Hypoxia enhances antibody-dependent dengue virus infection

Dengue virus (DENV) has been found to replicate in lymphoid organs such as the lymph nodes, spleen, and liver in postmortem analysis. These organs are known to have low oxygen levels (similar to 0.5-4.5% O-2) due to the vascular anatomy. However, how physiologically low levels of oxygen affect DENV infection via hypoxia-induced changes in the immune response remains unknown. Here, we show that monocytes adapted to 3% O-2 show greater susceptibility to antibody-dependent enhancement of DENV infection. Low oxygen level induces HIF1 alpha-dependent upregulation of fragment crystallizable gamma receptor IIA (Fc gamma RIIA) as well as HIF1 alpha-independent alterations in membrane ether lipid concentrations. The increased Fc gamma RIIA expression operates synergistically with altered membrane composition, possibly through increase membrane fluidity, to increase uptake of DENV immune complexes for enhanced infection. Our findings thus indicate that the increased viral burden associated with secondary DENV infection is antibody-dependent but hypoxia-induced and suggest a role for targeting hypoxia-induced factors for anti-dengue therapy.