The effect of plasma auto-IgGs on CD4+ T cell apoptosis and recovery in HIV-infected patients under antiretroviral therapy

Abstract

Although effective antiretroviral therapy (ART) suppresses HIV viral replication, prevents AIDS-related complications, and prolongs life, a proportion of patients fails to restore the patients' CD4 T cell number to the level of healthy individuals. Increased mortality and morbidity have been observed in these patients. In the current study, we have investigated the role of auto-IgGs in CD4 T cell apoptosis and recovery in a cross-sectional study. All HIV subjects were on viral-suppressive ART treatment with a different degree of CD4 T cell reconstitution. Total auto-IgG binding on CD4 T cell surfaces and its associated apoptosis and CD4 T cell recovery were analyzed by flow cytometry ex vivo. Total IgGs from plasma were tested for their binding capacities to CD4 T cell surfaces and their mediation to CD4 T cell death through NK cell cytotoxicity in vitro. HIV subjects had increased surface binding of auto-IgGs on CD4 T cells compared with healthy controls, and IgG binding was associated with elevated CD4 T cell apoptosis in HIV subjects but not in healthy controls. Plasma IgGs from HIV subjects bound to CD4 T cells and induced cell apoptosis through NK cytotoxicity in vitro. Soluble CD4 (sCD4) preincubation prevented NK cell-mediated CD4 T cell death. Our results suggest that plasma autoantibodies may play a role in some HIV patients with poor CD4 T cell recovery under viral-suppressive ART.

Effects of Early and Delayed Antiretroviral Therapy on Plasma Anti-CD4 Autoreactive IgG and Its Association With CD4+ T-Cell Recovery in Acute HIV-Infected Individuals

“…Several mechanisms may cause the blunted recovery of CD4 + T cells, including persistent inflammation, gut mucosal dysfunction, fibrosis of thymus, and lymphoid tissue (Hunt et al, 2003;Marchetti et al, 2008;Diaz et al, 2010;Lederman et al, 2011;Mavigner et al, 2012). In addition, increased levels of anti-CD4 IgG from non-responders induced CD4 + T cells apoptosis and play a role in poor CD4 + Tcell recovery in chronic HIV-infected individuals under ART (Luo et al, 2017a). The previous study suggests that increase of anti-CD4 IgG levels may be a novel mechanism for CD4 + T cell depletion in ART-treated chronically infected individuals.…”

“…The mechanisms of pathogenic anti-CD4 IgG production remain unknown, and persistent immune activation and inflammation after ART may contribute to the breakdown of tolerance (Xu et al, 2018). Furthermore, autoantigens from apoptotic CD4 + T cells, sCD4, or released HIV protein-bound CD4, may provide the antigen stimulation for generation of pathologic autoantibodies in post-ART HIV-infected individuals (Luo et al, 2017a). However, the exact mechanisms need further investigations.…”

“…Several mechanisms, such as persistent inflammation, fibrosis of thymus and lymphoid tissues, and gut mucosal dysfunction, are considered as factors for poor CD4 + T-cell recovery after viral-suppressive ART (Diaz et al, 2010;Kingkeow et al, 2015). Importantly, studies from others and from our team reveal that anti-CD4 autoantibodies play a role in CD4 + T cells depletion in ART-treated chronic HIV and SIV infection (Dalgleish, 1995;Kuwata et al, 2009;Luo et al, 2017a;Luo et al, 2017b). Moreover, elder age, longer duration of HIV infection and lower pre-ART CD4 + T-cell counts are associated with incomplete recovery of CD4 + T cells (Kaufmann et al, 2005;Stirrup et al, 2018).…”

“…Recently, we reported that the levels of anti-CD4 IgG are elevated in immune non-responders (aviremic, ART-treated, and CD4 + T-cell counts < 350 cells/µl) and anti-CD4 IgG purified in plasma from non-responders activates NK cells and induces CD4 + T-cell apoptosis through antibody-dependent cellular cytotoxicity (ADCC) (Lederman et al, 2011). Moreover, the percentage of surface auto-IgG on CD4 + T cells is associated with the percentage of CD4 + T-cell apoptosis and CD4 + T-cell counts under viral-suppressive ART (Luo et al, 2017a;Luo et al, 2017b). In an animal model, plasma levels of autoreactive antibodies against CD4 + T cells, but not anti-CD4 autoantibodies, was associated with progressive decline of CD4 + T cells in simian immunodeficiency virus (SIV)-infected rhesus macaques; and this association was observed in non-SIV animal models with immune activation and autoimmunity (Kuwata et al, 2009).…”

Link between Interleukin-23 and Anti-CD4 Autoantibody Production in Antiretroviral-Treated HIV-Infected Individuals

“…Potential mechanisms for poor CD4 1 T cell reconstitution are not fully understood, with possible explanations including low-nadir CD4 1 T cells, persistent immune activation, thymic insufficiency, lymphatic fibrosis, and gut mucosal dysfunction that leads to microbial translocation and inflammation (6)(7)(8)(9). Our recent study reveals that IgG anti-CD4 autoantibodies from immunologic nonresponders on virally suppressive ART (CD4 cell counts , 350 cells/ml) induced NK cell activation and antibody-dependent NK cell-mediated cytotoxicity (ADCC) against primary CD4 1 T cells (10,11).…”