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Review
. 2004 Apr;17(2):370-89.
doi: 10.1128/CMR.17.2.370-389.2004.

DNA vaccines against human immunodeficiency virus type 1 in the past decade

Malavika Giri  1 , Kenneth E Ugen, David B Weiner
Affiliations
Review

DNA vaccines against human immunodeficiency virus type 1 in the past decade

Malavika Giri et al. Clin Microbiol Rev. 2004 Apr.

Abstract

This article reviews advances in the field of human immunodeficiency virus type 1 (HIV-1) and AIDS vaccine development over the last decade, with an emphasis on the DNA vaccination approach. Despite the discovery of HIV-1 and AIDS in humans nearly 20 years ago, there is no vaccine yet that can prevent HIV-1 infection. The focus has shifted toward developing vaccines that can control virus replication and disease progression by eliciting broadly cross-reactive T-cell responses. Among several approaches evaluated, the DNA-based modality has shown considerable promise in terms of its ability to elicit cellular immune responses in primate studies. Of great importance are efforts aimed at improvement of the potency of this modality in the clinic. The review discusses principles of DNA vaccine design and the various mechanisms of plasmid-encoded antigen presentation. The review also outlines current DNA-based vaccine strategies and vectors that have successfully been shown to control virus replication and slow disease progression in animal models. Finally, it lists recent strategies that have been developed as well as novel approaches under consideration to enhance the immunogenicity of plasmid-encoded HIV-1 antigen in various animal models.

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Figures

FIG. 1.
FIG. 1.
Potential targets for an HIV-1 vaccine. HIV-1 vaccines can be designed to prevent virus entry and/or to control virus replication. To block virus entry, an HIV-1 vaccine should elicit neutralizing Ab against surface glycoproteins on the viral envelope, such as gp120 and gp41, that mediate binding and entry into host cells; to control virus replication, an HIV-1 vaccine should elicit cell-mediated (T-cell) immune responses to peptide epitopes derived from other structural components of the virus such as the matrix, capsid, nucleocapsid, viral enzymes (reverse transcriptase, protease, and integrase), and accessory proteins (vpr, vpu, nef, p7, rev, and tat). su, surface; tm, transmembrane.
FIG. 2.
FIG. 2.
Current model for HIV binding and entry into target cells. The native state of viral surface glycoproteins is readily triggered by binding of gp120 to CD4 and coreceptor. This conformational change leads to the prehairpin intermediate and frees the fusion peptide on gp41. The prehairpin intermediate spans the cell and virus membranes, with the transmembrane domain of gp41 anchored in the viral membrane and the fusion peptide inserted into the target cell membrane. N peptides and C peptides or anti-gp41 Ab (ab) are thought to prevent transition to the hairpin/fusion structure. The C-heptad repeat folds back onto the N-heptad repeat to generate the trimer-of-hairpins in the fusion structure. This brings the two membranes into close proximity, driving fusion (postfusion structure). Current strategies targeting inhibition of virus entry aim to design structured envelope vaccines that block the complex virus-host cell membrane fusion intermediates as indicated in the figure. gp, glycoprotein; ab, Ab that binds the C region of gp41; CD4-bs, CD4-binding site; co-bs, coreceptor-binding site. See the text for additional references.
FIG. 3.
FIG. 3.
Proposed mechanisms of Ag presentation. Step 1. Somatic cells following plasmid transfection can serve as Ag factories expressing the protein Ag encoded by the gene of interest (GOI). Somatic cells cannot serve as APCs since they lack costimulatory molecules; however, they may regulate immune responses by providing Ag for uptake by professional APCs. Step 2. Immature DCs can be transfected directly and, on maturation, can activate CD4 T cells, CD8 T cells, and B cells. Step 3. Immature DCs can acquire Ag, following uptake of transfected apoptotic muscle cells, and present the Ag to CD4 T cells and CD8 T cells. Alternatively, immature DCs and B cells, following uptake of secreted soluble Ag, can present Ag to CD4 T cells and CD8 T cells. P, promoter; AAA, polyadenylation signal; pcDNA3, plasmid vector.
FIG. 4.
FIG. 4.
Recent strategies to enhance DNA vaccine-elicited immune responses. Strategy 1. Construction of chimeric epitopes derived from different HIV-1 strains to elicit cross-reactive T-cell responses. Such cross-reactive T cells can target HIV-1-infected cells that express different Ag epitopes. Strategy 2. Inclusion of multiple HIV-1 genes in the plasmid vaccine to enhance vaccine-elicited immune responses and to control the rate of generation of escape mutants. Strategy 3. Enhancement of CD8 T-cell responses by coinjecting cytokine genes such as IL-12 and IL-15 along with HIV-1 vaccine Ag. IL-12 enhances Th1-type responses, and IL-15 enhances CD8 T-cell memory proliferation. Inclusion of CD40L can activate and deliver maturation signals to DCs, enhancing their Ag presentation ability and associated functions. See the text for explanation of the other strategies (strategies 4, 5, and 6) illustrated. GOI, gene of interest; P, promoter; AAA, polyadenylation signal; pcDNA3, plasmid vector; TCR, T-cell receptor.
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