Targeting latent HIV-1 Reservoirs with the Antibody-Drug Conjugate, Brentuximab Vedotin

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Despite the overwhelming success of the ability of combination antiretroviral therapy (cART) to reduce disease-related morbidity and mortality in HIV-1 infection, viral reservoirs persist in latently infected cells during intensive therapy. The main challenge in achieving a cure for HIV-1 is the persistence of these latent viral reservoirs, and novel strategies to eliminate residual infected cells in the setting of cART are urgently needed. We have recently identified an individual who lacked detectable HIV-1 in cells after receiving multiple cycles of the antibody-drug conjugate, brentuximab vedotin for refractory T cell/anablastic lymphoma. Brentuximab vedotin consists of a monoclonal antibody that binds to CD30, a cell surface membrane protein, that is expressed on certain tumor cells, such as those involved with Hodgkin's or other types of aggressive lymphomas, but minimally expressed on resting, healthy lymphocytes. Brentuximab is conjugated with a compound which enters and selectively kills antibody-bound cells. CD30 is expressed on activated lymphocytes, and to a greater extent, after viral infection. HIV-1 replication and disease progression have also been associated with higher levels of the soluble form of CD30. Furthermore, we have preliminary data that suggest that HIV-1-infected or viral reactivated cells may preferentially express CD30, making brentuximab vedotin an important, potential therapeutic agent for eliminating latent reservoirs in the setting of HIV-1 reactivation. The impact of brentuximab vedotin on HIV-1 persistence is not known and warrants further study. We hypothesize that latently HIV-1-infected cells can be induced to preferentially express higher levels of CD30 by transcriptional viral reactivation than by T-cell stimulation from exogenous cytokines or other agents alone. Brentixumab vedotin will therefore selectively target and clear viral reactivated cells leading to smaller latent HIV-1 reservoir size. Our aims for the R21 component of this grant are to: (1) determine the relationships between viral reactivation and T-cell activation and CD30 expression on human CD4+ T lymphocytes in primary laboratory models of latency, and, (2) determine these relationships in cells from HIV- 1-infected patients on suppressive antiretroviral therapy. Our aims for the R33 component are to: (3) determine the effects of brentuximab vedotin treatment on latent HIV-1 reservoir size, and, (4) on surface and soluble CD30 expression and T-cell activation in peripheral blood and tissue in an established humanized mouse model. The proposed, innovative studies will provide important insights into how antibody-drug conjugates can be used to selectively target and clear HIV-1-infected cells and aid in the development of novel strategies to combat HIV-1 persistence.