Pathological Role of Anti-CD4 Antibodies in HIV-Infected Immunologic Nonresponders Receiving Virus-Suppressive Antiretroviral Therapy

Abstract

Increased mortality and morbidity occur among human immunodeficiency virus (HIV)-infected patients in whom CD4+ T-cell counts do not increase despite viral suppression with antiretroviral therapy (ART). Here we identified an underlying mechanism. Significantly elevated plasma levels of anti-CD4 immunoglobulin G (IgG) were found in HIV-positive immunologic nonresponders (ie, HIV-positive individuals with CD4+ T-cell counts of ≤350 cells/μL), compared with levels in HIV-positive immunologic responders (ie, HIV-positive individuals with CD4+ T-cell counts of ≥500 cells/μL) and healthy controls. Higher plasma level of anti-CD4 IgG correlated with blunted CD4+ T-cell recovery. Furthermore, purified anti-CD4 IgG from HIV-positive immunologic nonresponders induced natural killer (NK) cell-dependent CD4+ T-cell cytolysis and apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. We also found that anti-CD4 IgG-mediated ADCC exerts greater apoptosis of naive CD4+ T cells relative to memory CD4+ T cells. Consistently, increased frequencies of CD107a+ NK cells and profound decreases of naive CD4+ T cells were observed in immunologic nonresponders as compared to responders and healthy controls ex vivo. These data indicate that autoreactive anti-CD4 IgG may play an important role in blunted CD4+ T-cell reconstitution despite effective ART.

Drug Use is Associated with Anti-CD4 IgG-mediated CD4+ T Cell Death and Poor CD4+ T Cell Recovery in Viral-suppressive HIV-infected Individuals Under Antiretroviral Therapy

“…Because the plasma levels of anti-CD8 IgGs were very low [39], we used anti-CD4 IgG-depleted total IgGs from HIV+ drug users as a negative control and a human anti-CD4 monoclonal Ab (mAb, zanolimumab) as a positive control for ADCC assays. Detailed methods were descried in our recent work [39]. Notably, purified anti-CD4 IgGs from aviremic ART-treated HIV+ drug users induced CD4+ T cell cytolysis (Fig.…”

“…Development of plasma anti-CD4 IgG detection was published in our previous study [39]. Briefly, human soluble CD4 protein (sCD4, Progenics Tarrytown, NY) was diluted and used to detect anti-CD4 IgG in plasma by ELISA.…”

“…Methods of antibody purification in plasma were published in our previous study [39]. Briefly, total IgGs were purified from plasma using protein A/G agarose beads following the manufacturer’s instruction (Pierce, Pittsburgh, PA), and high affinity anti-CD4 specific IgGs were purified from plasma using NHS Mag Sepharose (GE Healthcare, Wauwatosa, WI) covalently coupled with soluble CD4 protein (sCD4, Progenics Tarrytown, NY; and MyBiosource, San Diego, CA).…”

“…Method of ADCC was published in our previous study [39]. Briefly, NK cells and CD4+ T cells were isolated from PBMC from aviremic ART-treated HIV+ subjects using NK cell enrichment kit and CD4 cell enrichment kit (StemCell, BC, Canada).…”

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

“…The percentage of auto‐IgG binding on CD4 + T‐cell surfaces was associated with increased CD4 + T‐cell apoptosis and inversely correlated with absolute CD4 + T‐cell counts. Furthermore, purified anti‐CD4 IgG from HIV‐1‐infected INRs bound to CD4 + T cells and induced cell apoptosis through NK‐mediated Ab‐dependent cell‐mediated cytotoxicity (ADCC) in vitro . This study suggests that autoreactive anti‐CD4 IgG may play a vital role in unsatisfactory CD4 + T‐cell reconstitution despite effective ART.…”