Abstract

HIV-1 matrix protein p17 variants (vp17s) derived from non-Hodgkin's 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 to 118 (Ala–Ala) or 125 to 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 Gag precursor polyprotein (Pr55Gag) by cellular aspartyl proteases. Binding of Pr55Gag to phosphatidylinositol-(4,5)-bisphosphate was indispensable for allowing the unconventional secretion of both wildtype p17 and vp17s. Indeed, here we demonstrate that inhibition of Pr55Gag binding to phosphatidylinositol-(4,5)-bisphosphate by using neomycin, or its enzymatic depletion achieved by overexpression of 5ptaseIV, significantly impair the secretion of p17s. 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.

Highlights

  • Been shown, even after prolonged HIV-1 suppression [4]

  • In light of the emerging role of the microenvironment in promoting and sustaining the growth and survival of tumor cells [37, 38], the possibility that HIV-1–encoded proteins derived from infected cells and endowed with peculiar biologic properties contribute to lymphomagenesis was entertained

  • Biologically active vp17s capable of augmenting clonogenic proliferation of lymphoma cell lines were detected in lymphoma tissue of patients with non-Hodgkin’s lymphoma (NHL) and mirrored in their plasma counterparts [6]

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Summary

Introduction

Been shown, even after prolonged HIV-1 suppression [4]. Taken together, these findings strongly suggest that p17 may be chronically present in the tissue microenvironment of HIV-1–seropositive (HIV+) patients, even during the pharmacological control of viral replication. We report that biologically active NHL-a101 and NHL-a102 vp17s are released by cells nucleofected with plasmid-expressing Gag or viral mutants.

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