenous challenge doses of a hybrid human/simian virus construct called "SHIV." This infectious virus combines the core of SIV with the protein coat of HIV. Over the next six months, tests showed all four of the females to be free of infection.
A Deadly Viral Shiv Called "SHIV"
Shortly after being born, the neonatal monkeys received their antibody shots, followed a few hours latter by SHIV. They got this challenge dose by mouth - a route that simulates transmission of the AIDS virus from an infected woman to her infant. A separate cohort of control newborn monkeys got SHIV orally, but without receiving antibody treatment. Over the next six months, the controls had persistent SHIV infection, while their antibody-treated contemporaries had none.
"This is the first demonstration," Ruprecht pointed out, "that - contrary to widely held opinion - neutralizing antibodies actually do work. When used in a synergistic combination, they can be powerful enough to protect against even mucosal viral exposure."
Ruprecht counted the three ways that HIV can pass from an infected woman to her infant:
"The first way, which infects maybe 10 percent to 20 percent of the infants, is in utero - which means before the onset of labor, as long as the fetal membranes are intact.
"Most of the infants, roughly 70 percent, seem to get infected interpartum - in the actual delivery process through the birth canal. That virus exposure from mucous membranes during delivery may be the most important route.
"And an additional 10 percent to 15 percent acquire the virus from their mother's milk, during breast feeding. That last mode of transmission can be avoided by bottle feeding."
Potential AIDS Vaccine - After Clinical Trials
From the co-authors' in vivo results, Ruprecht went on, "we may gain insights that can be used to develop a safe, effective AIDS vaccine. But first of all, we have to distinguish between passive and active immunization. Active is giving a shot of a protein or virus to a naove - nonimmunized - animal or person, to induce immune responses. So once the vaccine is gone, the recipient will still recognize its important parts, and will make antibodies and immune T cells on his or her own.
"Passive immunization," Ruprecht added, "is different. It means administering specific antibodies or T cells that recognize certain structures on the antigen. The three antibodies we used recognized important structures of the HIV envelope glycoprotein, whereas in passive immunization the protection lasts only as long as the antibodies stick around. They have a natural decay, and once gone, immunity is gone, too."
Before these super-antibodies can come into general use, she noted, "they need to undergo clinical trials for safety and efficacy. And as our goal is to prevent mother-to-infant transmission, this involves newborns. Normally, any therapeutic entity must be tested in adults before it can be given to children. I know," she observed, "that in Europe there are tests ongoing, using two of these three monoclonal antibodies."
Meanwhile, she revealed, "I would like to make our approach work in Africa. We now need to adapt our antibody selection to the type of virus that is circulating there. We've just been funded by a one-year grant from the NIH to start preliminary experiments, in collaboration with a group in Zambia, at the university hospital in Lusaka.