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. 2003 Oct;77(19):10348-56.
doi: 10.1128/jvi.77.19.10348-10356.2003.

Cellular immunity elicited by human immunodeficiency virus type 1/ simian immunodeficiency virus DNA vaccination does not augment the sterile protection afforded by passive infusion of neutralizing antibodies

John R Mascola  1 , Mark G Lewis, Thomas C VanCott, Gabriela Stiegler, Hermann Katinger, Michael Seaman, Kristin Beaudry, Dan H Barouch, Birgit Korioth-Schmitz, Georgia Krivulka, Anna Sambor, Brent Welcher, Daniel C Douek, David C Montefiori, John W Shiver, Pascal Poignard, Dennis R Burton, Norman L Letvin
Affiliations

Cellular immunity elicited by human immunodeficiency virus type 1/ simian immunodeficiency virus DNA vaccination does not augment the sterile protection afforded by passive infusion of neutralizing antibodies

John R Mascola et al. J Virol. 2003 Oct.

Abstract

High levels of infused anti-human immunodeficiency virus type 1 (HIV-1) neutralizing monoclonal antibodies (MAbs) can completely protect macaque monkeys against mucosal chimeric simian-human immunodeficiency virus (SHIV) infection. Antibody levels below the protective threshold do not prevent infection but can substantially reduce plasma viremia. To assess if HIV-1/SIV-specific cellular immunity could combine with antibodies to produce sterile protection, we studied the effect of a suboptimal infusion of anti-HIV-1 neutralizing antibodies in macaques with active cellular immunity induced by interleukin-2 (IL-2)-adjuvanted DNA immunization. Twenty female macaques were divided into four groups: (i). DNA immunization plus irrelevant antibody, (ii). DNA immunization plus infusion of neutralizing MAbs 2F5 and 2G12, (iii). sham DNA plus 2F5 and 2G12, and (iv). sham DNA plus irrelevant antibody. DNA-immunized monkeys developed CD4 and CD8 T-cell responses as measured by epitope-specific tetramer staining and by pooled peptide ELISPOT assays for gamma interferon-secreting cells. After vaginal challenge, DNA-immunized animals that received irrelevant antibody became SHIV infected but displayed lower plasma viremia than control animals. Complete protection against SHIV challenge occurred in three animals that received sham DNA plus MAbs 2F5 and 2G12 and in two animals that received the DNA vaccine plus MAbs 2F5 and 2G12. Thus, although DNA immunization produced robust HIV-specific T-cell responses, we were unable to demonstrate that these responses contributed to the sterile protection mediated by passive infusion of neutralizing antibodies. These data suggest that although effector T cells can limit viral replication, they are not able to assist humoral immunity to prevent the establishment of initial infection.

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Figures

FIG. 1.
FIG. 1.
Study scheme and experimental groups. Twenty female macaques were divided into the four experimental groups shown. DNA immunizations were administered at 0, 4, 8, and 24 weeks. SHIV-89.6P vaginal challenge occurred at week 38, 1 day after infusion of either IVIG or the 2F5 and 2G12 MAbs.
FIG. 2.
FIG. 2.
(A) Plasma anti-gp120 antibody titers were measured during the course of immunizations. In this and subsequent panels, the upward arrows indicate DNA immunizations and the downward arrow indicates the day of SHIV challenge. Note the high antibody titer at week 40 in the second panel, resulting from passive infusion of the MAbs 2F5 and 2G12. (B) Percentage of CD8+ T cells that stained with the Mamu-A01/p11C tetramer. The eight Mamu-A*01 allele-positive animals were evenly distributed into the four groups of animals. Thus, four animals received DNA Env-Gag immunization (left panel) and four received sham DNA (right panel). (C) Pooled peptide ELISPOT assay for IFN-γ-secreting PBMC. All DNA-immunized animals had detectable IFN-γ-secreting cells. In order to best visualize the data, the y axis of the second panel has been expanded to accommodate two animals with particularly high responses. (D) IFN-γ-secreting cells at week 26 (2 weeks after the fourth DNA immunization). All 10 DNA-immunized animals are shown. The response to each peptide pool is shown using a stacked column graph. An asterisk indicates ELISPOT data after CD8 T-cell depletion. Note the expanded y axis used for the right panel.
FIG. 3.
FIG. 3.
Postchallenge plasma viral RNA and peripheral CD4 T-cell counts. (A) Plasma viremia was determined using a branched-chain DNA amplification assay with a limit of detection of 500 RNA copies/ml. An asterisk indicates animals with no detectable viremia. (B) CD4 T cells per microliter of whole blood. Animals are identified by the same symbols shown in the plasma viremia graphs above.
FIG. 4.
FIG. 4.
Postchallenge p11C tetramer-positive CD8 T cells. (A) Four Mamu-A*01 monkeys received DNA gag/env immunization, and four received sham DNA. Closed symbols indicate monkeys that received IVIG infusion; open symbols indicate infusion of the MAbs 2F5 and 2G12. Here and in panel B below, arrows at week 38 indicate time of SHIV challenge. An asterisk indicates animals that were completely protected against SHIV challenge. (B) Postchallenge pooled peptide ELISPOT assays for IFN-γ-secreting PBMC. (C) Development of plasma neutralizing antibodies against the SHIV-89.6P challenge virus is not affected by prior DNA immunization encoding the JR-FL Env glycoprotein. Note that week 0 assays were run prior to passive infusion of antibodies.
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