Longitudinal Study Of Immunoactivation And Exploration Of Therapeutic Efficacy In SIVmac239-Infected Rhesus Macaques With Combined Antiretroviral Therapy

Human immunodeficiency virus(HIV)infection can be effectively controlled by antiretroviral therapy(ART),but the integration of HIV into the host genome cannot be eliminated.Majority of infected persons need lifelong ART treatment to avoid viral rebound after drug withdrawal.In addition,due to the existence of continuous immune activation in vivo,the incidence of chronic diseases and mortality in ART treated patients are still higher than that in healthy persons.Restoring the immune system function of HIV infected patients and eliminating the HIV reservoir are the goals of the functional cure of AIDS.The latent-infected non-human primate model established by ART is an important tool for the exploration of functional cure.This study used this animal model to study the following two parts:Part Ⅰ:Longitudinal Study of Sustainable Immune Activation on ART-Treated SIVmac239-Infected Rhesus MacaquesThe term immune activation describes the activation of the cellular components of the immune system,which may in turn lead to systemic inflammation.Immune activation is associated with HIV disease progression as well as the increased morbidity and mortality in HIV-infected patients despite antiretroviral therapy.However,the relationship between the replication of the virus and the persistence of immune activation is unclear.It is helpful to understand the relationship between virus replication,abnormal immune activation and disease progression by comparing the changes of immune cells and inflammatory cytokines between pre-infection phase and the virus suppression phase,or in the case of virus replication,comparing the changes of immune cells and inflammatory cytokines between the chronic infection phase and the virus rebound phase after drug withdrawal.In this study,eight monkeys were randomly selected and monitored for 28 days to acquire baseline immune function before i.v.administration of 100 TCID50 of SIVmac239 and virus replication for 98 days,followed by standard ART for 90 days,and 49 days monitoring after discontinuing ART.Four SIV-dependent stages,SIV-negative(SN,’baseline’),SIV-emerged(SE,’infection’),SIV-suppressed(SS,’treatment’),and SIV-rebounded(SR,’withdrawal’),were stratified according to plasma viral RNA quantification.We performed comparisons of host immune function between SS and SN,and between SR and SE.Compared to the SN stage,increased CD38+HLA-DR-CD4+/CD8+T-cell subsets and PD-1+ memory CD4+/CD8+T-cell subsets and elevated cytokines including MIP-1β,IL-8 and IL-10(SS vs SN,p<0.05)was shown in the SS stage.Compared to the SE stage,the SR phase exhibited an accelerated immune activation against SIV with increased numbers of PD-1+CD4+Tcm cells,decreased PD-1+CD4+TEM cells and enhanced pro-inflammatory cytokine levels including TNF-α,IL-6,IL-1β and IFN-y(SR vs SE,p<0.05).Longitudinal studies of latent-infected rhesus monkeys have shown that abnormal immune activation persistently increased with or without viral replication which may contributes to the understanding of the relationship between viral replication and host immunity,and provides important informations for the landscape of abnormal immune activation in SIV-infected rhesus macaques undergone ART treatment.Part Ⅱ:Therapeutic Efficacy and the Features of Virus Reservoirs by Potent HIV Fusion Inhibitor Combined with ART in SIV-Infected Rhesus MacaquesART can effectively control the HIV replication but hardly achieve the HIV cure due to the persistence of viral reservoirs.Exploring the strategies of eliminating the HIV reservoirs for achieving the functional cure of AIDS is the hot spots in the current AIDS fields.Our previous study on HIV fusion inhibitors found that LP-98 can effectively suppress virus replication in SHIV-infected monkeys and achieved posttreatment control in a subset of treated monkeys.This led us to explore whether combining a potent HIV fusion inhibitor with ART regimen would be more effective in prolonging viral rebound time and even achieving a functional cure.In this study,15 Chinese rhesus monkeys were selected and randomly divided them into three groups.All animals were infected with 100 TCID50 SIVmac239 through intravenous route,and 3 months treatment began on 98 days post infection:one group received ART therapy,one group received LP-98+ART combined therapy,and the remaining group was treated as the model control without any treatment.Additional 2 months observation after discontinuing ART to monitor virus rebound in infected monkeys from each group.In addition,Total DNA,QVOA and flow cytometry were used to analyze the characteristics of virus reservoir in SIV-infected monkeys treated with LP-98+ART.These results showed that the time of viral rebound after withdrawal of LP-98+ART was generally later than that of ART alone.The study on virus reservoir showed that the IUPM was less in the inguinal lymph nodes of infected monkeys in LP-98+ART combined therapy group,and the proportion of Tfh,CD32+rTcM,PD-1+rTcm and TIGIT+rTcm in the inguinal lymph nodes of infected monkeys increased significantly after LP-98+ART treatment.Our study preliminarily explored the therapeutic efficacy of LP-98+ART combined therapy and analyzed the characteristics of virus reservoirs,which provided more informations for exploring novel functional cure strategies of AIDS.