Enhancement of HIV infection by dendritic cells
Transmission of HIV is likely to be facilitated by the interaction of the virus with dendritic cells (DCs), which are abundant at mucosal surfaces and traffic to draining lymph nodes. Dendritic cells have the ability to dramatically enhance viral infectivity of CD4+ T cells. We have shown that HIV can binds to DCs through a specific interaction of the viral envelope glycoprotein with the C-type lectin DC-SIGN. However we have observed that this binding event is not necessary for enhanced infectivity. The enhanced infectivity requires the internalization of HIV into a specialized compartment. We are examining the mechanism by which viral internalization results in increased infectivity of target T cells. To this end, we are using RNAi approaches in dendritic cells to interrogate the role of selected cellular pathways.
Immune control of retroviral infection in vivo
To study the function of DCs in vivo, we have prepared transgenic mice whose DCs express diphtheria toxin receptor, allowing their specific elimination within hours after treatment with diphtheria toxin. Studies with these mice have demonstrated that dendritic cells are required for controlling Friend virus (FV) infection, a model retrovirus in mice. We have also determined that Myd88 is a critical component of the response to FV. Indeed in Myd88-deficient mice, the antibody response to FV is reduced. We are now dissecting the molecular pathway that leads FV to signal through Myd88. Encouraged by these results, we have begun to examine whether HIV can also activate innate immune system responses. Dendritic cells are highly resistant to infection with HIV, yet they can efficiently transmit virus to T cells. We hypothesize that HIV has evolved to exploit DC, avoiding productive infection and thus bypassing activation of innate immune functions, while enhancing trans-infection of T cells. We are studying means by which HIV can activate innate immunity, as this may facilitate development of more effective vaccines.
Ménager MM, Littman DR. (2016) Actin Dynamics Regulates Dendritic Cell-Mediated Transfer of HIV-1 to T Cells. Cell. 2016 Feb 11;164(4):695-709 [Pubmed]
Seay, K., Qi, X., Zheng, J.H., Zhang, C., Chen, K., Dutta, M., Deneroff, K., Ochsenbauer, C., Kappes, J.C., Littman, D.R., & Goldstein, H. (2013) Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. PLoS One. 8(5):e63537. PMC3655194.
Streeck, H., D’Souza, M.P., Littman, D.R., & Crotty, S. (2013) Harnessing CD4+ T cell responses in HIV vaccine development. Nature Medicine 19:143-9. PMC3626561.
Manel, N. and Littman, D.R. (2011) Hiding in plain sight: how HIV evades innate immune responses. Cell 147(2), 271-4.