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Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains vi, 143 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

MicroRNAs (miRNAs) function as key regulators in immune responses and cancer development. In the contexts of infection with oncogenic viruses, miRNAs are engaged in viral persistence, latency establishment and maintenance, and oncogenesis. In this review, we summarize the potential roles and mechanisms of viral and cellular miRNAs in the host-pathogen interactions during infection with selected tumor viruses and HIV, which include (i) repressing viral replication and facilitating latency establishment by targeting viral transcripts, (ii) evading innate and adaptive immune responses via toll-like receptors, RIG-I-like receptors, T-cell receptor, and B-cell receptor pathways by targeting signaling molecules such as TRAF6, IRAK1, IKKε, and MyD88, as well as downstream targets including regulatory cytokines such as tumor necrosis factor α, interferon γ, interleukin 10, and transforming growth factor β, (iii) antagonizing intrinsic and extrinsic apoptosis pathways by targeting pro-apoptotic or anti-apoptotic gene transcripts such as the Bcl-2 family and caspase-3, (iv) modulating cell proliferation and survival through regulation of the Wnt, PI3K/Akt, Erk/MAPK, and Jak/STAT signaling pathways, as well as the signaling pathways triggered by viral oncoproteins such as Epstein-Barr Virus LMP1, by targeting Wnt-inhibiting factor 1, SHIP, pTEN, and SOCSs, and (v) regulating cell cycle progression by targeting cell cycle inhibitors such as p21/WAF1 and p27/KIP1. Further elucidation of the interaction between miRNAs and these key biological events will facilitate our understanding of the pathogenesis of viral latency and oncogenesis and may lead to the identification of miRNAs as novel targets for developing new therapeutic or preventive interventions.

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The past 10 years has seen mother to child transmission (MTCT) of HIV-1 shift from being one of the predominant forces in the global epidemic to a phenomenon that is largely preventable and envisioned as being on the path to elimination. This thesis is based on two cohorts of Kenyan infants recruited before and after the development of effective antiretroviral interventions to prevent MTCT. Two main lines of enquiry are pursued with the aim to contribute to improved health outcomes of infants affected by HIV-1. The first seeks to further our understanding of the capacity of the infant cytotoxic T lymphocyte (CTL) response to influence viral evolutionary dynamics in early infection. Chapter 3 presents a modern phylogenetic analysis of longitudinal viral sequences derived from infants following in utero or peripartum infection. The results indicate that despite high levels of viral replication, infant CTL selection pressure plays a significant role in shaping early viral evolution. The second stems from an accumulating body of evidence that suggests that infants born to HIV-1 infected mothers who themselves are free from infection, termed HIV-1 exposed uninfected (HEU) infants, nevertheless face significantly higher rates of infectious disease- associated morbidity and mortality than HIV-1 unexposed infants. This study therefore sought to characterise the immunological status of HEU infants with particular emphasis on the phenotypic and functional properties of the T cell compartment. Chapter 4 presents the immunological characterisation of a cohort of healthy Kenyan infants recruited as a control population at two time points in early life. Chapter 5 present a cross-sectional comparison of HEU and control infant cohorts. The results suggest a level of altered immunological reactivity with respect to the T helper type 1 (Th1) response to polyclonal stimulation. In addition a compromised memory Th1 response was observed following polyclonal stimulation and following stimulation with Bacillus Calmette-Guerin and tetanus toxoid vaccine antigens.