Human immunodeficiency virus type 1 (HIV-1) matrix protein p17 variants (vp17s) derived from non-Hodgkin lymphoma (NHL) tissues of HIV-1-seropositive (HIV) patients promote B cell growth by activating the Akt signaling pathway. It is fundamental to understand the role played by vp17s in producing a microenvironment that fosters lymphoma development and progression. Therefore, we asked whether vp17s could be secreted from infected cells in their biologically active form. In this study, we show that two B cell growth-promoting vp17s, NHL-a101 and NHL-a102, characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn), respectively, are secreted from HIV-1-infected Jurkat T-cells during the active phase of viral replication. Secretion of biologically active vp17s also occurred in HeLa cells nucleofected with a plasmid expressing the entire Gag gene, following proteolytic cleavage of the precursor Gag polyprotein (Pr55) by cellular aspartyl proteases. Binding of Pr55 to PI(4,5)P was indispensable for allowing the unconventional secretion of both wild-type p17 and vp17s. Indeed, here we demonstrate that inhibition of Pr55 binding to PI(4,5)P by using neomycin, or its enzymatic depletion achieved by overexpression of 5ptaseIV, significantly impair p17s secretion. We also demonstrated that heparan sulfate proteoglycans were involved in tethering p17s at the cell surface. This finding opens up an interesting way for investigating whether tethered p17s on the surface of HIV-1 reservoirs may represent a likely target for immune-mediated killing.
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