Use of mutant SIV DNA immunization to mimic attenuated virus vaccines

The most effective viral vaccines for humans have been attenuated viruses. However, a major concern with attenuated viruses is safety, especially retroviruses that integrate into the host's genome and have a high mutation rate such as HIV-1. With the advent of techniques that allows in vivo expression of a DNA construct, it is theoretically possible to duplicate the steps of viral replication, in effect imitating an attenuated virus vaccine, without a replicating agent. In vitro transfection with an SIV nucleocapsid mutant DNA results in expression of non-infectious virus particles, containing the full complement of viral proteins, but deficient in genomic RNA. We propose that immunization of animals with this DNA will lead to expression of virus-like particles that bud from cells and bind and fuse to susceptible cells. To test this hypothesis, macaques with NC mutant DNA and challenged with pathogenic SIV(Mne). All control animals became persistently infected, with high plasma viral levels (10(5)-10(6) RNA genome equivalents/ml and 3 of the 4 control animals developed AIDS (CD4 cells less than 200 cells/microliter) by 56 weeks post challenge. All DNA-vaccinated animals, except one, showed low virus loads without development of AIDS 2 years post challenge. Since DNA vaccination resulted in minimum to undetectable anti-SIV antibodies, in vivo experiments are in progress in attempts to enhance expression of the DNA by utilization of CMV promoters and altered injection routes. In addition, experiments are in progress to assess whole killed SIV vaccines that may eventually be used as a boost component of the DNA vaccination.

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