Administration of Recombinant Rhesus Interleukin-12 during Acute Simian Immunodeficiency Virus (SIV) Infection Leads to Decreased Viral Loads Associated with Prolonged Survival in SIVmac251-Infected Rhesus Macaques

Abstract

The ability of recombinant rhesus interleukin-12 (rMamu-IL-12) administration during acute simian immunodeficiency virus SIVmac251 infection to influence the quality of the antiviral immune responses was assessed in rhesus macaques. Group I (n= 4) was the virus-only control group. Group II and III received a conditioning regimen of rMamu-IL-12 (10 and 20 μg/kg, respectively, subcutaneously [s.c.]) on days −2 and 0. Thereafter, group II received 2 μg of IL-12 per kg and group III received 10 μg/kg s.c. twice a week for 8 weeks. On day 0 all animals were infected with SIVmac251 intravenously. While all four group I animals and three of four group II animals died by 8 and 10 months post infection (p.i.), all four group III animals remained alive for >20 months p.i. The higher IL-12 dose led to lower plasma viral loads and markedly lower peripheral blood mononuclear cell and lymph node proviral DNA loads. During the acute viremia phase, the high-IL-12-dose monkeys showed an increase in CD3⁻CD8α/α⁺and CD3⁺CD8 α/α⁺cells and, unlike the control and low-IL-12-dose animals, did not demonstrate an increase in CD4⁺CD45RA⁺CD62L⁺naive cells. The high-IL-12-dose animals also demonstrated that both CD8α/α⁺and CD8α/β⁺cells produced antiviral factors early p.i., whereas only CD8α/β⁺cells retained this function late p.i. Long-term survival correlated with sustained high levels of SIVgag/poland SIVenvcytotoxic T lymphocytes and retention of high memory responses against nominal antigens. This is the first study to demonstrate the capacity of IL-12 to significantly protect macaques from SIV-induced disease, and it provides a useful model to more precisely identify correlates of virus-specific disease-protective responses.