Regulation Of Immune Checkpoints Contributes To The Durable Control Of SHIV_SF162P3 Infection In Rhesus Macaques

The vast majority of HIV-infected individuals generally show the characteristics of HIV progression,such as rapid viral replication and loss of CD4+T cells in the absence of antiretroviral therapy(antiretroviral therapy,ART).However,there are a small subset of HIV-infected people who can effectively control viral infection,that is,elite controllers(elite controllers,ECs)who can spontaneously control viral replication,and posttreatment controllers(posttreatment controllers,PTCs)who can control viral replication post ART.ECs and PTCs can be considered as research models for HIV remission or HIV cure to clarify the mechanism of HIV control.In recent years,various studies have shown that immune checkpoints(immune checkpoints,ICs)can regulate the HIV latency and T cell function to affect the progress of HIV infection.However,it is still unknown whether immune checkpoints pose vital role on the formation of ECs and PTCs.Therefore,we exploit the rhesus monkey models of ECs and PTCs to explore the role and mechanism of ICs in the durable control of virus.Clarifying the specific mechanism of the HIV control is conducive to the development and optimization of HIV treatment strategies to achieve long-term virus remission.Part Ⅰ:Lower expression of BTLA and TIGIT on T lymphocytes determines the durable control of SHIVSF162P3 infection in rhesus macaques treated with LP-98HIV reservoir and immune response are two key factors affecting the formation of PTCs.Small HIV reservoir and robust immune response promote the effective HIV control of PTCs.The expression of immune checkpoint(ICs)on T cells has been proved to be closely related to HIV latency and HIV-specific T cell immune function.However,it is not clear whether they play an immunological role in the formation of PTCs.In this study,we have analyzed the expression and immunological effects of ICs in SHIVSF162P3 infected monkeys with stable virological control(stable virologic control,SVC)and stable virological rebound(stable virologic rebound,SVR)treated with a powerful HIV fusioninhibitory lipopeptide LP-98 to explore the effect of ICs on durable control SHIVSF162P3 for PTCs.We have found that the frequencies of CD4+T cells,resting CD4+T cells and resting central memory CD4+T cells(central memory CD4+T cell,CD4+TCM)expressing TIGIT and BTLA are significantly reduced in superficial or deep lymph nodes of SVC monkeys respectively when compared with SVR monkeys.Simultaneously,the decreased expression of TIGIT on CD8+T cells in peripheral blood and lymph nodes of SVC monkeys is accompanied by the stronger SIV specific CD8+T cell function.In addition,RNA sequencing also reveals that TIGIT mainly regulates the antiviral immune system in superficial lymph node mononuclear cells(lymph node mononuclear cells,LNMCs),while BTLA promote the deep virus latency in deep LNMCs,facilitating to drive effective control of virus.Part Ⅱ:Lower expression of BTLA and TIGIT on T lymphocytes contributes to the durable control of SHIVSF162P3 infection in elite control rhesus macaquesThe researches that focus on elite controllers have revealed the virological and immunological mechanisms to achieve spontaneous control of HIV,in which host genetic factors,immune response factors and viral factors are closely related to the phenotype of ECs,providing a potential theoretical basis for the development of HIV functional cure therapy.Recently,a growing number of studies have shown that immune checkpoints(ICs)participate in affecting the progress of HIV infection by enriching virus latency and inhibiting T cell response,where the role and molecular mechanism of ICs in the formation of ECs are unclear and need to be studied.In this study,we have selected 8 rhesus monkey models infected with SHIVSF162P3 via mucosal route,and divide them into progressive group(progressors,PGs)and elite control group(ECs)according to the plasma viral load.The ICs expression,provirus level and SIV-specific CD8+T cell function are detected and analyzed to explore whether ICs regulate virus latency and T cell immune response to determine the control of virus in ECs.We have found that the frequencies of total ICs+CD4+and CD8+T cells in peripheral bloods of EC monkeys are significantly lower than those of PG monkeys before virus challenge.In addition,compared with PG monkeys,the frequencies of resting CD4+T cells expressing BTLA in peripheral bloods and BTLA/TIGIT in superficial and deep lymph nodes of EC monkeys decrease significantly post virus challenge,which are positively correlated with the level of provirus.EC monkeys elicit stronger virus-specific CD8+T cell responses accompanied by the attenuation of TIGIT expression.In additional,RNA sequencing results show that BTLA and TIGIT mainly manage effective virus control by interacting with immune regulatory signal pathways in peripheral blood mononuclear cells(peripheral blood mononuclear cells,PBMCs).In conclusion,this study exploits PTCs and ECs animal models to investigate the role and related mechanisms of ICs in the formation of HIV controllers.Our findings demonstrate that BTLA and TIGIT are potential targets for HIV treatment,proposing that the combined blocking of BTLA and TIGIT is conducive to reducing the HIV latency and improving the T cell immune responses,and achieving durable control of HIV and provide a novel strategy for HIV treatment.