Innate immune responses in acute HIV-1 infection: protective or pathogenic?

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ORAL PRESENTATION

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Innate immune responses in acute HIV-1 infection: protective or pathogenic? Persephone Borrow1*, Andrea Stacey1, Angharad Fenton-May1, Oliver Dibben1, Elizabeth Haygreen1, Tanja Emmerich1, Norma Kim2, Elizabeth Marshall1, Kerry Lavender1, Myron Cohen3, Paul Goepfert4, Ian Williams5, Dennis Wallace2, George Shaw6, Beatrice Hahn6, Christina Ochsenbauer4, John Kappes4, Philip Norris7, Andrew McMichael1, Barton Haynes8 From Frontiers of Retrovirology: Complex retroviruses, retroelements and their hosts Cambridge, UK. 16-18 September 2013 Background The importance of events in acute HIV-1 infection (AHI) in determining the subsequent disease course prompts a need to understand the virus-immune system interactions in this phase of infection that impact on concurrent and ensuing viral replication and pathogenesis. The speed with which innate responses can be mobilized following pathogen exposure suggests they may play critical roles in AHI. We sought to characterise the innate responses activated during AHI and identify components of the response that contribute to control of viremia or conversely promote immune activation and virus replication. Materials and methods Peripheral blood samples were cryopreserved at serial timepoints from subjects acutely infected with HIV. The dynamics of systemic up-regulation of cytokines/ chemokines were analysed using Luminex multiplex assays and ELISAs, and activation of innate cell subsets was evaluated by multiparameter flow cytometry. Spearman correlation analyses and multiple regression modelling were employed to determine relationships between innate variables and assess their impact on viral control. Primary HIV isolates were derived from plasma cryopreserved at timepoints in acute and chronic infection and their sensitivity to control by IFN alpha and IFN beta was evaluated using in vitro assays. The IFN sensitivity of viruses generated from infectious molecular clones (IMCs) corresponding to deduced founder and paired 6-month virus sequences was also assessed. 1 Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK Full list of author information is available at the end of the article

Results The increase in viremia in AHI was associated with rapid activation of systemic innate responses, evidenced by a reduction in the circulating dendritic cell frequency, elevations in plasma levels of type 1 interferon (IFN) and other cytokines and chemokines, and natural killer (NK) cell activation and proliferation. Some components of the innate response, e.g. strong NK cell responses, correlated with establishment of lower set-point viral loads, whereas others, such as inflammatory cytokine production, correlated with establishment of higher set-point viral loads. However multiple regression modelling illustrated that the association between any one component of the innate response and set-point viremia was confounded by other interlinked innate variables. To seek evidence that type 1 IFN exerts selective pressure on HIV replication du