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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-01-0086.
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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1153-1159
CHEMOKINES
DNA vaccines encoding human immunodeficiency virus-1
glycoprotein 120 fusions with proinflammatory chemoattractants induce
systemic and mucosal immune responses
Arya Biragyn,
Igor M. Belyakov,
Yen-Hung Chow,
Dimiter S. Dimitrov,
Jay A. Berzofsky, and
Larry W. Kwak
From the Experimental Transplantation and Immunology
Branch, Center for Cancer Research, National Cancer Institute, and the
Molecular Immunogenetics and Vaccine Research Section, Metabolism
Branch, National Cancer Institute, Bethesda, MD; and the Laboratory of
Experimental and Computational Biology, National Cancer Institute,
Frederick, MD.
DNA immunizations with glycoprotein 120 (gp120) of human
immunodeficiency virus-1 (HIV-1) usually require boosting with protein or viral vaccines to achieve optimal efficacy. Here, we demonstrate for
the first time that mice immunized with DNA encoding gp120 fused with
proinflammatory chemoattractants of immature dendritic cells, such as  -defensin 2, monocyte chemoattractant
protein-3 (MCP-3/CCL7) or macrophage-derived chemokine
(MDC/CCL22), elicited anti-gp120 antibodies with high titers of
virus-neutralizing activity. The immunogenicity was further augmented
with the use of chemokine fusion constructs with gp140, gp120 linked to
the extracellular domain of gp41 via a 14-amino acid spacer
peptide sequence. This construct elicited antibodies with more
effective neutralizing activity than corresponding
constructs expressing gp120. Responses were dependent on physical
linkage with chemokine moiety, as no immunity was detected following
immunization of mice with DNA encoding a free mixture of chemokine and
gp120. Although the route of immunization was inoculation into skin,
both systemic and mucosal CD8+ cytolytic immune responses
were elicited in mice immunized with DNA expressing MCP-3 or
-defensin 2 fusion constructs. In contrast, no cytotoxic T
lymphocyte activity (CTL) was detected in mice immunized with DNA
encoding gp120 either alone or as fusion with MDC. Therefore, the
potential for broad application of this approach lies in the induction
of mucosal CTL and neutralizing antibodies to HIV-1 envelope, both key
requirements for prevention of viral transmission and clearance of
pathogenic HIV from mucosal reservoirs.
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