Human immunodeficiency virus (HIV) disease has been significantly controlled following the introduction of antiretroviral therapy (ART) [1]. 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 [3], 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) [8]. 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mcdonald, David Joseph
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Medical University of South Carolina
Schools of Medicine
United States
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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
Powell, Anna M; Luo, Zhenwu; Martin, Lisa et al. (2017) The induction of CD80 and apoptosis on B cells and CD40L in CD4+ T cells in response to seasonal influenza vaccination distinguishes responders versus non-responders in healthy controls and aviremic ART-treated HIV-infected individuals. Vaccine 35:831-841
Luo, Zhenwu; Li, Zhen; Martin, Lisa et al. (2017) Increased Natural Killer Cell Activation in HIV-Infected Immunologic Non-Responders Correlates with CD4+ T Cell Recovery after Antiretroviral Therapy and Viral Suppression. PLoS One 12:e0167640

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