Inhibition of TLR2-Mediated Immune Responses by the HIV-1 Envelope Transmemvrane Domain

Etai Rotem 1 Eliran Moshe Reuven 1 Mohammad Ali 1 Roland Schwartzer 2 Andrea Gramatica 2 Anthony Futerman 1 Yechiel Shai 1
1Department of Biological Chemistry, Weizmann Institute of Science, Rehovot
2Institut für Biologie, AG Molekulare Biophysik, Humboldt-Universität zu Berlin, Berlin

To successfully infect and persist within its hosts, HIV-1 uses a number of means to manipulate the immune system. Utilizing several immunosuppressive segments of its gp41 fusion protein, HIV-1 inhibits T-cell activation by targeting the T-cell receptor complex [1]. Apart from T-cells, HIV-1 infects other CD4+ cell populations such as mononuclear phagocytes and dendritic cells (DCs) [2]. However, little is known about the ability of HIV-1 to modulate innate immune responses of these cells, particularly by targeting members of the Toll-Like receptor (TLR) family. TLRs expressed on the cell membrane are recruited to cholesterol-enriched membrane microdomains upon their ligand recognition. The HIV-1 ENV is also targeted to these membrane microdomains through a well-defined localization signal located adjacent to its transmembrane domain (TMD). Additionally, dendritic cells infected with HIV-1 were shown to have limited TLR responsiveness [3]. Taken together, we hypothesized that the ENV plays a role in impairment of TLR-induced responses. Addressing this question we investigated the inhibitory effect of the HIV-1 ENV on TLR2-mediated immune response and its mechanism of action[4]. We revealed that the ENV TMD associates with TLR2 TMD in the membrane resulting in reduced TLR2-mediated signaling and decreased pro-inflammatory cytokine secretion in-vitro. Furthermore, mutation in the ENV TMD demonstrated the importance of the conserved GxxxG motif in mediating this interaction and inhibition. Additionally, the administration of the ENV TMD in-vivo to lipotechoic acid(LTA)/Galactosamine-mediated septic mice resulted in a significant decrease in mortality and tissue damage. Overall, due to the high functional homology of viral ENV proteins this function may be a general trait of viral-induced immune modulation.

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  4. Reuven,E.M.,et al.PLoSPathog,2014








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