Early short-term antiretroviral therapy is associated with a reduced prevalence of CD8⁺FoxP3⁺ T cells in simian immunodeficiency virus-infected controller rhesus macaques

Regulatory T cells contain a mix of CD4 and CD8 T cell subsets that can suppress immune activation and at the same time suppress immune responses, thereby contributing to disease progression. Recent studies have shown that an increased prevalence of CD8⁺FoxP3⁺ T regulatory cells was associated with immune suppression and diminished viral control in simian immunodeficiency virus (SIV)-infected rhesus macaques. Preventing an increase in the prevalence of CD8 T regulatory subsets is likely to lead to a better long-term outcome. Here we show that short-term antiretroviral therapy initiated within 1 week after SIV infection was associated with lower viral set point and immune activation after withdrawal of therapy as compared to untreated animals. Early short-term treated controller animals were found to have better SIV-specific immune responses and a significantly lower prevalence of immunosuppressive CD8⁺FoxP3⁺ T cells. Lower levels of CD8⁺FoxP3⁺ T cells coincided with preservation of CD4 ⁺FoxP3⁺ T cells at homeostatic levels, and significantly correlated with lower immune activation, suggesting a role for viral infection-driven immune activation in the expansion of CD8⁺FoxP3 ⁺ T cells. Interestingly, initiation of continuous therapy later in infection did not reduce the increased prevalence of CD8⁺FoxP3 ⁺ T cells to homeostatic levels. Taken together, our results suggest that early antiretroviral therapy preserves the integrity of the immune system leading to a lower viral set point in controller animals, and prevents alterations in the homeostatic balance between CD4⁺ and CD8 ⁺ T regulatory cells that could aid in better long-term outcome.