Impeding HIV-1-associated Non-Hodgkin's Lymphoma development by antagonizing Vpr

Division Of Basic Sciences - Nci

Investigators

Abstract

The primary goal of this proposed research is to determine whether the HIV-1-induced Vpr-VprBP-Plk4 complex we discovered plays an important role in promoting the tumorigenic activity of HIV-1-non-infectable B cells and whether antagonizing this interaction thwarts the neoplastic transformation of B cells and ensuing lymphoma development. Our data demonstrated that the ability of the CT (80-96) motif of Vpr to bind to the cryptic polo-box domain (CPB) of Plk4 is critically required for forming the Vpr-VprBP-Plk4 complex and inducing centrosome overamplification. Therefore, we plan to perform a series of cell-based and mouse model experiments to assess the capacity of Vpr in promoting lymphoma development and find a plausible method to negate it specifically. To this end, we will 1) investigate whether recombinant Vpr (rVpr), but not its respective rVpr(1-79), can directly promote the proliferation of Pfeiffer cells in the tumor microenvironment-mimicking 3D-Matrigel and whether the provision of a Vpr CT motif-specific antibody can neutralize this Vpr activity. We will also 2) use an advanced C57BL/6 Rag2-/ Gamma c-/- CD47-/- Bone Marrow-Liver-Thymus (BLT) mouse with a humanized immune system to examine whether HIV-1 but not its respective Vpr(1-79) mutant can induce cellular transformation of B cells. Since blood-borne Vpr is thought to transduce accessible cells, the rVpr and the Vpr CT-specific antibody will be valuable reagents to address whether the Vpr in the bloodstream contributes to B cell lymphoma development and whether this process can be interrupted by antagonizing the Plk4-binding Vpr CT motif. Since other viral factors, such as Tat and Nef, could also contribute to this process, we plans to analyze the potential cooperative action of these factors along the course of our research. HIV-1 is thought to promote the development of NHL, one of the three Acquired Immunodeficiency Syndrome (AIDS)-defining cancers closely associated with HIV-1 progression to AIDS. The current prevailing view is that HIV-1 infection contributes to NHL development through yet ill-defined events, including loss of immune surveillance, chronic inflammation, and persistent B cell activation. The goal of our research is to investigate whether Vpr released into the bloodstream of people living with HIV-1 transduces HIV-1 non-susceptible B lymphocytes, resulting in Plk4-mediated centrosome amplification and aneuploidy that ultimately contributes to the development of B-cell NHL. This approach, which is fueled by our discovery of a novel ternary Vpr-VprBP-Plk4 complex and HIV-1-induced centrosome amplification in primary CD4+ T and B cells represents a new direction of research that could lead to innovative treatment methods or therapeutic strategies applicable to combating HIV-1-associated cancers.