Abstract
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.
Highlights
Clues regarding the features of an effective cellular immune response capable of controlling a chronic lentiviral infection have come from humans who naturally restrict Human Immunodeficiency Virus (HIV) replication referred to as long-term nonprogressors/elite controllers (LTNP/EC) [1,2,3,4]
We evaluated rhesus macaques infected with Simian Immunodeficiency Virus (SIV), a lentivirus closely related to Human Immunodeficiency Virus (HIV)
In contrast to most SIV-infected rhesus macaques that develop progressive disease, a small proportion are able to control SIV replication and remain healthy for prolonged durations. We found that these longterm nonprogressor/elite controller (LTNP/EC) macaques have CD8+ T cells that are extremely effective at killing SIVinfected cells
Summary
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) [1,2,3,4]. LTNP/EC show an enrichment of some MHC class I alleles, B*57 and B*27 [5,6,7,8], and their CD8+ T cell responses are focused on epitopes restricted by these alleles [6,9]. MHC class I alleles are associated with control of SIV infection, Mamu B*08 and B*17 [15,16]. The CD8+ T cells of LTNP/EC carrying these alleles preferentially recognize Mamu B08 and B17-bound SIV epitopes [17]. The 2–4 log increase in SIV plasma viremia seen after in vivo CD8+ T cell depletion in both LTNP/EC and progressors in vivo [18,19,20] provides further support that SIV is controlled by the CD8+ T cell response in these animals
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