Hansen, S.G. et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523-527

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, Aug 24, 2015
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    • "Finally this construct showed interesting properties with ability to mimics the early stages of natural infection of primate lentivirus and to generate in vivo additional sources of antigens. Those extra sources of antigens will be presented by APCs to lymphocytes T and B cells and should help to improve greatly the antigen-specific immune responses similarly to those seen in LAV-immunized animals and Nef-defective HIV-1-infected LTNP individuals that efficiently control their infections [18] [60] [83]. This promising data promoted initiation of immunogenicity studies in cynomologus macaques a more appropriate model for HIV-1 vaccine studies. "
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    Vaccine 03/2015; 33(19). DOI:10.1016/j.vaccine.2015.03.021 · 3.49 Impact Factor
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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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    ABSTRACT: Infection of macaques with chimeric viruses based on SIVMAC but expressing the HIV-1 envelope (Env) glycoproteins (SHIVs) remains the most powerful model for evaluating prevention and therapeutic strategies against AIDS. Unfortunately, only a few SHIVs are currently available. Furthermore, their generation has required extensive adaptation of the HIV-1 Env sequences in macaques so they may not accurately represent HIV-1 Env proteins circulating in humans, potentially limiting their translational utility. We developed a strategy for generating large numbers of SHIV constructs expressing Env proteins from newly transmitted HIV-1 strains. By inoculating macaques with cocktails of multiple SHIV variants, we selected SHIVs that can replicate and cause AIDS-like disease in immunologically intact rhesus macaques without requiring animal-to-animal passage. One of these SHIVs could be transmitted mucosally. We demonstrate the utility of the SHIVs generated by this method for evaluating neutralizing antibody administration as a protection against mucosal SHIV challenge.
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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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