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. 2004 Jan;78(1):146-57.
doi: 10.1128/jvi.78.1.146-157.2004.

A single injection of recombinant measles virus vaccines expressing human immunodeficiency virus (HIV) type 1 clade B envelope glycoproteins induces neutralizing antibodies and cellular immune responses to HIV

Clarisse Lorin  1 , Lucile Mollet, Frédéric Delebecque, Chantal Combredet, Bruno Hurtrel, Pierre Charneau, Michel Brahic, Frédéric Tangy
Affiliations
Free PMC article

A single injection of recombinant measles virus vaccines expressing human immunodeficiency virus (HIV) type 1 clade B envelope glycoproteins induces neutralizing antibodies and cellular immune responses to HIV

Clarisse Lorin et al. J Virol. 2004 Jan.
Free PMC article

Abstract

The anchored and secreted forms of the human immunodeficiency virus type 1 (HIV-1) 89.6 envelope glycoprotein, either complete or after deletion of the V3 loop, were expressed in a cloned attenuated measles virus (MV) vector. The recombinant viruses grew as efficiently as the parental virus and expressed high levels of the HIV protein. Expression was stable during serial passages. The immunogenicity of these recombinant vectors was tested in mice susceptible to MV and in macaques. High titers of antibodies to both MV and HIV-Env were obtained after a single injection in susceptible mice. These antibodies neutralized homologous SHIV89.6p virus, as well as several heterologous HIV-1 primary isolates. A gp160 mutant in which the V3 loop was deleted induced antibodies that neutralized heterologous viruses more efficiently than antibodies induced by the native envelope protein. A high level of CD8+ and CD4+ cells specific for HIV gp120 was also detected in MV-susceptible mice. Furthermore, recombinant MV was able to raise immune responses against HIV in mice and macaques with a preexisting anti-MV immunity. Therefore, recombinant MV vaccines inducing anti-HIV neutralizing antibodies and specific T lymphocytes responses deserve to be tested as a candidate AIDS vaccine.

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Figures

FIG. 1.
FIG. 1.
Constructions of recombinant MV-envHIV89.6. (A) Full-length gp160 and secreted gp140 HIV-1 Env proteins. Shaded boxes indicate V1, V2, and V3 regions; dashed boxes show the transmembrane domain. Amino acid positions are indicated. The BbsI and MfeI restriction sites used to introduce the ΔV3-AAELDKWASAA mutation are also indicated. (B) pMV(+) vectors with ATU containing a green fluorescent protein (GFP) gene in positions 2 and 3. The MV genes are indicated as follows: N, nucleoprotein; PVC, phosphoprotein and V C proteins; M, matrix; F, fusion; H, hemagglutinin; and L, polymerase. T7, T7 RNA polymerase promoter; T7t, T7 RNA polymerase terminator; ∂, hepatitis delta virus ribozyme.
FIG. 2.
FIG. 2.
Expression of HIV-189.6 envelope glycoproteins in recombinant MVs. gp160, gp140, and MV nucleoprotein (N) detected in lysates of Vero cells infected with MV-EnvHIV viruses. (A) HIV proteins were probed with mouse monoclonal anti-HIV gp120 antibody; (B) MV N protein was probed with monoclonal anti-MV N antibody.
FIG. 3.
FIG. 3.
Growth kinetics of recombinant MV-EnvHIV89.6 viruses on Vero cells. Vero cells were infected with EdB-tag MV and MV- EnvHIV89.6 viruses at an MOI of 0.01. At each time point, cells were collected, and cell-associated virus titers were determined by using the TCID50 method on Vero cells.
FIG. 4.
FIG. 4.
Anti-HIV and anti-MV antibody titers in IFN-α/βR−/− CD46+/− mice immunized with MV-EnvHIV89.6 viruses. (A) Anti-MV and anti-HIV antibody titers detected 28 days after injection of increasing doses of MV-gp160 (three mice per group). (B to D) Anti-MV (B), anti-HIV (C), and anti-ELDKWAS (D) antibody titers were detected in sera from animals 28 days after the injection of 5 × 106 TCID50 of MV-gp160/gp140 viruses (░⃞) and MV-gp160/gp140 ΔV3-ELDKWAS (▪) viruses (six mice per group). The results are expressed as the mean values ± the standard deviation.
FIG. 5.
FIG. 5.
Characterization of MV- and HIV-specific T cells in mice immunized by MV2-gp160HIV89.6. (A) Enumeration of gp120-specific IFN-γ-ELISpots. Two groups of three mice were inoculated with 5 × 106 TCID50 of MV2-gp160 virus and then euthanized 7 days or 1 month postinoculation. ELISPOT assays were performed with splenocytes from immunized mice. Stimulation with HIV-gp120 purified protein (▪) or irrelevant BSA (□). (B) Fluorescence-activated cell sorting analysis of CD8+ (upper panel) and CD4+ (lower panel) T cells producing IFN-γ in mice splenocytes collected 7 days after immunization with 5 × 106 TCID50 of MV2-gp160. Ex vivo splenocytes were stimulated either with medium (left panel), HIV gp120 (middle panel), or EdB-tag MV (right panel). The percentages are given according to the total CD8+ and CD4+ counts.
FIG. 6.
FIG. 6.
Anti-MV and anti-HIV antibody titers in mice and macaques immunized with MV2-gp140HIV89.6 virus months after MV priming. (A) Mice (three per group) were vaccinated with 105 TCID50 of EdB-tag MV and then inoculated twice with 5 × 106 TCID50 of MV2-gp140 virus as indicated (arrows). (B) Cynomolgus macaques (animals 432 and 404) were vaccinated with Rouvax and were then inoculated twice with 5 × 106 TCID50 of MV2-gp140 virus as indicated (arrows).
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