Metabolic plasticity of HIV-specific CD8+ T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection

Abstract

Nature MetabolisM T cells ex vivo can be isolated from HICs but not from cART individuals 8,10,18 (Fig. 1a). In the present study, it was first investigated whether this capacity of HIC CD8 + T cells could be found among naive, central memory, transitional memory and effector memory CD8 + T cell subsets (see Supplementary Fig. 1). As expected, naive CD8 + T cells from HICs had no HIV-suppressive capacity. In contrast, all sorted memory CD8 + T cell subsets from HICs, but not from cART individuals, suppressed HIV infection as efficiently as bulk CD8 + T cells (Fig. 1b). Therefore, although effector memory cells probably had more immediate antiviral capacity 12 , HIVspecific CD8 + TCMs from HICs can efficiently react to counteract HIV-1 infection during co-culture. These results support the view that the strong antiviral potential of HICs is already embedded in the programme of their HIV-specific CD8 + TCMs. Distinct gene expression profile in HIV-specific CD8 + TCMs from HICs. A comparison was then made of the single-cell gene expression profiles (96 genes associated with CD8 + T cell function, differentiation, metabolism and survival (see Supplementary Fig. 2 and Supplementary Data 1) of HIV-specific CD8 + TCMs from five HICs whose CD8 + T cells had strong HIV-suppressive capacity and from five cART individuals (see Supplementary Table 1). Cells from cART individuals and HICs analysed in the present study shared not only the same differentiation status but also the same activation phenotype, as defined by flow cytometry (Fig. 1c and see Supplementary Table 2). Despite their similar phenotype, t-SNE (t-distributed stochastic neighbour-embedding algorithm)-based

Optimal maturation of the SIV-specific CD8+T-cell response after primary infection is associated with natural control of SIV. ANRS SIC study

“…This was traduced in a dependency on glucose of HIV-specific CD8+ T-cells from non-controllers to react to HIV antigens, while HIV-specific CD8+ T-cells from controllers were characterized by metabolic plasticity and being able to exert their function even in conditions of glucose deprivation. Of note, these differences in the metabolic program of cells from controllers and non-controllers could also be recapitulated with SIV-specific CD8+ T-cells from SICs and VIR CyMs from the present study (Angin et al, 2019b), further corroborating the validity of our CyM model to study the development of the protective CD8+ T-cell responses characteristics of HIV/SIV controllers. The present results extend these observations and support a key role for long-lived memory responses in the control of SIV.…”

“…In a recent single cell study (Angin et al, 2019b), we also found differences in the program of HIV-specific CM CD8 + T-cells from HIV controllers and non-controllers on cART: whereas HIV-specific CM CD8 + T-cells from HIC upregulated the expression of effectors genes linked with mTORC2 activation and cell survival (including CD127), central memory cells from non-controllers had a skewed profile associated with mTORC1 activation (including T-bet) and glycolysis. This was traduced in a dependency on glucose of HIV-specific CD8+ T-cells from non-controllers to react to HIV antigens, while HIV-specific CD8+ T-cells from controllers were characterized by metabolic plasticity and being able to exert their function even in conditions of glucose deprivation.…”

“…Plasma viremia was monitored longitudinally in all animals using quantitative real-time RTqPCR with a limit of detection of 12.3 copies/mL (Angin et al, 2019a). Viral RNA was prepared from 100 μl of cell-free plasma.…”

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

“…The ability of IL-15 to enhance ADCC and augment NK cell mediated killing of HIV-infected target cells ex vivo (Garrido et al, 2018) may prove vital in the development of a functional cure for HIV. Our findings together with a recent report of IL-15 mediated metabolic reprogramming improving the efficacy of HIV-specific CD8 T cells from non-controllers (Angin, 2019), highlight the complementary effects of such an approach to simultaneously re-invigorate multiple arms of the immune response.…”

“…Metabolic inflexibility has been recently described to underline dysfunctional HIV-specific CD8 T cells (Angin, 2019). In particular, the polyfunctionality of CD8 T cells from spontaneous HIV-1 controllers was more reliant on mitochondrial function rather than glycolysis and differences in glucose dependency described in SIV-specific CD8 T cells have been found to correlate with their capacity to supress SIV infection.…”