HIV-1 reservoirs continue to exist in latent form despite long-term suppression of circulating virus with antiretroviral therapy. The main challenge in achieving a cure for HIV-1 infection is the persistence of these latent viral reservoirs. To dat, there has only been one functional """"""""cure"""""""" of HIV-1 infection in an individual who underwent myeloablative allogeneic hematopoietic stem cell transplant for acute myeloid leukemia with donor cells lacking functional CCR5, a co-receptor used by HIV-1 to enter host cells. Reduction of HIV-1 reservoirs with pre-transplant cytotoxic chemotherapy likely contributed to viral eradication;however, the effects of cytotoxic chemotherapy with or without hematopoietic stem cell transplant (HSCT) on the viral reservoir and host factors and immune responses are largely unknown. Our study will provide greater insight into the persistence and evolution of HIV-1 that will have practical implications for therapeutics aimed at eliminating HIV reservoirs. We propose to investigate the effect of cytotoxic chemotherapy and/or HSCT on viral reservoir size, evolution, and immune function in HIV-1 infected individuals with hematologic malignancies initiating systemic anti-neoplastic therapy. We hypothesize that cytotoxic chemotherapy or HSCT reduces pools of latently infected cells, and will be manifested as a long-term reduction in the amount of total and integrated HIV-1 DNA. We also hypothesize that there is no significant evolution during immune reconstitution following cytoreductive therapy, but reductions in HIV-1 DNA and subsequent re-expansion of CD4+ lymphocyte subsets and other tissue compartments may lead to changes in the diversity of the remaining viral reservoir.
Specific aims of this proposal include: 1) investigate the effects of chemotherapy or HSCT for hematologic malignancy on peripheral blood and bone marrow reservoir size, 2) study the changes in residual viremia, lymphocyte activation, and HIV-specific immune responses before and after chemotherapy, and, 3) investigate the effects of cytotoxic chemotherapy on HIV-1 evolution, tissue compartmentalization, and reservoir diversity. This five-year study will utilize innovative approaches to investigate reservoir dynamics such as 454 deep sequencing and assays to detect and quantify low levels of HIV-1 DNA from host tissue and plasma viremia below the limit of detection of standard tests. Measures of lymphocyte activation, host-entry factors and HIV-specific immunity will also be integrated into the research plan in collaboration with immunologists and evolutionary virologists. The candidate is currently an Instructor of Medicine at Harvard Medical School in the Division of Infectious Diseases at the Brigham and Women's Hospital (BWH), and plans on further training that will lead to an independent academic career in translational virology and patient-oriented research. This project will be conducted under the mentorship of Dr. Daniel Kuritzkes and Dr. Manish Sagar at the BWH.
We will investigate the effect of cytotoxic chemotherapy and hematopoietic stem cell transplant on viral reservoir size, diversity and immune function in a prospective cohort of HIV-1 infected individuals with hematologic malignancies initiating systemic anti-neoplastic therapy. These studies will provide greater insight into the persistence of HIV-1 that will have practical implications for novel therapeutics aimed at eliminating HIV reservoirs.
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|Henrich, Timothy J; Kuritzkes, Daniel R (2013) HIV-1 entry inhibitors: recent development and clinical use. Curr Opin Virol 3:51-7|
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