Chimpanzees inoculated with one HIV-1 strain can resist later infection with a different strain, according to scientists from the National Institutes of Health (NIH) and two other institutions. Successful protection, their experiments show, depends on the infectiousness of the first strain.
Unlike humans, chimpanzees infected with HIV-1 fail to develop disease. The scientists reasoned that an initial HIV infection might act like a weakened live-virus vaccine such as the Sabin polio vaccine.
In this study, the first infection simulated the effect of a successful attenuated HIV-1 vaccine," says Riri Shibata, Ph.D., the study's lead author. "The virus induced protective immunity against a subsequent HIV-1 infection. Scientists now have a model system that can help develop an attenuated HIV-1 vaccine for humans."
Dr. Shibata, a Fogarty visiting associate with the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, plans to present the study data on Wednesday, Feb. 1 at the Second National Conference on Human Retroviruses and Related Infections in Washington, D. C.
For their study, they used two chimpanzees infected three and seven years earlier, respectively, with the laboratory-grown HIV- 1 strain IIIB. They tried to superinfect the animals by exposing them to multiple high doses of HIV-1-DH-12, a strain recently isolated from an AIDS patient and known to thrive in chimpanzee cells.
In September 1993, the scientists injected one animal with a dose of DH-12 known to induce infection in a chimpanzee. In the ensuing four and a half months, they used a technique called polymerase chain reaction (PCR), which can detect minute amounts of virus, to determine if the DH-12 virus successfully infected the chimpanzee. Repeated PCR tests consistently found evidence of IIIB but not of DH-12, suggesting that the animal was protected from the DH-12 challenge.
In January 1994, the investigators gave the first chimpanzee a second DH-12 dose 10 times larger than the first. They also gave the same larger dose of DH-12 to the second IIIB-infected chimpanzee. Multiple PCR tests and virus isolations in both animals over the next four months were positive for IIIB but always negative for DH-12.
In May 1994, the researchers exposed the second chimpanzee to another dose of DH-12 100 times larger than the first. They also took 10 milliliters (about two teaspoonsful) of blood from a third chimpanzee experimentally infected with DH-12 four months earlier and injected it into the first IIIB-infected chimpanzee to mimic the type of exposure that occurs to an intravenous drug user. To date, both IIIB-infected chimpanzees show no evidence of DH-12 infection by either PCR or virus isolation techniques, Dr. Shibata plans to report.
Before the study, in both animals the scientists could detect neutralizing antibodies against the IIIB strain but not against the DH- 12 strain, suggesting that cell-mediated immunity was responsible for the protection observed. This finding will be investigated further to delineate what component(s) of the immune system may be responsible for resistance to infection.
To evaluate how potent an attenuated vaccine must be to protect an animal from a subsequent HIV-1 infection, the scientists recently challenged two more chimpanzees inoculated earlier with SF2, a different HIV-1 strain. SF2 also does not induce disease in chimpanzees but is much weaker than IIIB, generating only very low levels of virus in infected animals.
In September 1994, the scientists inoculated each of the two SF2-infected chimpanzees with a low-dose of DH-12. In contrast to the experiments with the IIIB-infected animals, the two SF2-infected animals became infected with DH-12 within four weeks of exposure. However, they had 35- to 50-fold less DH-12 in their blood than did an unvaccinated chimpanzee exposed to DH-12.
These studies show that chimpanzees can be protected from a subsequent challenge with HIV-1, provided the animals are first immunized with a potent attenuated live-virus vaccine. Experiments in progress will ascertain how the extent of virus attenuation correlates with resistance to subsequent HIV infection.
Dr. Shibata works as a microbiologist in NIAID's Laboratory of Molecular Microbiology, headed by Malcolm A. Martin, M.D., senior author on the study. Study collaborators include Christine Broscius, B.S., of NIAID in Bethesda, Md.; Patrice Frost, D.V.M., and Zimra Israel, Ph.D., of the Coulston Foundation in Almagordo, N.M.; Thomas Matthews, Ph.D., of Duke University in Durham, N.C.; and Larry O. Arthur, Ph.D., of the National Cancer Institute facility in Frederick, Md.
NIAID supports investigators and scientific studies at universities, medical schools, hospitals and research institutions in the United States and abroad aimed at preventing, diagnosing and treating such illnesses as AIDS, tuberculosis and asthma as well as allergies. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.