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postgraduate thesis: HIV Tat and mycobacteria-induced innate immune responses

TitleHIV Tat and mycobacteria-induced innate immune responses
Authors
Issue Date2012
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Au, K. [區建兒]. (2012). HIV Tat and mycobacteria-induced innate immune responses. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4985864
AbstractAcquired Immunodeficiency Syndrome (AIDS) and tuberculosis (TB) have posed diagnostic and therapeutic challenges globally. Nowadays, it is estimated that 34 millions people are living with Human Immunodeficiency Virus (HIV). About 2 millions of people die from AIDS-related causes currently in each year. Tuberculosis is the most common presenting illness and leading cause of death among AIDS patients. Emerging studies suggest that HIV and Mycobacterium tuberculosis (Mtb), the causative pathogen of TB, act synergistically to accelerate decline of immune functions and cause the death. Mtb infection usually remains latent. Only small portion of infected individuals develops active TB. However HIV infection boosts the risk of reactivation of TB and susceptibility to new Mtb infection. In contrast, Mtb infection dysregulates cytokines production and induces HIV viral replication. Although it is well-known that HIV and Mtb potentiate each other in disease development, mechanisms of interaction of the two pathogens remain not well-elucidated. The aim of this study is to investigate the interaction of HIV viral protein Tat with mycobacteria infection, which may provide insights in the interplay between HIV and Mtb infections. HIV viral transactivator protein, Tat, plays a critical role in HIV replication; and its induction of apoptosis in CD4+ T cells contributes to immune defects. In this study, Tat was demonstrated to dysregulate immune responses against mycobacteria such as autophagy, a tightly regulated bacterial clearance mechanism. With pretreatment of the primary human blood monocyte-derived macrophages with Tat, the interferon-γ (IFN-γ)-induced Signal Transducer and Activator of Transcription-1 (STAT-1) phosphorylation was suppressed. Inhibition of STAT-1 phosphorylation ultimately led to downregulation of autophagy-associated gene, microtubule-associated protein light chain 3 (LC3) expressions. Of note, Tat was demonstrated to inhibit the colocalization of Bacillus Calmette Guerin (BCG) and IFN-γ-induced autophagosomes under fluorescent microscopy examination. In addition to the inhibition of bactericidal autophagy, Tat was found to manipulate cytokines production. Tat was demonstrated to enhance mycobacteria-induced tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) production. TNF-α and IL-1β have been well-demonstrated in literatures that can limit bacterial growth. They, however, have been also shown as important contributors to the increase of HIV viral replication in HIV and mycobacteria coinfection. Mtb-induced TNF-α production can induce transcriptional activation of the HIV long terminal repeat (LTR) promoter while blocking of IL-1β production decreases HIV replication. Tat enhancement of these cytokines production may therefore contribute to the knowledge of the increased viral replication in HIV and mycobacteria coinfection. Furthermore, new microRNAs, up-and-coming fine-tuners of innate immunity, were discovered. MicroRNAs, a family of non-coding RNAs, can regulate gene expressions post-transcriptionally and control various developmental and cellular processes. They can target mRNAs of cellular signaling molecules, transcription factors or cytokines as to regulate the immunity. Herein, microRNA-1303, originally with unknown function, was shown to regulate mycobacteria-induced TNF-α production and affect the Tat enhancement of TNF-α production. Taken together, the results of this study demonstrated that HIV viral protein, Tat could dysregulate immune responses to mycobacteria. The study of the dysregulation may further elucidate the interplay between HIV and mycobacteria infections.
DegreeDoctor of Philosophy
SubjectHIV infections
Mycobacterial diseases
Viral proteins
Dept/ProgramPaediatrics and Adolescent Medicine
Persistent Identifierhttp://hdl.handle.net/10722/193389

 

