Important note: Information in this article was accurate in May 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, May 17, 1999
Daniel J. DeNoon, Senior Editor
Monkeys primed with intradermal HIV DNA and boosted with recombinant fowlpox virus (rFPV)-expressed HIV protein developed very low-level infections but remained disease free after challenge with pathogenic SHIV (chimeric virus with an HIV coat over an SIV backbone). Deployment of such a vaccine in areas with a high incidence of infection would be expected to greatly reduce HIV transmission as well as AIDS morbidity and mortality.
"The ability to achieve stringent containment of serial SHIV challenges using intradermal DNA priming and recombinant pox virus boosters holds promise for the development of a vaccine capable of considerably reducing viral replication and thus stemming the transmission of AIDS," concluded Harriet L. Robinson of Yerkes Primate Research Center, Atlanta, Georgia, and colleagues.
Robinson et al. reported their findings in the journal Nature Medicine ("Neutralizing Antibody-Independent Containment of Immunodeficiency Virus Challenges by DNA Priming and Recombinant Pox Virus Booster Immunizations," Nat Med 1999 May;5(5):526-34.
The effective immune responses elicited by the vaccine did not depend on neutralizing antibodies. The vaccine would therefore avoid problems presented by the extraordinary diversity of HIV surface antigens and would be effective against a wide range of HIV strains.
Moreover, the studies suggested that each challenge with SHIV actually boosted anti-HIV immune responses.
"If our hypotheses are correct, the boosting of responses by challenge infections should bolster the effectiveness of the vaccine in the high-risk populations which are the chief source of transmission," Robinson et al. suggested.
The elegant study design compared eight different vaccination protocols in groups of four rhesus macaques:
All of the HIV DNA and rFPV vaccines expressed the gag, pol, env, and nef genes of the nonpathogenic SHIV-IIIb.
Priming immunizations were given at 0, 4, and 26 weeks; booster immunizations were given at 46 and 66 weeks. Two weeks after the second booster immunization, all animals were challenged intravenously with the vaccine-homologous SHIV-IIIb (10 macaque-infectious doses). Subsequent challenges were given to animals who showed no detectable viral RNA and from whom no more than one co-cultivation assay demonstrated the presence of infected cells.
After the first challenge, 10 animals met the criteria for second challenge: one in the i.d./i.d. group, two in the i.d./prt group, three in the i.d./rFPV group, one in the gg/rFPV group, and three in the cont/prt group. Without additional boosting, these animals received another SHIV-IIIb challenge 43 weeks after the first challenge.
"Unexpectedly, the intradermal DNA priming provided better containment of the SHIV-IIIb challenge than the gene-gun DNA priming (P=0.01)," Robinson et al. reported. "Six of the 12 monkeys primed with DNA delivered intradermally had undetectable levels of plasma viral RNA after the first two challenges, whereas all of the monkeys primed with DNA delivered by gene gun had easily detected levels of viral RNA after the first or second challenge."
All animals receiving the second challenge showed evidence of SHIV-IIIb infection. For some, infection could only be detected by co-cultivation of serum with highly susceptible cells.
Six animals - three in the i.d./rFPV group, two in the i.d./prt group, and one in the i.d./i.d. group - met the criteria for third challenge. This was made 19 weeks after the second challenge with the highly pathogenic SHIV89.6P virus, which resulted in high viral loads and precipitous drop in CD4 T cell counts in unvaccinated control animals.
"All of the monkeys given the third challenge were protected against the rapid loss of CD4(+) cells," Robinson et al. reported. "Four did not have detectable levels of viral RNA by PCR assay. Three of these did not have detectable levels of co-cultivation positive cells. The two monkeys that did have detectable levels of viral RNA by PCR assay had titers 0.001 percent of those of the naive control monkeys. By eight weeks after challenge, these two monkeys had reduced their levels of viral RNA to below background."
Neutralizing antibody could be detected at different titers at different phases of the trial, but were not associated with protection. The animals therefore appeared to be protected by cell-mediated immunity, but HIV specific cytotoxic lymphocyte (CTL) responses were far lower than those seen in previous studies in which monkeys were protected by live, attenuated virus vaccines.
"This raises the possibility that the protective response might have been mediated by a nonlytic T-cell activity," Robinson et al. suggested.
Vaccine protection could not be predicted by the animals' CTL or antibody levels prior to challenge, and no differences in this regard could be seen between the gene-gun and intradermal DNA-vaccinated monkeys.
"This could reflect the possibility that intradermal but not gene-gun DNA inoculations prime T-cell responses with suppressive activity for HIV-1 infections," Robinson et al. wrote.
The authors suggested that their findings bear direct relevance to human HIV vaccination.
"Unlike antibody that can prevent infection, cell-mediated immune responses act after infection, and thus afford immunodeficiency virus infections the opportunity to establish proviral DNA," they warned. "HIV-1 vaccines that operate after infection, despite even very low levels of infection (below those able to be detected by RT-PCR) will not prevent the long-term persistence of virus and the potential for re- emergent virus."
This research was supported by National Institutes of Health grants, including the Yerkes Primate Research Center Base Grant.
The corresponding author for this study is Harriet L. Robinson, Yerkes Regional Primate Research Center, Atlanta, Georgia 30329.
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