Novel Application of Nonhuman Primate Tethering System for Evaluation of Acute Phase SIVmac251 Infection in Rhesus Macaques (Macaca mulatta)

Abstract

Infection of rhesus macaques with simian immunodeficiency virus (SIV) is the preferred animal model for the development and testing of human immunodeficiency virus (HIV) vaccines, and animals protected from SIV challenge by live attenuated vaccines are an invaluable tool for determining immune correlates of protection. The acute phase of SIV infection, in which immune responses are most critical for slowing disease progression, occurs within the first 4 weeks of exposure. The small window of time available for observing critical immune responses makes obtaining adequate blood samples with sufficient frequency difficult. This study is the first to apply a previously reported nonhuman primate (NHP) tether system to study viral immunology. The use of the tether allows for frequent blood sampling without using restraints or sedation, thereby reducing the potentially confounding physiological changes induced by stress. We performed comparative analysis of acute phase immune responses in vaccinated and unvaccinated animals challenged with SIV-mac251. Our results demonstrate live attenuated vaccine-induced protection, which is associated with small increases in the cytotoxic T-cell (CTL) response to immunodominant epitopes, but not with increases in antibody titers. Additionally, vaccination was shown to establish a pool of antigen-specific CD8+ memory cells available for expansion after challenge. The confirmatory nature of these data indicates the validity of using the tether system for evaluation of acute phase anti-SIV responses and can be applied to the study of immune responses in other viral infections in which frequent sampling in small windows of time would be useful.

Transcriptional profiling of peripheral CD8+T cell responses to SIVΔnef and SIVmac251 challenge reveals a link between protective immunity and induction of systemic immunoregulatory mechanisms

“…Recent studies have reported that, in spite of robust virus specific CTL responses in vaccinated animals that show protection to SIV, they appear to generate low responses to the more prevalent immunodominant epitopes (Keckler et al, 2007). Our findings further highlight the importance of regulating systemic cytolytic responses and provide evidence that leukocyte immunoglobulin-like receptors may play an important role in this process.…”

Maintenance or Emergence of Chronic Phase Secondary Cytotoxic T Lymphocyte Responses after Loss of Acute Phase Immunodominant Responses Does Not Protect SIV-Infected Rhesus Macaques from Disease Progression

“…Using the tether system to study the acute phase after viral challenge, we recently demonstrated that all the macaques inoculated with the live-attenuated SIV vaccine were protected from pathogenic SIV infection [32]. As Table 1 shows however, while three (16037, 16041, and 16044) of four animals controlled SIV infection very efficiently and remained SP or LTNP, one vaccinated animal (16040, Mamu A * 01 + ) progressed to simian AIDS (SAIDS) at 118 weeks postchallenge.…”

“…These eight animals were placed on a tether system during the first 4 weeks of infection in order to demonstrate the usefulness of this technology in the study of viral immunology during the acute phase of infection. Details of the placement of the tether system, which allowed for blood sampling without sedation, are provided elsewhere [32]. …”

“…For those epitopes of known restriction, tetramer studies were performed to ensure that it was the CD8+ T lymphocytes that recognized the epitope (data not shown). For epitopes of unknown restriction, CD107 and Cytoxilux (OncoImmunin, Inc.) assays were utilized to determine that apoptosis of target autologous lymphoblastoid B cells was peptidespecific and that the CD8+ T lymphocyte population was positive for degranulation in a peptide-specific manner [32]. Epitopes identified by IFN- γ ELISPOT are putative only, because they were determined by single 15-mer peptides or overlapping regions of two or more 15-mer peptides that contain the 8- to 10-amino acid epitope.…”

Increases in NKG2C Expression on T Cells and Higher Levels of Circulating CD8+B Cells Are Associated with Sterilizing Immunity Provided by a Live Attenuated SIV Vaccine

“…These factors include anentropic specificity and repertoire depth of CD8 T cells, 12 localized innate immune responses, 13 inhibition of CD4 T-cell recruitment, 14 CD8 T-cell-related transcription factor profiles, 15,16 env-specific antibodydependent cell-mediated cytotoxicity, 17 antibodies, [18][19][20] the location, effector functions and phenotype of CD8 + T cells, [21][22][23][24][25][26][27] the interactions between types of challenge and viral load, 28 and the contribution of CD4 + T lymphocytes [29][30][31] ; we also reported an association between increases in cytotoxic T lymphocyte (CTLs) specific for conserved epitopes and vaccine-induced protection. 32 However, the relative contribution of each of these factors to the overall protective response remains unclear. Therefore, it is likely that multiple effector mechanisms are involved in vaccine-induced protection and innate, humoral and cell-mediated immunity may all be required for protection.…”