Risk Factors And Related Mechanisms Of Immune Reconstitution After Highly Active Antiretroviral Therapy Among PLWHIV

BackgroundAIDS is a potentially life-threatening disease caused by human immunodeficiency virus(HIV)infection,which is one of the major global public health problems endangering human health.However,due to the different levels of economic development and antiretroviral drug selectivity in different countries,there is still a long way to go to end HIV infection.HIV mainly invades the immune system of the human body,which is mainly manifested in the progressive decrease of CD4+T lymphocytes in clinical practice,which ultimately leads to the deficiency of human immune function,causing various opportunistic infections and tumours.At present,treatment guidelines around the world suggest that HAART should be carried out immediately once HIV infection is confirmed,so as to inhibit HIV replication,retain or restore CD4 cell count and immune function,reduce incidence rate and mortality,and extend the survival period of patients to the general population.After the start of HAART,in individuals with good compliance and no drug-resistance related mutations,the plasma viral load decreased to undetectable levels,while the increase of peripheral CD4+T cell count was a complex process.At the same time,despite the complete inhibition of virology,there are still 9-45%of individuals unable to achieve satisfactory immune reconstitution results.These individuals tend to be more prone to disease progression.The risk of AIDS and nonAIDS events(such as cardiovascular disease,liver disease and cancer)is significantly increased,and the risk of death is also significantly increased.However,we currently lack strategies for early identification of these populations,and there is no effective treatment for them.Therefore,it is increasingly important to understand the pathophysiological mechanism of the lack of immune reconstitution,design the measurement methods to discover these mechanisms,and propose therapies suitable for each situation.At present,HIV persistent infection has been proved to cause immune aging,but its specific mechanism is not clear,and has become a focus of research in the field of HIV research in recent years.On the one hand,the immune aging caused by HIV will weaken the immune response and immune monitoring ability;On the other hand,the chronic inflammation caused by the continuous replication of HIV accelerates the immune aging and ultimately increases the risk of poor prognosis.Therefore,clarifying the characteristics and specific mechanism of immune aging in HIV-infected patients is crucial to improve the immune reconstitution after HAART treatment and reduce the incidence of poor prognosis of HIV infection.AimsBy sorting out the data of a large retrospective cohort of our research group,we explore the influencing factors of HIV immune reconstitution,as well as its relationship with immune aging and the underlying mechanism,so as to distinguish immune nonresponders at an early stage,and propose possible effective individualized intervention measures and treatment programs according to their characteristics,reduce the incidence of AIDS and non-AIDS related events in this group of people,improve their quality of life and prolong their life.Materials and Methods1.SubjectsThe patient’s information and samples of this study are from a retrospective cohort study of our research group.510 PLWHIV patients who met the inclusion and exclusion criteria and were followed up regularly for a long time.Each patient in this study received full informed consent and signed the informed consent form.Inclusion criteria:1.HIV diagnosis;2.Understand and sign the informed consent;3.Receiving HAART treatment and regular follow-up;4.At the same time,he did not participate in any other research.Exclusion criteria:1.The researcher judged that the patient had missing data;2.Those who have been treated with steroids or cytotoxic drugs;3.The patient has tumor disease and autoimmune disease;4.Patients who have received organ transplantation;5.The patient is in pregnancy;6.Patients have poor compliance,irregular medication and drug resistance;7.The patient is infected with other viruses;8 Transfer or death during follow-up.2.The phenotypes of CD4,CD8+T lymphocytes and B cells in peripheral blood and their corresponding subgroup frequenciesResuscitate the frozen PBMC and analyze the frequency of CD4,CD8+T lymphocytes and B cells and the expression of their subsets in the peripheral blood of non-AIDS and AIDS patients with acquired immune reconstitution(IR)and nonimmune reconstitution(NIR)by flow cytometry.3.Detecting the function of CD4,CD8+T lymphocytes and B cells in peripheral bloodFlow cytometry was used to analyze and compare the cytokine IFN secreted by CD4,CD8+T lymphocytes in peripheral blood of patients with acquired immune reconstitution(IR)and non-immune reconstitution(NTR)in non-AIDS stage and AIDS stage-γ、TNF-α Level,expression of cytotoxic receptor CD 107a and cytokine IFN secreted by B cells-γ、TNF-α The difference between the expression level of IL-10 and IL-104.Dynamically detecting the function of CD4,CD8+T lymphocytes and B cells in peripheral blood at baseline and Week 48Flow cytometry was used to analyze and compare the cytokine IFN secreted by CD4,CD8+T lymphocytes in patients with non-AIDS and AIDS at the time of acquiring immune reconstitution(IR)and non-immune reconstitution(NIR)peripheral blood baseline and Week 48-γ、TNF-α Level,expression of cytotoxic receptor CD 107a and cytokine IFN secreted by B cells-γ、TNF-α The difference between the expression level of IL-10 and IL-10Results1.Age is an independent risk factor for immune reconstitution in PLWHIV population after HAART treatmentIn the non-AIDS population,multivariate regression analysis showed that the baseline age([OR],0.961;95%[CI],0.935-0.987;P=0.003)was an independent predictor of immune reconstitution;Similarly,in the population with AIDS,multivariate regression analysis showed that baseline age([OR],0.950;95%[CI],0.918-0.984;P=0.004)was an independent predictor of immune reconstitution;2.HAART treatment can significantly inhibit HIV RNA and promote the recovery of CD4+T cellsAfter one year of HAART treatment,the number of CD4+T lymphocytes in patients with non-AIDS and AIDS increased,and the quantity of HIV RNA virus decreased.3.CD4+na?ve T is significantly higher in IR population than in NIR populationAmong the patients with non-AIDS,the frequency of CD4+na?ve T lymphocytes of immature cell phenotype with low differentiation in peripheral blood in IR group was significantly higher than that in NIR group(P=0.020);Among the patients with AIDS,the frequency of CD4+na?ve T lymphocytes of immature cell phenotype with low differentiation in peripheral blood in IR group was significantly higher than that in NIR group(P=0.002).4.There is no significant difference in the functions of CD4,CD8+T lymphocytes and B cells between IR and NIR populations at baseline and Week 48.conclusion1.Age at baseline of HAART treatment can independently predict immune reconstitution of PLWHIV population;2.CD4+na?ve T cells in NIR population were significantly lower than those in IR population,indicating that poor immune reconstitution was associated with immune aging phenotype.