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

Abstract

27Highly efficient virus-specific CD8 + T-cells are associated with immune control of HIV 28 infection, but it remains unclear how these cells are generated and maintained over time. 29 We used a macaque model of spontaneous control of SIVmac251 infection to monitor the 30 development and evolution of potent antiviral CD8 + T-cell responses. SIV-specific CD8 + T-31 cells emerged during primary infection in all animals. However, the ability of CD8 + T cells to 32 suppress SIV replication was low in early stages but increased after a period of maturation, 33 temporally linked with the establishment of sustained low-level viremia in controller 34 macaques. SIV-specific CD8 + T-cells with a central memory phenotype expressed higher 35 levels of survival markers in controllers versus non-controllers. In contrast, a persistently 36 skewed differentiation phenotype was observed among central memory SIV-specific CD8 + T-37 cells in non-controllers since primary infection, typified by relatively high expression levels of 38 T-bet.

Modeling SIV kinetics supports that cytotoxic response drives natural control and unravels heterogeneous populations of infected cells

“…Consistent with Passaes et al (23) , we defined as “controllers” individuals having two consecutive plasma SIV-RNA lower than 400 cp/mL and with no consecutive SIV-RNA higher than 400 cp/mL afterwards, while others were defined as viremic. With this definition, 12 individuals were defined as controllers (3 in the non-M6/high inoculum, 4 in non-M6/low inoculum, 5 in the M6 groups) and 4 were characterized as viremic (3 in the non-M6/high inoculum, 1 in M6/high inoculum, 0 in the non-H6/low inoculum groups).…”

“…Our hypothesis of a central role of the cytotoxic response is also consistent with measurements of CD8 + T-cell cytotoxic activity (Figures 3 and 4). Overall, we found our predictions of the actively producing infected cells half-life to match in several animals the change in ex vivo CD8 + T-cell dependent direct antiviral activity but not with the frequency of SIV-specific CD8 + T cells, indicating that the key determinant of control is not the magnitude per se but rather the cytotoxic potential of the CD8 + T-cell response (23) . However it should be acknowledged that this is not the case for all NHPs.…”

“…In order to develop a model to predict the mechanisms associated with natural control of HIV/SIV infections and to characterize the different cell compartments contributing to HIV/SIV reservoirs, we took advantage of the ANRS SIC study (23) . Briefly, we analyzed the kinetics of SIV-RNA and SIV-DNA of cynomolgus macaques naturally controlling (n=12) and non-controlling (n=4) SIV infection, monitored for virologic and immunologic parameters along 18 months.…”

“…Kinetics of SIV-RNA and SIV-DNA loads are described in (23) (see also Figure S1). In brief, all macaques showed a similar pattern during acute infection, with a median SIV-RNA at peak of 6.2 (min-max: [5.13; 7.09]) log cp/mL and a median time to peak of 14 days ([11-17]).…”

“…Data used in this study were obtained from the ANRS SIC study (23) . Briefly, it included 16 male cynomolgus macaques, all infected intrarectally with SIV mac251 and followed for 18 months after viral exposure without any treatment.…”