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. 2007 May;81(10):5202-11.
doi: 10.1128/JVI.02881-06. Epub 2007 Mar 7.

Long-term control of simian immunodeficiency virus replication with central memory CD4+ T-cell preservation after nonsterile protection by a cytotoxic T-lymphocyte-based vaccine

Miki Kawada  1 , Tetsuo Tsukamoto, Hiroyuki Yamamoto, Akiko Takeda, Hiroko Igarashi, David I Watkins, Tetsuro Matano
Affiliations

Long-term control of simian immunodeficiency virus replication with central memory CD4+ T-cell preservation after nonsterile protection by a cytotoxic T-lymphocyte-based vaccine

Miki Kawada et al. J Virol. 2007 May.

Abstract

Induction of virus-specific CD8(+) cytotoxic T-lymphocyte (CTL) responses is a promising strategy for AIDS vaccine development. However, it has remained unclear if or how long-term viral containment and disease control are attainable by CTL-based nonsterile protection. Here, we present three rhesus macaques that successfully maintained Env-independent vaccine-based control of simian immunodeficiency virus (SIV) mac239 replication without disease progression for more than 3 years. SIV-specific neutralizing antibody induction was inefficient in these controllers. Vaccine-induced Gag-specific CTLs were crucial for the chronic as well as the primary viral control in one of them, whereas those Gag-specific CTL responses became undetectable and CTLs specific for SIV antigens other than Gag, instead, became predominant in the chronic phase in the other two controllers. A transient CD8(+) cell depletion experiment 3 years postinfection resulted in transient reappearance of plasma viremia in these two animals, suggesting involvement of the SIV non-Gag-specific CTLs in the chronic SIV control. This sustained, neutralizing antibody-independent viral control was accompanied with preservation of central memory CD4(+) T cells in the chronic phase. Our results suggest that prophylactic CTL vaccine-based nonsterile protection can result in long-term viral containment by adapted CTL responses for AIDS prevention.

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Figures

FIG. 1.
FIG. 1.
Follow-up of the macaques after SIVmac239 challenge. Upper panels, peripheral CD4+ T-cell counts (cells/μl); lower panels, plasma viral loads (viral RNA copies/ml plasma); left panels, the seven noncontrollers; right panels, the five controllers. All seven noncontrollers developed AIDS and were euthanized during the observation period (Table 1). Macaques V5, V6, and V8 received anti-CD8 antibody treatment starting from week 118, week 156, and week 156, respectively.
FIG. 2.
FIG. 2.
SIVmac239-specific neutralizing antibody levels in plasma. Plasma titers for killing 10-TCID50 SIVmac239 replication in the noncontrollers (top panel), including unvaccinated control animals, and in the controllers (bottom panel) are shown.
FIG. 3.
FIG. 3.
Virus-specific CD8+ T-cell responses in sustained controllers V6 (left panels) and V8 (right panels). (A) Gag-specific and SIV-specific CD8+ T-cell frequencies in PBMCs. (B) Dot plots gated on CD3+ lymphocytes after Gag-specific or SIV-specific stimulation.
FIG. 4.
FIG. 4.
CD8+ cell depletion experiments starting at week 156 in sustained controllers V6 (left panels) and V8 (right panels). (A) Peripheral CD8+ T-cell counts (per μl). (B) Plasma viral loads (viral RNA copies/ml plasma). (C) Virus-specific CTL responses at week 160 in V6 and at week 166 in V8. Dot plots gated on CD3+ lymphocytes after Gag-specific or SIV-specific stimulation are shown.
FIG. 5.
FIG. 5.
Changes in peripheral memory CD4+ T-cell counts. Noncontrollers are indicated in black or blue, and controllers are indicated in red. (A) Peripheral memory CD4+ (CD4+ CD95+) T-cell counts (per μl). (B) Peripheral central memory CD4+ (CD4+ CD95+ CD28+) T-cell counts (per μl). (C) Representative density plots (macaque V4 prechallenge) for determining peripheral memory CD4+ T-cell percentages. The left panel is a density plot gated on lymphocytes, and in this plot, CD3+ CD4+ lymphocytes are gated for the right panel of the density plot. In the right panel, we determined the percentages of central memory (CD95+ CD28+) CD4+ T cells and memory (CD95+ CD28+ plus CD95+ CD28−) CD4+ T cells.
FIG. 6.
FIG. 6.
Statistical analysis indicating preservation of central memory CD4+ T-cell counts in the controllers. The ratios of central memory CD4+ T-cell counts at week 12 to week 0 (A), week 70 to week 0 (B), and week 70 to week 12 (C) in the noncontrollers (except for rapid progressor V2 in panels B and C) and the controllers are plotted. The longer bars indicate geometric mean values, and the regions between the shorter bars indicate the 95% confidential intervals. Statistical analysis was performed with the t test and nonparametric Mann-Whitney U-test using the Prizm software.
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