5th International AIDS Society Conference on HIV Pathogenesis and Treatment Cape Town - July 19 - 22, 2009

IMPACT OF NK-DC CROSSTALK ON HIV REPLICATION AND PERSISTENCE IN DENDRITIC CELLS - CONTRIBUTION OF HMGB1

IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract No. MOAA203

M.-L. Gougeon, H. Saidi, M.-T. Melki
Institut Pasteur, Antiviral Immunity, Biotherapy and Vaccine Unit, Paris, France

BACKGROUND: HIV-1 has evolved ways to exploit DCs, thereby facilitating viral dissemination and allowing evasion of antiviral immunity. The fate of DCs is extremely dependent on the interaction with autologous NK cells. Here, we investigate the impact of NK-DC crosstalk on the fate of HIV-infected DCs.

METHODS: Immature DCs (iDCs) were derived from CD14+ bead-purified monocytes cultured in the presence of IL-4 and GM-CSF. NK cells were negatively selected, and kept either unstimulated, or activated (aNK) by a combination of PHA and rhIL-2. In some experiments, iDCs were infected with either R5-HIV-1BAL or X4-HIV-1NDK, and the impact of 24h NKDC crosstalk on the fate of HIV-1-infected DCs was analyzed.

RESULTS: aNK cells efficiently triggered maturation of infected DCs, but this was associated with a strong impairment of mature DCs to induce Th1 polarization. Moreover, the crosstalk between aNK cells and infected DCs resulted in a dramatic increase in viral replication and HIV-DNA in DCs. HMGB1 was crucial in this process, and inhibition of HMGB1 activity by glycyrrhizin or specific antibodies abrogated HIV-1 replication in DCs. The pivotal role of HMGB1 was confirmed by the ability of exogenous rhHMGB1 to trigger HIV-1 replication and DNA expression in infected DCs.

CONCLUSIONS: This study provides evidence for the crucial role of NK-DC crosstalk in promoting viral replication and dissemination in DCs, and it challenges the question of the in vivo involvement of HMGB1 in HIV-1 replication and replenishment of viral reservoirs in DCs.

2009-07-22
MOAA203
Oral Abstract Session: MOAA2 - Subversion of Immune Responses in HIV Infection

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