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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-01-0086.
Submitted January 15, 2002
Accepted April 9, 2002
DNA vaccines encoding HIV-1 gp120 fusions with proinflammatory chemo-attractants induce systemic and mucosal immune responses
Arya Biragyn*, Igor M Belyakov, Yen Hung Chow, Dimiter S Dimitrov, Jay A Berzofsky, and Larry W Kwak
Experimental Transplantation and Immunology Branch, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, Bethesda, MD, USA
Laboratory of Experimental and Computational Biology, National Cancer Institute-Frederick, Frederick, MD, USA
* Corresponding author; email: arya{at}mail.ncifcrf.gov.
DNA immunizations with gp120 of HIV-1 usually require boosting with protein or viral vaccines to achieve optimal efficacy. Herein, we report a novel and simple strategy which substantially augments immunogenicity of otherwise weakly immunogenic DNA vaccines expressing gp120, by vaccinating mice with DNA encoding gp120 fused with inflammatory chemo-attractants of immature DC, such as ß-defensin 2, MCP-3 or MDC. DNA immunizations encoding these fusions, but not gp120 alone, elicited anti-gp120 antibodies with high titers of virus neutralizing activity. Moreover, chemokine fusion constructs with gp140, gp120 linked to the extracellular domain of gp41 via a 14 a.a. spacer peptide sequence, elicited more effective broadly neutralizing antibodies, which inhibit infection of pseudotype virus expressing heterologous envelopes, than corresponding constructs expressing gp120. Even though the route of immunization was inoculation into skin, both systemic and mucosal CD8+ cytolytic immune responses were elicited in mice immunized with fusion constructs of gp120 with ß-defensin 2 or MCP-3. In contrast, fusion constructs with MDC, a Th2 specific chemokine, induced predominantly antibody responses and no CTL. Thus, the potential for broad application of this approach lies in the induction of mucosal CTL and neutralizing antibodies to HIV-1 Env, key requirements for prevention of viral transmission and clearance of pathogenic HIV from mucosal reservoirs.
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