Virus-Host Interactions in HIV-1 Pathogenesis and Viral Immune Evasion

Human viruses such as the Human Immunodeficiency virus (HIV-1) causes chronic diseases and is a major public health concern. My dissertation focuses on the molecular interactions between the virus and the host, tackling two major topics in HIV-1 research. The first topic focuses on HIV-1 pathogenesis and the factors contributing towards AIDS disease progression. Using genetics and pharmacological approaches, we demonstrated the interaction between the viral envelope and the CCR5 receptor contributes to the killing of uninfected bystander CD4 T cells in vitro and in vivo. This study suggests therapeutic strategies targeting CCR5 may reduce HIV-1 pathogenesis and AIDS disease progression. The second topic focuses on how HIV-1 escapes from restriction factors, a critical part of our innate immune defense against HIV-1. We discovered the TET2 methylcytosine dioxynase is a new HIV-1 restriction factor that binds to HIV-1 cDNA and inhibits viral reverse transcription. The viral accessory protein Vpr hijacks the CRL4VprBP E3 ligase to promote the degradation of TET2 and thereby relieving this restriction. Lastly, we also discovered an alternative role of TET2 in modulating the Type-1 interferon antiviral response in HIV-1 inhibition. We demonstrated TET2 is essential for the interferon-mediated induction of antiviral proteins that targets HIV-1 replication, including MX2 and IFITM3. We report a new restriction factor TET2 that inhibits HIV-1 through various mechanisms, and we elucidated the mechanism how Vpr promotes HIV-1 escape from this immune defense. In summary, my dissertation research unraveled the contributions of different virus-host interactions towards viral pathogenesis and viral immune evasion, which may provide new therapeutic targets for HIV-1 treatments.Doctor of Philosoph

A unified constitutive model for asymmetric tension and compression creep-ageing behaviour of naturally aged Al-Cu-Li alloy

A set of unified constitutive equations is presented that predict the asymmetric tension and compression creep behaviour and recently observed double primary creep of pre-stretched/naturally aged aluminium-cooper-lithium alloy AA2050-T34. The evolution of the primary micro- and macro-variables related to the precipitation hardening and creep deformation of the alloy during creep age forming (CAF) are analysed and modelled. Equations for the yield strength evolution of the alloy, including an initial reversion and subsequent strengthening, are proposed based on a theory of concurrent dissolution, re-nucleation and growth of precipitates during artificial ageing. We present new observations of so-called double primary creep during the CAF process. This phenomenon is then predicted by introducing effects of interacting microstructures, including evolving precipitates, diffusing solutes and dislocations, into the sinh-law creep model. In addition, concepts of threshold creep stress σth and a microstructure-dependant creep variable H, which behave differently under different external stress directions, are proposed and incorporated into the creep model. This enables prediction of the asymmetric tension and compression creep-ageing behaviour of the alloy. Quantitative transmission electron microscopy (TEM) and related small-angle X-ray scattering (SAXS) analysis have been carried out for selected creep-aged samples to assist the development and calibration of the constitutive model. A good agreement has been achieved between the experimental results and the model. The model has the potential to be applied to creep age forming of other heat-treatable aluminium alloys

Regulatory T Cells Contribute to HIV-1 Reservoir Persistence in CD4 + T Cells Through Cyclic Adenosine Monophosphate-Dependent Mechanisms in Humanized Mice in Vivo

Background. Regulatory T cells (Tregs) suppress T-cell immune activation and human immunodeficiency virus type 1 (HIV-1) replication, but the role of Tregs in HIV-1 reservoir persistence is poorly defined. Methods. Tregs were depleted by denileukin diftitox in humanized mice with chronic HIV-1 infection. Viral replication in lineage cells was determined by p24 expression. Levels of HIV-1 RNA and DNA in human cells, as well as replication-competent-virus- producing cells, were measured to quantified viral replication and reservoirs. Results. Treg depletion resulted in a blip of HIV-1 replication in T cells but not in myeloid cells. The major activated reservoir cells were memory CD4+ T cells in vivo. Interestingly, the transient activation of viral replication led to HIV-1 reservoir reduction after viremia resuppression, as indicated by the quantity of HIV-1 DNA and replication-competent-virus-producing cells. Furthermore, we demonstrated that Tregs use cyclic adenosine monophosphate (cAMP)-dependent protein kinase A pathway to inhibit HIV-1 activation and replication in resting conventional T cells in vitro. Conclusion. Tregs suppress HIV-1 replication in T cells and contribute to HIV-1 reservoir persistence. cAMP produced in Tregs is involved in their suppression of viral gene activation and expression. Treg depletion combined with combination antiretroviral therapy provides a novel strategy for HIV-1 cure

