Rabies-Based Vaccine Could be Effective Against HIV

[J220]

From Thomas Jefferson University ( http://www.jefferson.edu/news/index.cfm?artid=2007/article14028.html )

Jefferson Scientists Find Rabies-Based Vaccine Could be Effective Against HIV

Rabies, a relentless, ancient scourge, may hold a key to defeating another implacable foe: HIV. Scientists at Jefferson Medical College in Philadelphia have used a drastically weakened rabies virus to ferry HIV-related proteins into animals, in essence, vaccinating them against an AIDS-like disease. The early evidence shows that the vaccine – which doesn’t protect against infection – prevents development of disease.

Reporting April 1, 2007 in the Journal of Infectious Diseases, the scientists showed that two years after the initial vaccination, four vaccinated non-human primates were protected from disease, even after being “challenged” with a dangerous animal-human virus. Two control animals developed an AIDS-like disease.

Matthias Schnell, Ph.D., professor of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University, and his co-workers tested the effects of inserting two different viral proteins into the rabies virus genome, and using such viruses-based vaccines in preventing disease in rhesus macaques. One was a glycoprotein on the surface of HIV, while the other was an internal protein from simian immunodeficiency virus (SIV). They used the latter because HIV does not cause disease in monkeys.

The idea was that such rabies’ vehicles, or “vectors,” would help attract a strong response from the animal’s immune system, though the rabies virus used cannot cause disease. Such vectors are based on a type of rabies vaccine strain that has been used for more than 20 years in oral vaccines against rabies in wildlife in Europe. The study was aimed at studying the safety and effectiveness of the rabies vaccine approach against HIV and related diseases.

Four macaques were immunized with both vaccines, while two animals received only a weakened rabies virus. After they gave the animals an initial vaccination, they then tried two different immune system boosts, but didn’t see enhanced immune responses. They then developed a new vector, a viral surface protein from another virus, vesicular stomatitis virus (VSV). Two years after the initial immunization, they gave a booster vaccine with the rabies-VSV vector, and saw SIV/HIV-specific immune responses.

The group then challenged the animals with SIV and measured various parameters of infection, such as immune system CD4 cell count, amount of virus in the bloodstream and immune system antibody response. They found that those animals that were given the test vaccine could control the infection. The control animals without the experimental vaccine had high levels of virus and a loss of CD4 cells.

“We still need a vaccine that protects from HIV infection, but protecting against developing disease can be a very important step,” Dr. Schnell says, noting that he and his colleagues aren’t sure how long the viral immunity will last.

According to Dr. Schnell, the study demonstrated a “proof of principle” – that is, that the method used is technically possible. He says that the results indicate the need for future studies in larger groups of animals, and that these currently are underway. In addition, one key question remains unanswered: Is such a rabies-based vaccine feasible as an HIV vaccine in humans?


Media Only Contact:
Steven Benowitz
Thomas Jefferson University Hospital
Phone: 215-955-6300

Published: 4-2-2007

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these are very ingenous ways to vaccinate therapudically against HIV seems to me like there could be some amazing developments here in this technique

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Even though great success has been made in the therapy of HIV-1 infection during the last several years (1, 2), the development of a protective HIV-1 vaccine still remains a major goal in halting the HIV-1 pandemic. Most successful vaccines against viral diseases have been composed of killed or attenuated viruses (for review, see ref. 3). This approach seems not to be suitable for HIV-1 because killed HIV-1 virus induces only a poor neutralizing antibody response and no cytotoxic T lymphocyte (CTL) response. The use of attenuated strains of HIV-1 may not be possible based on recent reports indicating that even attenuated simian immunodeficiency virus (SIV) strains can cause an AIDS-like disease in monkeys (4, 5). Nonetheless, the finding that rhesus macaques vaccinated with live, nef-deleted SIV were completely protected against challenge with live, pathogenic SIV (6) emphasizes the hypothesis that recombinant viruses are excellent candidates for live vaccines against HIV-1. The most widely used recombinant viral vectors are based on vaccinia virus or canarypox virus expressing HIV-1 genes, mostly the HIV-1 envelope protein, gp160 (7-10). These vectors were able to induce a CTL response and seroconversion in a variety of animals, including humans, but they were unable to induce high-titer neutralizing antibodies against HIV-1 and failed to completely protect chimpanzees from HIV-1 challenge



Rabies virus (RV) is a negative-stranded RNA virus of the rhabdovirus family, and it possesses a relatively simple, modular genome organization coding for five structural proteins (12). The suitability of RV as an expression vector has been recently shown and indicates its potential use as a viral vaccine vector (13, 14). We utilized a RV vaccine strain-based vector, which is nonpathogenic for a wide range of animal species when administrated orally or intramuscularly. This approach shows advantages over other viral vectors, for several reasons. First, its modular genome organization makes genetic modification easier than for the majority of more complex genomes of DNA and plus-stranded RNA viruses. Second, large foreign genes that are expressed from the RV genome are highly stable (14). Third, rhabdoviruses have a cytoplasmic replication cycle, and there is no evidence for recombination and/or integration into the host cell genome (15). In contrast to most other viral vectors, only a negligible seropositivity exists in the human population to RV, and immunization with a RV-based vector against HIV-1 would not interfere with immunity against the vector itself. Because oral immunization against RV with a RV vaccine strain was successful and apathogenic in chimpanzees (J. Cox and U. Wulle, personal communication), a RV-based vector may also be promising in inducing a mucosal immunity against HIV-1. In addition, RV grows to high titers (109 foci-forming units) in various cell-lines without killing the cells, which probably results in longer expression of HIV-1 genes compared with a cytopathogenic vector. The results with nef-deleted SIV, which protects against lethal SIV challenge, indicates that long term expression of the HIV-1 viral genes may be the key to inducing protection against HIV-1 infection.

Our results indicated that recombinant RVs are excellent vectors for B cell priming. RV also can induce strong CTL responses (42, 43). Preliminary data demonstrated that the recombinant RV expressing HIV-1 envelope protein induces a specific CTL response against HIV-1NL4-3 gp160. Further experiments will analyze whether similar B cell and CTL responses against expressed foreign proteins, such as HIV-1 gp160 or Gag, are possible and will analyze whether recombinant RVs expressing multiple HIV-1 antigens are even more potent live-viral vectors.