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. 1998 Sep 1;95(18):10803-8.
doi: 10.1073/pnas.95.18.10803.

beta-chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques

J L Heeney  1 , V J Teeuwsen, M van Gils, W M Bogers, C De Giuli Morghen, A Radaelli, S Barnett, B Morein, L Akerblom, Y Wang, T Lehner, D Davis
Affiliations

beta-chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques

J L Heeney et al. Proc Natl Acad Sci U S A. .

Abstract

One of the obstacles to AIDS vaccine development is the variability of HIV-1 within individuals and within infected populations, enabling viral escape from highly specific vaccine induced immune responses. An understanding of the different immune mechanisms capable of inhibiting HIV infection may be of benefit in the eventual design of vaccines effective against HIV-1 variants. To study this we first compared the immune responses induced in Rhesus monkeys by using two different immunization strategies based on the same vaccine strain of HIV-1. We then utilized a chimeric simian/HIV that expressed the envelope of a dual tropic HIV-1 escape variant isolated from a later time point from the same patient from which the vaccine strain was isolated. Upon challenge, one vaccine group was completely protected from infection, whereas all of the other vaccinees and controls became infected. Protected macaques developed highest titers of heterologous neutralizing antibodies, and consistently elevated HIV-1-specific T helper responses. Furthermore, only protected animals had markedly increased concentrations of RANTES, macrophage inflammatory proteins 1alpha and 1beta produced by circulating CD8(+) T cells. These results suggest that vaccine strategies that induce multiple effector mechanisms in concert with beta-chemokines may be desired in the generation of protective immune responses by HIV-1 vaccines.

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Figures

Figure 1
Figure 1
Individual HIV-1gp120, V2-, and V3- specific IFN-γ (a), IL-2 (b) and IL-4 (c) cytokine-secreting cells per 4 × 105 PBMC (26). Controls (n = 2 FluISCOM plus n = 2 wtFP) grouped together with HIV-1 ISCOM and HIV-1FP groups, respectively. The y axis for each cytokine is used based on the optimal working range for each cytokine. IFN-γ (0 -100), IL-2 (0–15), and IL-4 (0–100), respectively.
Figure 2
Figure 2
Concentration of β-chemokines produced by CD8+ enriched T cells from animals 2 weeks before challenge. Values expressed as pg/ml from each individual animal plotted per group; HIV-1 vaccinees (HIV-1 ISCOM) protected, HIV-1 vaccinees (HIV-1 FP) not protected, and controls (two Flu Pr8 ISCOM, two FP wild type). (a) Concentrations of RANTES produced per individual animal plotted per group. (b) Concentrations of MIP-1α produced per individual animal plotted per group. (c) Concentrations of MIP-1β produced per individual animal plotted per group. (d) Concentrations of the control chemokine MCP-1 produced per individual animal plotted per group.
Figure 3
Figure 3
Correlation of the concentration of β-chemokines with type-1 (a; IFN-γ) or type-2 (b; IL-4) T helper responses. In animals protected from vaccine challenge a correlation of β-chemokines produced just before challenge (RANTES, MIP-1α, and MIP-1β) was found with both the number of IFN-γ- and IL-4-secreting cells. Protected animals have high numbers of all three β-chemokines produced in relationship with both the number of gp120-specific IFN-γ- and IL-4-secreting cells.
Figure 4
Figure 4
β-chemokine inhibition of infection of rhesus PBMCs with the challenge virus SHIVSF13. Inhibitory concentrations (ng/ml) of (a) RANTES; (b) MIP-1α, and (c) MIP-1β. Lack of inhibition of SHIVSF13 infection with the control C-C chemokine MCP-1 (d).
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