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The detailed study of immune effector mechanisms in primate models of infectious disease has been limited by the inability to adoptively transfer lymphocytes from vaccinated animals into naïve immunocompetent recipients. Recent advances in our understanding of the Major Histocompatibility Complex diversity of Mauritian cynomolgus macaques enabled the establishment of a breeding program to generate Major Histocompatibility Complex (MHC)-identical animals. The current study utilised this resource to achieve an improved model of adoptive transfer of lymphocytes in macaques. The effect of route of transfusion on persistence kinetics of adoptively transferred lymphocytes was evaluated in an autologous transfer system. Results indicated that peripheral persistence kinetics were comparable following infusion by different routes, and that cells were detectable at equivalent levels in lymphoid tissues six weeks post-infusion. In a pilot-scale experiment, the persistence of adoptively transferred lymphocytes was compared in MHC-identical siblings and MHC-identical unrelated recipients. Lymphocytes transferred intra-peritoneally were detectable in the periphery within one hour of transfer and circulated at detectable levels in the periphery and lymph nodes for 10 days. Donor lymphocytes were detectable at higher levels in MHC-identical siblings compared with unrelated animals, however the total time of persistence did not differ. These results demonstrate a further refinement of the lymphocyte adoptive transfer system in Mauritian cynomolgus macaques and provide a foundation for hitherto impractical experiments to investigate mechanisms of cellular immunity in primate models of infectious disease. [ABSTRACT FROM AUTHOR]

Live attenuated measles virus is one of the most efficient and safest vaccines available, making it an attractive candidate vector for a HIV/AIDS vaccine aimed at eliciting cell-mediated immune responses (CMI). Here we have characterized the potency of CMI responses generated in mice and non-human primates after intramuscular immunisation with a candidate recombinant measles vaccine carrying an HIV-1 insert encoding Clade B Gag, RT and Nef (MV1-F4). Eight Mauritian derived, MHC-typed cynomolgus macaques were immunised with 105 TCID50 of MV1-F4, four of which were boosted 28 days later with the same vaccine. F4 and measles virus (MV)-specific cytokine producing T cell responses were detected in 6 and 7 out of 8 vaccinees, respectively. Vaccinees with either M6 or recombinant MHC haplotypes demonstrated the strongest cytokine responses to F4 peptides. Polyfunctional analysis revealed a pattern of TNFα and IL-2 responses by CD4+ T cells and TNFα and IFNγ responses by CD8+ T cells to F4 peptides. HIV-specific CD4+ and CD8+ T cells expressing cytokines waned in peripheral blood lymphocytes by day 84, but CD8+ T cell responses to F4 peptides could still be detected in lymphoid tissues more than 3 months after vaccination. Anti-F4 and anti-MV antibody responses were detected in 6 and 8 out of 8 vaccinees, respectively. Titres of anti-F4 and MV antibodies were boosted in vaccinees that received a second immunisation. MV1-F4 carrying HIV-1 Clade B inserts induces robust boostable immunity in non-human primates. These results support further exploration of the MV1-F4 vector modality in vaccination strategies that may limit HIV-1 infectivity. [ABSTRACT FROM AUTHOR]

In order to test the hypothesis that CD8+ cytotoxic T lymphocytes mediate protection against acute superinfection, we depleted >99% of CD8+ lymphocytes in live attenuated simian immunodeficiency virus macC8 (SIVmacC8) vaccinees from the onset of vaccination, maintained that depletion for 20 days, and then challenged with pathogenic, wild-type SIVmacJ5. Vaccinees received 5 mg per kg of humanized anti-CD8 monoclonal antibody (MAb) 1 h before inoculation, followed by the same dose again on days 3, 7, 10, 13, and 17. On day 13, peripheral CD8 + T lymphocytes were >99% depleted in three out of four anti-CD8 MAb-treated vaccinees. At this time attenuated SIVmacC8 viral RNA loads in anti-CD8 MAb-treated vaccinees were significantly higher than control vaccinees treated contemporaneously with nonspecific human immunoglobulin. Lymphoid tissue CD8+ T lymphocyte depletion was >99% in three out of four anti-CD8 MAb-treated vaccinees on the day of wild-type SIVmacJ5 challenge. All four control vaccinees and three out of four anti-CD8 MAb-treated vaccinees were protected against detectable superinfection with wild-type SIVmacJ5. Although superinfection with wild-type SIVmacJ5 was detected at postmortem in a single anti-CD8 MAb-treated vaccinee, this did not correlate with the degree of preceding CD8+ T lymphocyte depletion. Clearance of attenuated SIVmacC8 viremia coincided with recovery of normal CD8+ T lymphocyte counts between days 48 and 76. These results support the view that cytotoxic T lymphocytes are important for host-mediated control of SIV primary viremia but do not indicate a central role in protection against acute superinfection conferred by inoculation with live attenuated SIV. [ABSTRACT FROM AUTHOR]