Impact of CCR5∆32/∆32 Allogenic Hematopoietic Stem Cell Transplant on Adaptive Immune Parameters in HIV Infection

Abstract

Introduction: Human Immunodeficiency Virus (HIV) is a chronic viral infection without a cure. While antiretroviral medications allow people with the infection live long and healthy lives, treated HIV remains associated with a degree of immune exhaustion that is linked to poor clinical outcomes. One individual, the so called “Berlin Patient”, was cured of HIV with a CCR5∆32/∆32 stem cell transplant. It remains unclear how such a transplant impacts the long standing immune exhaustion of HIV. Purpose: To examine changes in immune phenotype and function after a CCR5∆32/∆32 stem cell transplant in the context of HIV infection. Methods: A person living with HIV received a CCR5∆32/∆32 allogenic hematopoietic stem cell transplant for chronic myeloid leukemia. The inducible viral reservoir in peripheral blood was quantified both pre and post-transplant. Immune exhaustion marker expression on T cells and B cell subsets were determined by polychromatic flow cytometry. T and B cell responses to HIV, cytomegalovirus (CMV), and influenza antigens were determined by ELISPOT and ELISA. We compared immune phenotype, immune function, and proviral reservoir to a matched local cohort. Results: Full donor engraftment was achieved and the HIV proviral reservoir was reduced, but not eliminated. At 9 months post-transplant, the recipient had an increase in phenotypically exhausted CD8+ T cells and immature B cells, but also an increase in activated CD8+ T cells and a decrease in exhausted memory B cells. CD4+ T cells showed variable changes in immune exhaustion While anti-HIV T cell responses were greatly diminished, anti-HIV B cell responses were not after transplant. Finally, B cell responses against CMV and influenza remained low, while anti-CMV T cell responses remained high. Conclusion: Taken together, these data suggest that a stem cell transplant with HIV-resistant stem cells may not reduce all immune exhaustion, but HIV reservoir is more limited. The transplanted immune cell phenotype is influenced by factors beyond HIV, including other viral infections post-transplant. Further examination of people living with HIV receiving CCR5∆32/∆32 stem cell transplants will further delineate the role of reversible immune exhaustion in HIV and other clinical outcomes.