With Minimal Systemic T-Cell Expansion, CD8⁺T Cells Mediate Protection of Rhesus Macaques Immunized with Attenuated Simian-Human Immunodeficiency Virus SHIV89.6 from Vaginal Challenge with Simian Immunodeficiency Virus

Abstract

The presence, at the time of challenge, of antiviral effector T cells in the vaginal mucosa of female rhesus macaques immunized with live-attenuated simian-human immunodeficiency virus 89.6 (SHIV89.6) is associated with consistent and reproducible protection from pathogenic simian immunodeficiency virus (SIV) vaginal challenge (18). Here, we definitively demonstrate the protective role of the SIV-specific CD8؉ T-cell response in SHIV-immunized monkeys by CD8؉ lymphocyte depletion, an intervention that abrogated SHIVmediated control of challenge virus replication and largely eliminated the SIV-specific T-cell responses in blood, lymph nodes, and genital mucosa. While in the T-cell-intact SHIV-immunized animals, polyfunctional and degranulating SIV-specific CD8 ؉ T cells were present in the genital tract and lymphoid tissues from the day of challenge until day 14 postchallenge, strikingly, expansion of SIV-specific CD8 ؉ T cells in the immunized monkeys was minimal and limited to the vagina. Thus, protection from uncontrolled SIV replication in animals immunized with attenuated SHIV89.6 is primarily mediated by CD8 ؉ T cells that do not undergo dramatic systemic expansion after SIV challenge. These findings demonstrate that despite, and perhaps because of, minimal systemic expansion of T cells at the time of challenge, a stable population of effectorcytotoxic CD8 ؉ T cells can provide significant protection from vaginal SIV challenge.

Gag p27-Specific B- and T-Cell Responses in Simian Immunodeficiency Virus SIVagm-Infected African Green Monkeys

“…The T-cell response was variable among the animals. In general, it appeared moderate, comparable to chronically SIVinfected RMs (9). Of note, T-cell responses were not consistently detected at all time points and not in all animals.…”

Augmented Replicative Capacity of the Boosting Antigen Improves the Protective Efficacy of Heterologous Prime-Boost Vaccine Regimens

“…The correlates of immune control in our murine studies are similar with those of previous vaccine studies in monkey models of SIV infection. Protective SIV-specific T cell responses elicited by attenuated SIV vaccines are associated with minimal anamnestic expansion and activation, whereas nonprotective T cell responses exhibit robust expansion and activation following SIV challenges (likely in response to uncontrolled viral replication) (39,42). Thus, our observations with Listeria and vaccinia virus challenges may be generalizable to human immunodeficiency virus (HIV)/SIV and other infections, suggesting that recall proliferation and activation of vaccine-elicited CD8 T cells correlate inversely with pathogen control.…”

Extralymphoid CD8 + T Cells Resident in Tissue from Simian Immunodeficiency Virus SIVmac239Δnef-Vaccinated Macaques Suppress SIVmac239 Replication Ex Vivo

“…An effective mucosal immune response elicited by live-attenuated SIV vaccination may prevent the initial CD4 ϩ T-cell depletion from the gut. Several recent studies confirm a critical protective role for CD8 ϩ T cells in the genital tract after vaccination with SHIV89.6, demonstrating that a mucosal immune response is capable of protecting against or ameliorating SIV infection (14)(15)(16)48). Another study has also demonstrated the presence of high-frequency, polyfunctional T-cell responses in the mucosal tissues of elite controllers, i.e., individuals who maintain plasma viral loads below 75 copies/ ml, compared to blood from the same individual, tissues of noncontrollers, and antiretroviral drug-treated patients.…”