Safety and Efficacy of Allogenic Adoptive Immune Therapy for Immune Reconstitution in Chronic HIV-1 Infected Patients

Overview

Combination antiretroviral therapy (ART) effectively suppresses viral replication, leading to a significant immune recovery and a dramatic reduction in the incidence of AIDS-defining events. However, approximately 20% of individuals who exhibit stable viral suppression by ART, but fail to achieve sufficient immune reconstitution and are considered immune nonresponders (INRs). These INRs often experience an increased risk of opportunistic infections and shorter life expectancy compared with matched immune responders.Therefore, efficiently treating these immune nonresponders has become one of the most difficult challenges in the clinic.

There is not a consensus definition of immunologic nonresponder individuals. In this study, we described patients whose cluster of differentiation 4（CD4)+ T-cell count remained below 200 cells/ul after 2 years of effective antiviral as immunologic nonresponders, in which viroimmunological dissociation implies a greater risk of AIDS related and non-AIDS-related illnesses. Immune-based therapy such as interleukin (IL)-2 and IL-7 have been shown to increase CD4 T-cell counts but yielded no clinical benefit in a large randomized study. We have reported that umbilical cord Tissue Mesenchymal Stem Cells (UC-MSC) treatment is safe and can significantly decrease systemic immune overactivation and improve immune reconstitution in INR patients. Meanwhile, we did not find that there was a significantly transitory increase in peripheral CD4 T-cell counts within 1-2 weeks since the onset of each MSC infusion. More important, umbilical cord-MSCs were found to be with a potential to produce IL-7 and T-cell growth factor transforming growth factor (TGF)-β in vitro and in vivo and preferentially expand CD4 T-cell response in the recipients. Therefore, development of novel interventions to reduce immune overactivation/inflammation and enhance immune reconstitution in INRs is a high priority. Granulocyte colony-stimulating factor (G-CSF)-mobilized donor peripheral blood mononuclear cells (MNCs) are a heterogeneous population of immune cells that have a potential role in immunomodulation and hemopoiesis. Here, we hypothesized that human leukocyte antigen (HLA)-mismatched MNCs transfusion can be used to comprehensively restore or boost the host holistic immune system for INR patients, to the degree similar as immune responders. The purpose of this study is to investigate the safety and initial efficacy of allogeneic adoptive immune therapy (AAIT) for INR patients. 20 INR patients received i.v. transfusion one round (3 times) of 2.0-3.0\*10E8 cells/kg of MNCs as the treated group. All of them received the conventional treatment for AIDS. The CD4 T cell numbers, HIV reservoir, side effects, symptom improvement, control of opportunistic infections and will be evaluated during the 96-week follow up.