Profound early control of highly pathogenic SIV by an effector-memory T cell vaccine

Vaccine and Gene Therapy Institute, Department of Molecular Microbiology, Oregon Health & Science University, Beaverton, Oregon 97006, USA.
Nature (Impact Factor: 42.35). 05/2011; 473(7348):523-7. DOI: 10.1038/nature10003
Source: PubMed

ABSTRACT The acquired immunodeficiency syndrome (AIDS)-causing lentiviruses human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) effectively evade host immunity and, once established, infections with these viruses are only rarely controlled by immunological mechanisms. However, the initial establishment of infection in the first few days after mucosal exposure, before viral dissemination and massive replication, may be more vulnerable to immune control. Here we report that SIV vaccines that include rhesus cytomegalovirus (RhCMV) vectors establish indefinitely persistent, high-frequency, SIV-specific effector memory T-cell (T(EM)) responses at potential sites of SIV replication in rhesus macaques and stringently control highly pathogenic SIV(MAC239) infection early after mucosal challenge. Thirteen of twenty-four rhesus macaques receiving either RhCMV vectors alone or RhCMV vectors followed by adenovirus 5 (Ad5) vectors (versus 0 of 9 DNA/Ad5-vaccinated rhesus macaques) manifested early complete control of SIV (undetectable plasma virus), and in twelve of these thirteen animals we observed long-term (≥1 year) protection. This was characterized by: occasional blips of plasma viraemia that ultimately waned; predominantly undetectable cell-associated viral load in blood and lymph node mononuclear cells; no depletion of effector-site CD4(+) memory T cells; no induction or boosting of SIV Env-specific antibodies; and induction and then loss of T-cell responses to an SIV protein (Vif) not included in the RhCMV vectors. Protection correlated with the magnitude of the peak SIV-specific CD8(+) T-cell responses in the vaccine phase, and occurred without anamnestic T-cell responses. Remarkably, long-term RhCMV vector-associated SIV control was insensitive to either CD8(+) or CD4(+) lymphocyte depletion and, at necropsy, cell-associated SIV was only occasionally measurable at the limit of detection with ultrasensitive assays, observations that indicate the possibility of eventual viral clearance. Thus, persistent vectors such as CMV and their associated T(EM) responses might significantly contribute to an efficacious HIV/AIDS vaccine.

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Available from: Scott G Hansen, Jul 21, 2015
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    • "Cell-Associated Viral RNA and DNA A hybrid real-time/digital PCR format and analysis approach, previously described (Hansen et al., 2011), was applied for determination of cell-associated viral loads in isolated PBMCs. Quantitative hybrid real-time/digital nested PCR were performed as previously described (Hansen et al., 2011). A total of 12 replicates of each DNA or RNA sample were tested with two of the replicates containing a spike of DNA or RNA standard, as appropriate, to monitor assay performance and to guide retest requirements. "
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    • "Intriguingly, high numbers of protective memory CD8 T cells have been generated in this way and shown to protect in murine malaria [83]. If they furthermore require continual stimulation for maintenance, then we currently find hope for protective T cell vaccines in the possibility of new kinds of vaccination, such as the chronic viral system developed by Hansen et al., as well as in the possibility that Tem may survive longer than previously thought [100] [252], a possibility that has not yet been explored enough in peripheral lymphoid organs to rule this out. "
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    • "Very recently, improved vector combinations have yielded results (measured in terms of protective immunity) that are slightly better than the results obtained by using plasmid DNA followed by replication-deficient AdHu5 viruses. These new strategies include (i) prime with plasmid DNA in the presence of cytokine genes such as IL-12 or GM-CSF (Lai et al., 2011; Winstone et al., 2011), (ii) genes encoding multimeric proteins (Lakhashe et al., 2011), (iii) boost of adenovirus-immunized animals with an optimized plasmid DNA (Hutnick et al., 2012), (iv) prime with rhesus cytomegalovirus (Hansen et al., 2011), and (v) prime with a different heterologous strain of adenovirus (Barouch et al., 2012). The precise reason for the superior performance of the heterologous prime-boost vaccination compared to the sequential use of the same vector is still a matter of controversy. "
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