Date Published: February 28, 2013
Publisher: Public Library of Science
Author(s): Daniel Mendoza, Stephen A. Migueles, Julia E. Rood, Bennett Peterson, Sarah Johnson, Nicole Doria-Rose, Douglas Schneider, Eva Rakasz, Matthew T. Trivett, Charles M. Trubey, Vicky Coalter, Claire W. Hallahan, David Watkins, Genoveffa Franchini, Jeffrey D. Lifson, Mark Connors, Guido Silvestri.
Although the study of non-human primates has resulted in important advances for understanding HIV-specific immunity, a clear correlate of immune control over simian immunodeficiency virus (SIV) replication has not been found to date. In this study, CD8+ T-cell cytotoxic capacity was examined to determine whether this function is a correlate of immune control in the rhesus macaque (RM) SIV infection model as has been suggested in chronic HIV infection. SIVmac251-infected human reverse transcriptase (hTERT)-transduced CD4+ T-cell clone targets were co-incubated with autologous macaque effector cells to measure infected CD4+ T-cell elimination (ICE). Twenty-three SIV-infected rhesus macaques with widely varying plasma viral RNA levels were evaluated in a blinded fashion. Nineteen of 23 subjects (83%) were correctly classified as long-term nonprogressor/elite controller (LTNP/EC), slow progressor, progressor or SIV-negative rhesus macaques based on measurements of ICE (weighted Kappa 0.75). LTNP/EC had higher median ICE than progressors (67.3% [22.0–91.7%] vs. 23.7% [0.0–58.0%], p = 0.002). In addition, significant correlations between ICE and viral load (r = −0.57, p = 0.01), and between granzyme B delivery and ICE (r = 0.89, p<0.001) were observed. Furthermore, the CD8+ T cells of LTNP/EC exhibited higher per-cell cytotoxic capacity than those of progressors (p = 0.004). These findings support that greater lytic granule loading of virus-specific CD8+ T cells and efficient delivery of active granzyme B to SIV-infected targets are associated with superior control of SIV infection in rhesus macaques, consistent with observations of HIV infection in humans. Therefore, such measurements appear to represent a correlate of control of viral replication in chronic SIV infection and their role as predictors of immunologic control in the vaccine setting should be evaluated.
Clues regarding the features of an effective cellular immune response capable of controlling a chronic lentiviral infection have come from humans who naturally restrict HIV replication referred to as long-term nonprogressors/elite controllers (LTNP/EC) –. LTNP/EC show an enrichment of some MHC class I alleles, particularly B*57 and B*27 –, and their CD8+ T cell responses are focused on epitopes restricted by these alleles , . HIV-specific CD8+ T cells of LTNP/EC display greater capacity to proliferate, upregulate granzyme (Gr) B and perforin expression, and suppress HIV replication or kill autologous HIV-infected CD4+ T cells in vitro compared to those of progressors , –. Our group has observed that delivery of active GrB to target cells resulting in efficient infected CD4+ T-cell elimination (ICE) clearly distinguishes LTNP/EC from untreated or treated progressors –, which supports these measurements are clear correlates of immune control in HIV infection.
In this study, the cytotoxic capacity of SIV-specific CD8+ T cells in response to SIV-infected CD4+ T-cell targets was measured in blood samples from rhesus macaques with different degrees of control over in vivo SIV replication. Consistent with some prior work in humans –, the SIV-specific CD8+ T cells of LTNP/EC were found to have increased cytotoxic capacity compared with those of progressors. Further, the ability of SIV-specific CD8+ T cells of LTNP/EC to eliminate SIV-infected CD4+ T cells was mediated by delivery of active GrB to target cells. These results provide a CD8+ T-cell function and potential mechanism that distinguish LTNP/EC from progressors and appear to represent a correlate of immune control in chronic SIV infection.