Coadministration of rapamycin with a DNA/MVA SIV vaccine improves memory CD8+ T cell response
Shanmugalakshmi Sadagopal, Kasey Stokdyk, Suefen Kwa, Rahul Basu, Sailaja Gangadhara, Rafi Ahmed, Smita S. Iyer, Koichi Araki, Rama Rao Amara
Shanmugalakshmi Sadagopal, Kasey Stokdyk, Suefen Kwa, Rahul Basu, Sailaja Gangadhara, Rafi Ahmed, Smita S. Iyer, Koichi Araki, Rama Rao Amara
View: Text | PDF
Research Article AIDS/HIV Immunology Infectious disease

Coadministration of rapamycin with a DNA/MVA SIV vaccine improves memory CD8+ T cell response

Abstract

Inhibiting the mammalian target of rapamycin (mTOR) during acute viral infection generates highly functional memory CD8+ T cells. We investigated the effects of inhibiting mTOR by using rapamycin during the effector and contraction phases of the immune response to a DNA prime and Modified Vaccinia Ankara (MVA) boost SIV vaccination in rhesus macaques. Rapamycin administered either during MVA boosts alone (DMR) or during both primes and boosts (DRMR) reduced the contraction of effector CD8+ T cells, resulting in higher frequencies of SIV-specific memory CD8+ T cells with enhanced quality, as indicated by expression of Bcl2 and CD127. Additionally, rapamycin reduced the frequency of proliferating CCR5+CD4+ T cells in the blood following the MVA boost. After SIVmac251 infection, rapamycin-treated macaques demonstrated marked expansion of SIV-specific CD8+ T cells (reaching up to 50% in blood and 25% in gut). The heightened expansion of SIV-specific CD8+ T cells in the DMR group was associated with markedly lower (2-logs compared with unvaccinated and 1-log compared with DM) peak viral load in the gut and set-point viremia, along with improved survival after infection. Thus, inhibiting the mTOR pathway during MVA boosts of a DNA/MVA vaccine enhances vaccine efficacy by improving memory CD4+ and CD8+ T cell function.

Authors

Shanmugalakshmi Sadagopal, Kasey Stokdyk, Suefen Kwa, Rahul Basu, Sailaja Gangadhara, Rafi Ahmed, Smita S. Iyer, Koichi Araki, Rama Rao Amara

×

Figure 4

Rapamycin reduces expression of CCR5 on vaccine-specific CD4+ T cells.

Options: View larger image (or click on image) Download as PowerPoint
Rapamycin reduces expression of CCR5 on vaccine-specific CD4+ T cells. (...
(A) Geometric means of frequencies of SIV-specific IFN-γ+CD4+ T cells measured temporally after MVA immunization in stimulated PBMCs after vaccination. Individual data points at MVA1 week 1 and MVA2 week 1 (n = 10/group). (B) Median frequencies of Bcl-2 on SIV-Gag–stimulated CD4+ T cells measured temporally after MVA immunization in stimulated PBMCs of immunized animals. Individual data at MVA1 week 5 and MVA2 week 5 (n = 10/group). (C) Representative flow plot of CCR5 and CFSE on SIV-Gag–stimulated CD4+ T cells from MVA2 week 12 time points. Frequencies of proliferating (CFSElo) CD4+ T cells, and frequencies of CCR5+ cells among proliferating (CFSElo) CD4+ T cells upon stimulation with pools of Gag and Env peptides. (D) Geometric means of Ki67+ and CCR5+ cells among total CD4+ T cells measured temporally after MVA immunizations. Individual frequencies of CCR5+ cells among Ki67+CD4+ T cells at MVA week 1. Mamu-A*01 animals are indicated by closed symbols. *P < 0.05; **P < 0.01 by 1-way ANOVA; 2-way ANOVA multiple comparisons tests were used to compare marker-positive frequencies between groups at various time points, except for CCR5+ cells among Ki67+CD4+ T cells, for which we used an unpaired, non-parametric Mann-Whitney test. For BCl2 data shown in B, we did not have data for 2 or 3 animals. For the CFSE proliferation data shown in C, we did not perform the assay on 1 animal in the DMR group due to insufficient cells. For the CCR5 expression on proliferating cells in C, we considered only samples in which proliferation was at least 1%. This excluded 6 animals (2 in DM, 3 in DMR, and 1 in DRMR).