HIV Immunopathogenesis: Inhibition of CD4+ T Cell Activation

Human immunodeficiency virus (HIV) infection causes profound impairment of CD4+ T cell immunity. Anti-retroviral therapy (ART) restores CD4+ T cell responses to common antigens, but HIV-specific responses remain deficient. The immunization of chronically HIV infected, ART treated subjects also leads to poor HIV-specific CD4+ T cell responses. The mechanisms are not fully understood. In this thesis, I demonstrate that HIV envelope glycoprotein (Env), when delivered in the form of a vaccine or when present on free viral particles, suppresses antigen-stimulated CD4+ T cell proliferation. I investigate the potential involvement of human T regulatory cells (Treg) using an in vitro model system. I show that Env exposure neither changes the frequency nor the suppressive activity of Treg cells in human PBMC, and that Env-induced suppression of CD4+ T cell proliferation is independent of Tregs. The studies of HIV-induced inhibition of CD4+ T cell immunity were then moved to an in vivo model to determine physiological significance. A macaque model of HIV-infected individuals treated with ART during chronic infection was used to study the effect of SIV antigen stimulation in lymph nodes early after immunization. CMV seropositive rhesus macaques were infected with pathogenic SIVmac251 and after 4 months, treated with D4T and PMPA for viral control and immune reconstitution. I studied the immune and viral responses to SIV and CMV antigen immunization in draining lymph nodes. Animals were immunized with both SIV gag and CMV pp65 encoding plasmids in both arms and legs, which allowed draining lymph nodes for each antigen to be obtained at the same time, thus allowing direct comparisons of the effect of each antigen stimulation in the same animal. I observed that both SIV and CMV antigen immunizations stimulated antigen-specific T cell responses in draining lymph nodes. The CMV-specific responses were found in the periphery for 50 days post-immunization, while the SIV-specific responses transiently appeared. The SIV antigen stimulation also induced transient SIV viral replication in the draining lymph nodes, suggesting a mechanism for the early loss and poor HIV-specific CD4+ T cell response observed in HIV-infected progressors

Enabling Work-conserving Bandwidth Guarantees for Multi-tenant Datacenters via Dynamic Tenant-Queue Binding

Today's cloud networks are shared among many tenants. Bandwidth guarantees and work conservation are two key properties to ensure predictable performance for tenant applications and high network utilization for providers. Despite significant efforts, very little prior work can really achieve both properties simultaneously even some of them claimed so. In this paper, we present QShare, an in-network based solution to achieve bandwidth guarantees and work conservation simultaneously. QShare leverages weighted fair queuing on commodity switches to slice network bandwidth for tenants, and solves the challenge of queue scarcity through balanced tenant placement and dynamic tenant-queue binding. QShare is readily implementable with existing switching chips. We have implemented a QShare prototype and evaluated it via both testbed experiments and simulations. Our results show that QShare ensures bandwidth guarantees while driving network utilization to over 91% even under unpredictable traffic demands.Comment: The initial work is published in IEEE INFOCOM 201

Fast-R2D2: A Pretrained Recursive Neural Network based on Pruned CKY for Grammar Induction and Text Representation

Recently CKY-based models show great potential in unsupervised grammar induction thanks to their human-like encoding paradigm, which runs recursively and hierarchically, but requires $O(n^3)$ time-complexity. Recursive Transformer based on Differentiable Trees (R2D2) makes it possible to scale to large language model pre-training even with complex tree encoder by introducing a heuristic pruning method. However, the rule-based pruning approach suffers from local optimum and slow inference issues. In this paper, we fix those issues in a unified method. We propose to use a top-down parser as a model-based pruning method, which also enables parallel encoding during inference. Typically, our parser casts parsing as a split point scoring task, which first scores all split points for a given sentence, and then recursively splits a span into two by picking a split point with the highest score in the current span. The reverse order of the splits is considered as the order of pruning in R2D2 encoder. Beside the bi-directional language model loss, we also optimize the parser by minimizing the KL distance between tree probabilities from parser and R2D2. Our experiments show that our Fast-R2D2 improves performance significantly in grammar induction and achieves competitive results in downstream classification tasks.Comment: EMNLP 202

Naturally Occurring Core Protein Mutations Compensate for the Reduced Replication Fitness of a Lamivudine-Resistant HBV Isolate

Hepatitis B virus (HBV) replicates its DNA genome through reverse transcription of an RNA intermediate. The lack of proofreading capacity of the viral DNA polymerase results in a high mutation rate of HBV genome. Under the selective pressure created by the nucleos(t)ide analogue (NA) antiviral drugs, viruses with resistance mutations are selected. However, the replication fitness of NA-resistant mutants is markedly reduced compared to wild-type. Compensatory mutations in HBV polymerase, which restore the viral replication capacity, have been reported to arise under continuous treatment with lamivudine (LMV). We have previously identified a highly replicative LMV-resistant HBV isolate from a chronic hepatitis B patient experiencing acute disease exacerbation. Besides the common YMDD drug-resistant mutations, this isolate possesses multiple additional mutations in polymerase and core regions. The transcomplementation assay demonstrated that the enhanced viral replication is due to the mutations of core protein. Further mutagenesis study revealed that the P5T mutation of core protein plays an important role in the enhanced viral replication through increasing the levels of capsid formation and pregenomic RNA encapsidation. However, the LMV-resistant virus harboring compensatory core mutations remains sensitive to capsid assembly modulators (CpAMs). Taken together, our study suggests that the enhanced HBV nucleocapsid formation resulting from core mutations represents an important viral strategy to surmount the antiviral drug pressure and contribute to viral pathogenesis, and CpAMs hold promise for developing the combinational antiviral therapy for hepatitis B