Adoptive transfer of simian immunodeficiency virus (SIV) naı̈ve autologous CD4+ cells to macaques chronically infected with SIV is sufficient to induce long-term nonprogressor status

Abstract

Abstract Adoptive transfer of autologous preinfection-collected peripheral blood mononuclear cells (PBMCs) or activated CD4+ T cells was performed in simian immunodeficiency virus (SIVmac239)–infected monkeys following short-term antiviral therapy with PMPA (9-R-[2-phosphonylmethoxypropyl] adenine). Short-term chemotherapy alone led to a transient decrease in plasma and cellular proviral DNA loads and transient rescue of gag/pol and env cytotoxic T-lymphocyte precursors (pCTLs). However, cessation of therapy allowed for SIV infection to resume its clinical course. PMPA chemotherapy coupled with infusions of either autologous pre-SIV infection–collected PBMCs or activated CD4+ T cells led to extended control of plasma and cellular proviral DNA loads after infusion, in spite of the fact that the transfused cells were not primed against SIV. However, qualitatively different antiviral defenses were induced by infusion of unfractionated and unmanipulated PBMCs versus purified and activated CD4+ T cells: PBMC infusions significantly favored development of SIVenv-specific pCTLs, neutralizing antibodies, and secretion of soluble noncytotoxic suppressor factors of SIV replication. In contrast, activated CD4+ T cells predominantly promoted CTL responses to SIVgag/pol and SIVenv. In addition, infusion of influenza-primed activated CD4+ T cells markedly enhanced influenza-specific pCTL responses, whereas infusion of similarly influenza-primed unfractionated PBMCs enhanced such pCTL responses only modestly, suggesting that the predominant immune defect after SIV infection lies in the T helper cell compartment rather than the effector cell compartment. Thus, adoptive immunotherapy with autologous “SIV naı̈ve” CD4+ lymphocytes was sufficient to rescue cell-mediated immune responses and induce long-term anti-SIV control and immune responses in the absence of continued antiviral chemotherapy.