The Berlin patient who has been effectively cured from HIV provides proof of concept for the feasibility of curing HIV infection from the human host. It is likely that at least four factors have contributed to HIV being cured in the Berlin patient: (i) prolonged and durable control of HIV infection prior to bone marrow transplant, (ii) cytotoxic chemotherapy killing the viral reservoir, (iii) being transplanted with CCR5 delta 32 cells which are resistant to infection, and (iv) a broadly effective immune response which was able to eradicate any residual infection. This case has spurred much scientific debate and speculation as to how to make cure of HIV a more generalizable and an achievable outcome. Given the potency of current antiretroviral agents, current efforts are focusing on developing novel ways of killing or purging the viral reservoir (eg SAHA), developing new approaches to generate cells which resist infection (eg Zinc finger nucleases for CCR5) and enhancing the immune control of HIV. TNF related apoptosis inducing factor (TRAIL) is a molecule whose principal function is as an effector of immune surveillance, and it has been implicated in the pathogenesis of both malignancies, as well as viral infections including HIV. Concerning the role of TRAIL in HIV, considerable evidence supports a role for TRAIL dysregulation occurring during HIV infection in vivo, and there is ample evidence that treatment of cells from HIV-infected patients on HAART with exogenous TRAIL, reduces the number of latently infected cells, as measured by undetectable levels of replication competent virus in quantitative co-culture assays. Since TRAIL is expressed by effector cells (i.e., CD8 and/or NK cells) of the immune system, we questioned why TRAIL-dependent natural immune mechanisms do not independently reduce the number of latently infected cells. We found that cells from HIV-infected patients produce a novel splice variant of TRAIL which we call TRAILshort, which antagonizes normal TRAIL signaling. We therefore propose a model whereby the production of TRAILshort by HIV-infected cells prevents these cells from being killed by either CTL or NK cells, and this allows a subset of infected cells to persist. The current research proposal concerns gaining understanding the biology of and developing ways to inhibit this TRAIL splice variant, which we have named TRAILshort (TRAILs). Since we have generated preliminary data which demonstrates that TRAILs blocks HIV induced killing of CD4 T cells, as well as killing induced by CTL and NK cells, we now propose to inhibit TRAILs as a means of increasing the rate at which HIV infected CD4 Tcells die, and thereby contributing to the goal of eradicating HIV infected cells, and a cure for HIV infection. In this regard, we have additional preliminary data indicating that inhibiting TRAILs achieves the goal of increasing killing of HIV infected T-cells, and enhancing both CTL and NK cell killing of target cells.
Recently, there has been great interest in developing novel strategies designed to cure HIV infection, using novel approaches to inhibit HIV replication, to purge HIV from the cells within which it hides, and/or the augment the immune response to HIV, such that the host immune system can eradicate HIV infected cells. The research strategy employed in the current proposal is predicated upon a unique discovery made by our lab, wherein we have identified a new molecule produced by HIV infected cells which functions to antagonize the normal immune response to HIV. This protein that we call TRAILshort is produced by HIV infected cells, and it prevents HIV infected cells from dying after they come in contact with the cytotoxic molecule TRAIL, which is normally produced by CD8 T cells and NK cells of the immune system. Under normal circumstances, HIV infection induces a broad immune response in infected patients, yet that immune response is unable to eradicate the infection for unknown reasons. The hypothesis being tested in this research is that eliminating TRAILshort production will allow for the CD8 T cells and NK cells which are already produced, to effectively kill HIV infected cells. Supported by extensive and encouraging preliminary data, we will study how HIV causes TRAILshort to be produced, what effect TRAILshort has on the survival of HIV infected CD4 T cells alone, and in combination with CD8 T cells or NK cells from the same patient, and whether differences in the expression of TRAILshort in HIV infected patients are associated with different degrees of control of HIV viral burden and replication.
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|Sainski, Amy M; Dai, Haiming; Natesampillai, Sekar et al. (2014) Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation. J Cell Biol 206:867-76|