Human immunodeficiency virus (HIV) disease has been significantly controlled following the introduction of antiretroviral therapy (ART) . This treatment dramatically improves immune function, suppresses HIV viral replication, and decreases morbidity and mortality [1, 2]. However, up to 25% of virologically suppressed individuals (~111,000 people in USA) fail to restore their CD4+ T cells to counts > 350 cells/L, even after long- term ART treatment and viral suppression , and increased morbidity and mortality have been observed in these patients [4-7]. Thymic fibrosis has been suggested a mechanism, and low nadir CD4+ T cell counts and T cell activation have been shown to associate with incomplete immune restoration after ART treatment [8-11], but mechanisms for immune non-response remain largely unknown. To better understand mechanisms of incomplete immune restoration, we performed a preliminary human study in 12 healthy controls, 17 immunologic responders (IRs) (aviremic and ART treated > 3 years, and CD4+ T cell counts > 500 cells/L) and 11 immunologic non-responders (INRs) (aviremic and ART treated > 3 years, and CD4+ T cell counts < 350 cells/L) . Elevated plasma levels of anti-CD4 IgGs were found in patients compared to controls and correlated with blunted CD4+ T cell recovery. Furthermore, purified anti-CD4 IgGs from plasma of aviremic long-term ART-treated subjects with CD4+ T cell counts below 350 cells/l, defined as ?immunologic non- responders?, induced antibody-dependent NK cell-mediated cytotoxicity against CD4+ T cells. We hypothesize that heightened level of anti-CD4 Ab contributes to the pathogenesis of CD4+ T cell losses in HIV infection. If our hypothesis is correct, a therapeutic strategy that targeting autoreactive B cells or anti-CD4 Abs could potentially optimize ART treatment to improve CD4+ T cell recovery and reduce mortality and morbidity in treated HIV-infected patients. This study will also provide important information in HIV vaccine design.
This proposed project is to investigate the mechanisms of autoantibody-mediated CD4+ T cell death and its contribution to poor CD4+ T cell recovery in antiretroviral treated HIV disease. The goals of the present project are to improve antiretroviral therapy in HIV disease.
|Xia, Huan; Jiang, Wei; Zhang, Xin et al. (2018) Elevated Level of CD4+ T Cell Immune Activation in Acutely HIV-1-Infected Stage Associates With Increased IL-2 Production and Cycling Expression, and Subsequent CD4+ T Cell Preservation. Front Immunol 9:616|
|Zhou, Zejun; Guille, Constance; Ogunrinde, Elizabeth et al. (2018) Increased systemic microbial translocation is associated with depression during early pregnancy. J Psychiatr Res 97:54-57|
|Xu, Wanli; Luo, Zhenwu; Alekseyenko, Alexander V et al. (2018) Distinct systemic microbiome and microbial translocation are associated with plasma level of anti-CD4 autoantibody in HIV infection. Sci Rep 8:12863|
|Jiang, Wei; Luo, Zhenwu; Martin, Lisa et al. (2018) 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. Curr HIV Res 16:143-150|
|Zhang, Tao; Sun, Kewei; Wang, Ya et al. (2018) Disruption of the gut-liver axis in the pathogenesis of acute-on-chronic liver failure. Eur J Gastroenterol Hepatol 30:130-135|
|Dai, Lu; Zhao, Mengmeng; Jiang, Wei et al. (2018) KSHV co-infection, a new co-factor for HPV-related cervical carcinogenesis? Am J Cancer Res 8:2176-2184|
|Jiang, Wei (2018) A protocol for quantizing total bacterial 16S rDNA in plasma as a marker of microbial translocation in vivo. Cell Mol Immunol 15:937-939|
|Zhou, Zejun; Powell, Anna Maya; Ramakrishnan, Vishwanathan et al. (2018) Elevated systemic microbial translocation in pregnant HIV-infected women compared to HIV-uninfected women, and its inverse correlations with plasma progesterone levels. J Reprod Immunol 127:16-18|
|Dai, Lu; Lin, Zhen; Jiang, Wei et al. (2017) Lipids, lipid metabolism and Kaposi's sarcoma-associated herpesvirus pathogenesis. Virol Sin 32:369-375|
|Luo, Zhenwu; Li, Zhen; Martin, Lisa et al. (2017) Pathological Role of Anti-CD4 Antibodies in HIV-Infected Immunologic Nonresponders Receiving Virus-Suppressive Antiretroviral Therapy. J Infect Dis 216:82-91|
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