Experimental vaccines based on live but weakened or attenuated forms of HIV could be safer thanks to a drug-susceptible HIV clone created by scientists at the National Institute of Allergy and Infectious Diseases (NIAID).
The clone can be eliminated from the body after use in the vaccine, according to Stephen M. Smith, M.D., and Kuan Teh Jeang, M.D., Ph.D., of NIAID's Laboratory of Molecular Microbiology. Dr. Smith plans to discuss the research Tuesday, Jan. 31, at the Second National Conference on Human Retroviruses and Related Infections in Washington, D.C.
Although attenuated live-virus vaccines have been licensed for several other diseases, many scientists think that such a vaccine based on HIV, which causes a fatal disease, may be too hazardous. HIV multiplies by inserting its genetic material into that of its hosts' cells, raising concerns that even if crippled so as not to cause disease, HIV could lead to long-term, unanticipated side effects.
To bypass this problem, Drs. Smith and Jeang added to HIV a foreign gene that codes for thymidine kinase (TK), a protein found in HSV-1, the herpes virus that causes cold sores. Cells that produce this protein can be selectively killed by a drug called ganciclovir.
The scientists found that under certain laboratory conditions, ganciclovir eliminated cells infected with HIV-TK. According to Dr. Smith, "This result suggests that after it has had a chance to work, an attenuated vaccine based on the HIV-TK clone could similarly be eliminated by co-administration of ganciclovir, reducing the concern about long-term adverse side effects."
Drs. Smith and Jeang created their virus clone by replacing nef, one of HIV's nine genes, with the foreign gene. The resulting HIV produced HSV-1 thymidine kinase, could infect T-cell lines and stimulated immune cells in the blood.
When they treated HIV-TK-infected cell cultures with ganciclovir, the NIAID scientists found no increased cell death due to HIV and no rise in levels of the HIV enzyme reverse transcriptase--an indirect measure of HIV activity. In untreated cell cultures, however, significant cell death occurred, and levels of reverse transcriptase rose.
Dr. Smith says the virus inhibition may occur via the drug- induced death of infected cells. "By killing infected cells before virus production occurs, ganciclovir interrupts the spreading HIV infection without influencing uninfected cells."
NIAID and the National Institutes of Health (NIH) Office of AIDS Research supported the research. NIAID, a component of NIH, supports research on immunology, allergy and AIDS, tuberculosis and other infectious diseases. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.