CAR/CXCR5-T cell immunotherapy is safe and potentially efficacious in promoting sustained remission of SIV infection

Abstract

AbstractDuring chronic human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection prior to AIDS progression, the vast majority of viral replication is concentrated within B cell follicles of secondary lymphoid tissues. We investigated whether infusion of T cells expressing an SIV-specific chimeric antigen receptor (CAR) and the follicular homing receptor, CXCR5, could successfully kill viral-RNA+ cells in targeted lymphoid follicles in SIV-infected rhesus macaques. In this study, CD4 and CD8 T cells from rhesus macaques were genetically modified to express antiviral CAR and CXCR5 moieties (generating CAR/CXCR5-T cells) and autologously infused into a chronically infected animal. At 2 days post-treatment, the CAR/CXCR5-T cells were located primarily in spleen and lymph nodes both inside and outside of lymphoid follicles. Few CAR/CXCR5-T cells were detected in the rectum and lung, and no cells were detected in the bone marrow, liver, brain, or ileum. Within follicles, CAR/CXCR5-T cells were found in direct contact with SIV viral RNA+ cells. We next infused CAR/CXCR5-T cells into ART-suppressed SIV-infected rhesus macaques, in which the animals were released from ART at the time of infusion. These CAR/CXCR5-T cells replicated in vivo within both the extrafollicular and follicular regions of lymph nodes and accumulated within lymphoid follicles. CAR/CXR5-T cell concentrations in follicles peaked during the first week post-infusion but declined to undetectable levels after 2 to 4 weeks. Overall, CAR/CXCR5-T cell-treated animals maintained lower viral loads and follicular viral RNA levels than untreated control animals, and no outstanding adverse reactions were noted. These findings indicate that CAR/CXCR5-T cell treatment is safe and holds promise as a future treatment for the durable remission of HIV.Author summaryA person infected with human immunodeficiency virus (HIV) has replicating virus concentrated within the follicles of lymphoid tissues. The cells needed to clear the infection, cytotoxic T lymphocytes, have limited access to follicles and, thus, the cytotoxic T lymphocytes are never completely able to clear all of the HIV from the body. In this study, we have produced immunotherapeutic T cells that home to follicles and clear infected cells. These T cells express a viral targeting chimeric antigen receptor (CAR) and a molecule called CXCR5, which leads to homing of the cells to follicles. Upon administration of these CAR T-cells to virus-infected primates, we found that the cells localized to the follicle, replicated, and directly interacted with infected cells. While the cells were not maintained in the animals for more than 4 weeks, most of the treated animals maintained lower levels of virus in the blood and follicles than untreated control animals. This study shows that this immunotherapy has potential as a treatment leading to long-term remission of HIV without the need for antiretroviral drugs.