Repeated Rectal SHIVSF162P3 Exposures Do Not Consistently Induce Sustained T Cell Responses Prior to Systemic Infection in the Repeat-Low Dose Preclinical Macaque Model

摘要

The macaque model of repeated SHIV exposures is increasingly used as a preclinical tool to evaluate biomedical HIV intervention strategies. It is unclear whether multiple virus exposures induce immune responses in macaques, as documented in uninfected individuals repeatedly exposed to HIV. We here address whether repeated, rectal SHIV_SF162P3 exposures lead to systemic T cell activation in 12 rhesus macaques, and whether this is associated with increased infection resistance. Eight macaques became systemically infected after 2–7 exposures, three macaques were less susceptible (infection after 10-12 exposures), and one macaque remained uninfected after 14 exposures. PBMCs were retrospectively monitored for increases in T cell activation by analyzing the proportion of CD8+ T cells, recently activated or proliferated T cells (markers CD38, Ki67), a marker for cytotoxicity (granzyme B), or T cell-produced plasma cytokines (IFN-γ, RANTES, IL-2). Repeated virus exposures did not induce sustained, potent, or diverse T cell responses prior to systemic infection. Some changes occurred in the analyzed parameters during repeated virus exposures, but similar T cell activities were also observed in five SHIV-unexposed control macaques. Thus, we found no evidence that delayed infection or resistance to infection was associated with systemic, long-lasting, protective T cell responses to repeated rectal virus exposures. Our results provide further insights into the repeat exposure macaque model. We find that this model can be used for testing biomedical prevention strategies without concern of eliciting a systemic vaccination effect.