The gut mucosal barrier is disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Lipopolysaccharide (LPS) and bacterial DNA. Perturbations in the gut barrier in HIV disease may stem from deletion of CD4+ T cells, loss of Th17 helper cells, disruption of enterocyte homeostasis and diminished humoral immunity. The consequences of a permeable gut barrier in HIV infection are not fully understood, although there is evidence that exposure to microbial products could contribute to chronic immune activation in HIV disease and may also play a role in limiting CD4+ T cell reconstitution during highly active antiretroviral therapy (HAART). Here, we consider the possibility that microbial translocation also could play an important role in B cell perturbations that are characteristic of HIV infection. These perturbations include polyclonal B cell activation, B cell dysfunction and depletion of the memory B cell subset. Memory B cell dysfunction and depletion are the focus of our proposed studies as our preliminary data demonstrate that the TLR4 ligand LPS, and HIV virions cooperate to induce memory B cell death in peripheral blood cell cultures in vitro, enhanced memory B cell apoptosis ex vivo and plasma levels of LPS in vivo, and decreased level of recall antibody EndoCab (neutralizing antibody against LPS) in vivo from HIV+ donors. Therefore, we hypothesize that heightened microbial translocation and HIV replication collaborate to drive peripheral memory B depletion. We hypothesize that certain immune signatures of B cell subsets will predict reduced antibody responsiveness to vaccination (especially for T cell independent recall antigens) in HIV infection. We propose to explore the mechanisms responsible for TLR/HIV-mediated memory B cell death and to investigate in vivo correlates of these findings including identifying the predictors for reduced vaccine (both T cell dependent and independent antigens) responsiveness in HIV infection. By determining the mechanisms of B cell depletion and perturbations in HIV disease, we may be better able to design interventions that will potentially improve immune responses to vaccines, reduce selected opportunistic infections (e.g. pneumococcus) and perhaps slow disease progression by restoring the immunologic barrier that protects against microbial translocation.
The purpose of the present study is to explore the mechanisms of peripheral memory B cell loss and reduced vaccine responsiveness in HIV infection. The goals of the present study are better to design interventions that will potentially improve immune responses to vaccines, reduce selected opportunistic infections (e.g. pneumococcus) and perhaps slow disease progression by restoring the immunologic barrier that protects against microbial translocation.
|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|
Showing the most recent 10 out of 29 publications