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 1
Rapamycin treatment during immunization with DNA/MVA SIV vaccine reduces contraction of Gag-CM9 tetramer+ CD8+ T cells.
