Vaccine and Infectious Disease Division

The Vpu protein is HIV’s weapon against immune system’s first line of defense

When cells are infected with HIV, IRF3 (green) co-localizes to the lysosome (red), where the protein is degraded (top). This is in contrast to uninfected cells (Control, bottom), where IRF3 is localized throughout the cell cytoplasm. HIV mediates this process through the expression of Vpu, which binds to and re-locates IRF3 and subsequently suppresses the innate immune response.

Our immune system consists of two types of response: the innate immune system can respond very quickly to invading pathogens but is non-specific, and the adaptive immune system is able to build a specific defense against a given foreign agent but takes longer to initially develop. HIV manages to successfully evade both these systems. VIDD affiliate investigator Dr. Michael Gale and colleagues previously showed that HIV infection induces destruction of the immune protein interferon regulatory factor 3 (IRF-3), which is involved in nearly all innate immune responses. Now, the researchers have expanded on that study to further dissect the molecular basis of HIV’s suppression of the innate immune system.

The scientists, which also included VIDD co-director Dr. Julie McElrath and affiliate investigator Dr. Florian Hladik, used a cell culture system, infecting human cells with HIV in vitro, to show that the HIV protein Vpu binds to and targets IRF-3 for degradation by the lysosome, organelles that normally break down cellular waste. The researchers also looked at HIV strains missing Vpu, and found that cells infected with this deficient virus were able to mount a robust innate immune response, suggesting that Vpu is wholly responsible for masking the virus from recognition by our innate immune system. These results indicate that Vpu or IRF-3 might be a target for therapies that aim to boost our innate immunity against HIV-1 infection.

 

Vpu deficient HIV strains stimulate innate immune signaling responses in target cells. Doehle BP, Chang K, Fleming L, McNevin J, Hladik F, McElrath MJ, Gale M Jr. J Virol. 2012 May 30.

Vpu mediates IRF3 depletion during HIV infection by a lysosomal-dependent mechanism. Doehle BP, Chang K, Rustagi A, McNevin J, McElrath MJ, Gale M Jr. J Virol. 2012 May 16.

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