Lack of Specific Regulatory T Cell Depletion and Cytoreduction Associated with Extensive Toxicity After Administration of Low and High Doses of Cyclophosphamide

Up to 93% of the human immunodeficiency virus (HIV) latent reservoir comprised defective proviruses, suggesting that a functional cure is possible through the elimination of a small population of cells containing intact virus, instead of the entire reservoir. Cyclophosphamide (Cy) is an established chemotherapeutic agent for immune cell cancers. In high doses, Cy is a nonselective cytoreductor, used in allogeneic stem-cell transplantation, while in a low dose, metronomic schedule, Cy selectively depletes regulatory T cells (Tregs). We administered low and high doses to simian immunodeficiency virus (SIV)-infected rhesus macaques (RM) to assess their effects on the SIV reservoirs. As a Treg-depleting agent, Cy unselectively depleted Treg and total lymphocytes, resulting in minimal immune activation and no viral reactivation. As a cytoreductive agent, Cy induced massive viral reactivation in elite controller RMs without ART. However, when administered with antiretroviral therapy (ART), Cy had substantial adverse effects, including mortality. Our study thus dissuades further investigation of Cy as an HIV cure agent.

Automated summary

A study found that a functional cure for HIV might be possible by eliminating a small population of cells containing intact virus, rather than the entire reservoir which mostly comprised defective proviruses. However, the chemotherapeutic agent Cyclophosphamide (Cy) showed adverse effects when administered with antiretroviral therapy (ART), discouraging further investigation of Cy as an HIV cure agent. This study highlights the complexities and challenges in developing a cure for HIV.