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Browsing Virology by Author "Cromarty, Ross Thomas."

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    In vitro modelling of the impact of anti-inflammatory drugs on cellular cytotoxicity, activation and inflammation.
    (2020) Cromarty, Ross Thomas.; Archary, Derseree.
    The relationship between inflammation and HIV has been a major focus of HIV research. In people living with HIV (PLWH), HIV-associated immune activation drives HIV disease progression. While genital inflammation has been significantly associated with increased risk for HIV acquisition and transmission, immune correlates for reduced HIV risk remain less well defined. In HIV-exposed seronegative individuals, the immune quiescent phenotype, characterised by regulated immune activation and inflammation, has been implicated in reducing HIV acquisition risk. Targeted management of inflammation, therefore, is a plausible strategy to mitigate the risk of HIV infection, and to slow HIV disease progression. Therefore, we sought to investigate how anti-inflammatory drugs affect TLR-mediated inflammation and impact HIV infection of CD4+ T cells. This study utilized an in vitro peripheral blood mononuclear cell (PBMC) model. PBMCs were either treated with the anti12 inflammatory drugs ibuprofen (IBF) or betamethasone (BMS) or were left untreated. Thereafter they were either left unstimulated or were stimulated with phytohaemagglutinin (PHA) or Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), LPS (TLR4) or R848 (TLR7/8) before exposure to HIV NL4-3 AD8. To assess inflammation, multiplexed ELISA was used to measure 28 proinflammatory, chemotactic, growth-related, adaptive response-related or regulatory cytokines. Flow cytometry was used to measure activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. Despite minimal immune activation, TLR stimulation elicited significant cytokine responses (p<0.05). TLR4 stimulation significantly reduced HIV infection of CD4+ T cells (p<0.01). With the addition of IBF, minimal immunosuppressive effects were observed. In contrast, BMS significantly dampened inflammation (p<0.05) and immune activation (p<0.05) regardless of the stimulation condition. Regardless of global immunosuppression, only with TLR4 stimulation did BMS significantly reduce HIV infection of CD4+ T cells (p=0.02). The finding that TLR4 stimulation reduces rather than increases susceptibility of CD4+ T cells to HIV infection, while BMS only affected HIV infection in the TLR4 condition, strongly suggests that additional factors, and not only inflammation play a powerful, although complex, role in determining HIV infection risk. Together, these data emphasize the importance of understanding signalling pathways induced during inflammation to identify novel targets to mitigate HIV infection.