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
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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

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Figure 5

Enhanced magnitude and quality of postinfection recall CD8+ and CD4+ T cell responses in rapamycin-treated macaques.

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Enhanced magnitude and quality of postinfection recall CD8+ and CD4+ T c...
(A) Geometric means of frequencies of Gag-CM9–specific tetramer+ cells among total CD8+ T cells measured temporally after infection in the gut of Mamu-A*01 macaques (n = 4/group). (B) Geometric means of SIV-specific IFN-γ+ cells among total CD8+ T cells measured temporally after infection in the gut (n = 10/group). (C) Geometric means of frequencies of Gag-CM9–specific tetramer+ cells among total CD8+ T cells measured temporally after infection in the blood of Mamu-A*01 macaques (n = 4/group). (D) Geometric means of SIV-specific IFN-γ+ cells among total CD8+ T cells measured temporally after infection in the blood (n = 10/group). (E) Correlation of frequencies of postinfection SIV-specific IFN-γ+CD8+ T cells with postvaccination memory SIV-specific IFN-γ+CD8+ T cells in blood. (F) Correlation of frequencies of postinfection (PI) Gag-CM9 tetramer+ CD8+ T cells in blood on week 2 after infection with plasma viral load at week 3 after infection. (G) Correlation of SIV-specific IFN-γ+CD8+ T cells in blood with plasma viral load at week 3 after infection. (H) Left: Geometric means of SIV-specific IFN-γ+ cells among total CD4+ T cells measured temporally after infection in blood (n = 10/group). Right: Frequency of IFN-γ+ cells among total CD4+ T cells shown individually at postinfection week 2 (n = 10/group). (I) Frequency of TNF-α+ cells among total CD4+ T cells shown individually at postinfection week 2 (n = 10/group). Mamu-A*01 animals are indicated by closed symbols. *P < 0.05, **P < 0.01 by 1-way ANOVA; 2-way ANOVA multiple comparisons were used to compare cytokine-positive frequencies between groups.