Gender- and Age-Specific Associations between Visceral Obesity and Renal Function Impairment

Objective: Although obesity is associated with an increased risk of chronic kidney disease, this trend becomes nonsignificant following adjustment for cardiovascular risk factors. The present study aims to investigate whether visceral obesity is independently associated with renal function impairment. Method: The medical records of 14,529 male and 10,561 female Chinese adults undergoing health check-ups during 2013–2015 were retrospectively collected. The baseline characteristics, including the degree of visceral fat and the percentage of body fat, were compared. The association between study groups and renal function impairment was investigated using regression models adjusted for confounding factors. Results: All variables differed significantly among non-obese, peripheral, and central type obese subjects, both younger and older, and of both genders, except for hsCRP in older male subjects (p = 0.053) and eGFR in older female subjects (p = 0.098). Unadjusted univariate analysis showed that central obesity contributed significantly to renal function impairment in all age groups and in both genders. After adjusting for possible confounding factors, only central obesity was found to be an independent factor of renal function impairment in all groups, except for men under 45 years of age. Conclusion: Visceral obesity is independently associated with renal function impairment in all ages and both genders, except for males younger than 45 years

Vpr Targets TET2 for Degradation by CRL4 VprBP E3 Ligase to Sustain IL-6 Expression and Enhance HIV-1 Replication

HIV-1 expresses several accessory proteins to counteract host anti-viral restriction factors to facilitate viral replication and disease progression. One such protein, Vpr, has been implicated in affecting multiple cellular processes, but its mechanism remains elusive. Here we report that Vpr targets TET2 for polyubiquitylation by the VprBP-DDB1-CUL4-ROC1 E3 ligase and subsequent degradation. Genetic inactivation or Vpr-mediated degradation of TET2 enhances HIV-1 replication and substantially sustains expression of the pro-inflammatory cytokine interleukin-6 (IL-6). This process correlates with reduced recruitment of histone deacetylase 1 and 2 to the IL-6 promoter, thus enhancing its histone H3 acetylation level during resolution phase. Blocking IL-6 signaling reduced the ability of Vpr to enhance HIV-1 replication. We conclude that HIV-1 Vpr degrades TET2 to sustain IL-6 expression to enhance viral replication and disease progression. These results suggest that disrupting the Vpr-TET2-IL6 axis may prove clinically beneficial to reduce both viral replication and inflammation during HIV-1 infection. HIV-1 Vpr protein counteracts host anti-viral restriction factors to facilitate viral replication and disease progression. Lv et al. demonstrate that Vpr promotes degradation of TET DNA dioxygenases. TET2 deletion or depletion enhances HIV-1 replication and sustains pro-inflammatory cytokine IL-6, while blocking IL-6 reduces Vpr's ability to enhance HIV-1 replication. © 2018 Elsevier Inc

Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs

Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1–infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1–induced immune hyperactivation and rescued anti–HIV-1 immune responses in T cells from HIV-1–infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1–infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1–associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART

CCR5 interaction with HIV-1 Env contributes to Env-induced depletion of CD4 T cells in vitro and in vivo

Abstract Background CD4 T cell depletion during HIV-1 infection is associated with AIDS disease progression, and the HIV-1 Env protein plays an important role in the process. Together with CXCR4, CCR5 is one of the two co-receptors that interact with Env during virus entry, but the role of CCR5 in Env-induced pathogenesis is not clearly defined. We have investigated CD4 T cell depletion mechanisms caused by the Env of a highly pathogenic CXCR4/CCR5 dual-tropic HIV-1 isolate R3A. Results We report here that R3A infection induced depletion of both infected and uninfected “bystander” CD4 T cells, and treatment with CCR5 antagonist TAK-779 inhibited R3A-induced bystander CD4 T cell depletion without affecting virus replication. To further define the role of Env-CCR5 interaction, we utilized an Env-mutant of R3A, termed R3A-5/6AA, which has lost CCR5 binding capability. Importantly, R3A-5/6AA replicated to the same level as wild type R3A by using CXCR4 for viral infection. We found the loss of CCR5 interaction resulted in a significant reduction of bystander CD4 T cells death during R3A-5/6AA infection, whereas stimulation of CCR5 with MIP1-β increased bystander pathogenesis induced by R3A-5/6AA. We confirmed our findings using a humanized mouse model, where we observed similarly reduced pathogenicity of the mutant R3A-5/6AA in various lymphoid organs in vivo. Conclusion We provide the first evidence that shows CCR5 interaction with a dual-tropic HIV-1 Env played a significant role in Env-induced depletion of CD4 T cells

Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression

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