title: Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia.
abstract: Primary HIV-1 infection induces a virus-specific adaptive/cytolytic immune response that impacts the plasma viral load set point and the rate of progression to AIDS. Combination antiretroviral therapy (cART) suppresses plasma viremia to undetectable levels that rebound upon cART treatment interruption. Following cART withdrawal, the memory component of the virus-specific adaptive immune response may improve viral control compared to primary infection. Here, using primary infection and treatment interruption data from macaques infected with simian/human immunodeficiency virus (SHIV), we observe a lower peak viral load but an unchanged viral set point during viral rebound. The addition of an autologous stem cell transplant before cART withdrawal alters viral dynamics: we found a higher rebound set point but similar peak viral loads compared to the primary infection. Mathematical modeling of the data that accounts for fundamental immune parameters achieves excellent fit to heterogeneous viral loads. Analysis of model output suggests that the rapid memory immune response following treatment interruption does not ultimately lead to better viral containment. Transplantation decreases the durability of the adaptive immune response following cART withdrawal and viral rebound. Our model's results highlight the impact of the endogenous adaptive immune response during primary SHIV infection. Moreover, because we capture adaptive immune memory and the impact of transplantation, this model will provide insight into further studies of cure strategies inspired by the Berlin patient.IMPORTANCEHIV patients who interrupt combination antiretroviral therapy (cART) eventually experience viral rebound, the return of viral loads to pretreatment levels. However, the "Berlin patient" remained free of HIV rebound over a decade after stopping cART. His cure is attributed to leukemia treatment that included an HIV-resistant stem cell transplant. Inspired by this case, we studied the impact of stem cell transplantation in a macaque simian/HIV (SHIV) system. Using a mechanistic mathematical model, we found that while primary infection generates an adaptive immune memory response, stem cell transplantation disrupts this learned immunity. The results have implications for HIV cure regimens based on stem cell transplantation.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Daniel B
authors.identifier: http://orcid.org/0000-0001-5684-9538
authors.initials: DB
authors.lastname: Reeves
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Peterson
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA jschiffe@fredhutch.org.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Schiffer
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D008251:Macaca; D008962:Models, Theoretical; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D014766:Viremia / Q000276:immunology*
chemical_list: D044966:Anti-Retroviral Agents
keywords: Berlin patient; SHIV; hematopoietic stem cell transplant; human immunodeficiency virus; macaque model; mathematical modeling