The HIV-1 Envelope Transmembrane Domain Binds TLR2 through a Distinct Dimerization Motif and Inhibits TLR2-Mediated Responses

Abstract

HIV-1 uses a number of means to manipulate the immune system, to avoid recognition and to highjack signaling pathways. HIV-1 infected cells show limited Toll-Like Receptor (TLR) responsiveness via as yet unknown mechanisms. Using biochemical and biophysical approaches, we demonstrate that the trans-membrane domain (TMD) of the HIV-1 envelope (ENV) directly interacts with TLR2 TMD within the membrane milieu. This interaction attenuates TNFα, IL-6 and MCP-1 secretion in macrophages, induced by natural ligands of TLR2 both in in vitro and in vivo models. This was associated with decreased levels of ERK phosphorylation. Furthermore, mutagenesis demonstrated the importance of a conserved GxxxG motif in driving this interaction within the membrane milieu. The administration of the ENV TMD in vivo to lipotechoic acid (LTA)/Galactosamine-mediated septic mice resulted in a significant decrease in mortality and in tissue damage, due to the weakening of systemic macrophage activation. Our findings suggest that the TMD of ENV is involved in modulation of the innate immune response during HIV infection. Furthermore, due to the high functional homology of viral ENV proteins this function may be a general character of viral-induced immune modulation.

The Atomic Structure of the HIV-1 gp41 Transmembrane Domain and Its Connection to the Immunogenic Membrane-proximal External Region

“…Studies motivated by the similarity between the sequence 694 GLRIVFAV 701 and a transmembrane section of the T-cell receptor ␣ subunit demonstrated the interaction of the gp41 TMD with CD3 partners in the TCR complex, resulting in the inhibition of T-cell proliferation (30). More recently, it has been reported that the gp41 TMD may also associate with the Toll-like receptor-2 TMD in the membrane, interfering with the receptor-mediated signaling and decreasing pro-inflammatory cytokine secretion (32). Collectively, these findings suggest that the sequence of the HIV-1 TMD plays critical functions beyond that of anchoring the Env complex to membranes (8 -11), although the structural requirements underlying these distinct functional roles remain to be determined.…”

HIV replication

“…For example, HIV-1 is inhibited and sensed by TRIM5a from nonhuman primates but resistant against the human ortholog because of adaptive mutations in its capsid protein [85]. Furthermore, detection of cytosolic RNA by RIG-I is antagonized by the viral protease [35], and TLR2-mediated and TLR9-mediated sensing are inhibited by gp41 and gp120, respectively [86][87][88]. Finally, it has been shown that the accessory protein Vpr recruits and activates the structure-specific endonuclease regulator SLX4 complex [89].…”

Interplay between HIV-1 and Toll-like receptors in human myeloid cells: friend or foe in HIV-1 pathogenesis?

“…In addition to TLR sensing of HIV-1 nucleic acids, some studies provided evidence for a direct recognition of HIV-1 products by surface TLRs. In particular, Reuven and coworkers [13] reported a physical interaction between HIV-1 gp41 and TLR2 in the membrane of murine macrophages. Likewise, a high-affinity, physical interaction between Tat and TLR4-MD2 has been described in monocytes [16].…”

“…However, signaling via TLRs has also been shown to promote HIV-1 infection in innate cells, directly by promoting HIV-1 transcription, or indirectly through cytokine induction [12]. Scattered evidence also suggests that at least some TLRs can sense HIV-1 by physically interacting with HIV components [13][14][15][16]. Overall, increasing evidence points to a functional role of TLRs in HIV-1 disease.…”