DC FieldValueLanguage
dc.contributor.authorAu, Kin-yi-
dc.contributor.author區建兒-
dc.date.accessioned2013-12-21T23:10:06Z-
dc.date.available2013-12-21T23:10:06Z-
dc.date.issued2012-
dc.identifier.citationAu, K. [區建兒]. (2012). HIV Tat and mycobacteria-induced innate immune responses. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4985864-
dc.identifier.urihttp://hdl.handle.net/10722/193389-
dc.description.abstractAcquired Immunodeficiency Syndrome (AIDS) and tuberculosis (TB) have posed diagnostic and therapeutic challenges globally. Nowadays, it is estimated that 34 millions people are living with Human Immunodeficiency Virus (HIV). About 2 millions of people die from AIDS-related causes currently in each year. Tuberculosis is the most common presenting illness and leading cause of death among AIDS patients. Emerging studies suggest that HIV and Mycobacterium tuberculosis (Mtb), the causative pathogen of TB, act synergistically to accelerate decline of immune functions and cause the death. Mtb infection usually remains latent. Only small portion of infected individuals develops active TB. However HIV infection boosts the risk of reactivation of TB and susceptibility to new Mtb infection. In contrast, Mtb infection dysregulates cytokines production and induces HIV viral replication. Although it is well-known that HIV and Mtb potentiate each other in disease development, mechanisms of interaction of the two pathogens remain not well-elucidated. The aim of this study is to investigate the interaction of HIV viral protein Tat with mycobacteria infection, which may provide insights in the interplay between HIV and Mtb infections. HIV viral transactivator protein, Tat, plays a critical role in HIV replication; and its induction of apoptosis in CD4+ T cells contributes to immune defects. In this study, Tat was demonstrated to dysregulate immune responses against mycobacteria such as autophagy, a tightly regulated bacterial clearance mechanism. With pretreatment of the primary human blood monocyte-derived macrophages with Tat, the interferon-γ (IFN-γ)-induced Signal Transducer and Activator of Transcription-1 (STAT-1) phosphorylation was suppressed. Inhibition of STAT-1 phosphorylation ultimately led to downregulation of autophagy-associated gene, microtubule-associated protein light chain 3 (LC3) expressions. Of note, Tat was demonstrated to inhibit the colocalization of Bacillus Calmette Guerin (BCG) and IFN-γ-induced autophagosomes under fluorescent microscopy examination. In addition to the inhibition of bactericidal autophagy, Tat was found to manipulate cytokines production. Tat was demonstrated to enhance mycobacteria-induced tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) production. TNF-α and IL-1β have been well-demonstrated in literatures that can limit bacterial growth. They, however, have been also shown as important contributors to the increase of HIV viral replication in HIV and mycobacteria coinfection. Mtb-induced TNF-α production can induce transcriptional activation of the HIV long terminal repeat (LTR) promoter while blocking of IL-1β production decreases HIV replication. Tat enhancement of these cytokines production may therefore contribute to the knowledge of the increased viral replication in HIV and mycobacteria coinfection. Furthermore, new microRNAs, up-and-coming fine-tuners of innate immunity, were discovered. MicroRNAs, a family of non-coding RNAs, can regulate gene expressions post-transcriptionally and control various developmental and cellular processes. They can target mRNAs of cellular signaling molecules, transcription factors or cytokines as to regulate the immunity. Herein, microRNA-1303, originally with unknown function, was shown to regulate mycobacteria-induced TNF-α production and affect the Tat enhancement of TNF-α production. Taken together, the results of this study demonstrated that HIV viral protein, Tat could dysregulate immune responses to mycobacteria. The study of the dysregulation may further elucidate the interplay between HIV and mycobacteria infections.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshHIV infections-
dc.subject.lcshMycobacterial diseases-
dc.subject.lcshViral proteins-
dc.titleHIV Tat and mycobacteria-induced innate immune responses-
dc.typePG_Thesis-
dc.identifier.hkulb4985864-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePaediatrics and Adolescent Medicine-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b4985864-
dc.date.hkucongregation2013-

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