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Objective: A number of trials in primates using a wide range of putative vaccines based on simian immunodeficiency virus (SIV) have been performed and are summarised here. Methods: Rhesus macaques and African green monkey (AGMs) were immunised with the test vaccines and challenged with live virus to test the efficacy of the induced or transferred immune responses to protect from infection or disease development. Results: In initial studies, successful protection from challenge by whole inactivated virus vaccines was subsequently shown to be mediated by immune responses to human cell rather than viral proteins. Passive transfer of neutralising antibodies failed to protect against challenge. The induction of SIV-specific cytotoxic T lymphocytes (CTLs) using lipopeptides also failed to protect from infection, and whereas the frequency of post-infection CTLs (as measured by limiting dilution CTL assay and MHC/tetramer staining) correlated inversely with the cell-associated virus load, no correlation with the plasma virus load was observed. No immunological correlation of protection could be identified in macaques immunised with live attenuated SIV, with sterilising immunity being induced as early as 10 weeks after infection with the attenuated virus. Similarly, whole inactivated virus and passive IgG transfer failed to protect the natural host AGM species from challenge with apathogenic SIVagm, although live attenuated SIVagm afforded some protection despite the lack of overt vaccine virus replication. Conclusions: ‘Traditional’ types of vaccine are either ineffective or inappropriate for use in humans. Current efforts are therefore focusing on the rapidly evolving field of genetic vaccines based on vector DNA and recombinant, attenuated viral and bacterial vectors.

To investigate whether vaccination of macaques with attenuated simian immunodeficiency virus (SIV)macC8 could induce long-term protective immunity against rectal exposure to SIVsm and intravenous exposure to the more divergent HIV-2.Eight months after vaccination with live attenuated SIVmacC8, four cynomolgus monkeys were challenged with SIVsm intrarectally and another four vaccinated monkeys were challenged with HIV-2 intravenously. Sixteen months after SIVmacC8 vaccination, another two monkeys were challenged with SIVsm across the rectal mucosa. Two vaccinees shown to be protected against SIVsm were rechallenged 8 months after the first challenge. Ten naive animals were used as controls. Serum antigenaemia, virus isolation, antibody responses, cell-mediated immunity and CD4+ and CD8+ T-cell subpopulations were monitored. PCR-based assays were used to distinguish between virus populations.At the time of challenge, eight out of 10 vaccinees were PCR-positive for SIVmacC8 DNA but no virus could be isolated from peripheral blood mononuclear cells. After SIVsm challenge, three out of six vaccinees were repeatedly SIVsm PCR-negative. In one of the three infected monkeys, the challenge virus was initially suppressed but the monkey ultimately developed AIDS after increased replication of the pathogenic virus. Rechallenged monkeys remained protected. All HIV-2-challenged vaccinees became superinfected. All controls became infected with either SIVsm or HIV-2. At the time of challenge the vaccinees had neutralizing antibodies to SIVmac but no demonstrable cross-neutralizing antibodies to SIVsm or HIV-2. Titres of antigen-binding or neutralizing antibodies did not correlate with protection. Cytotoxic T-cell responses to SIV Gag/Pol and virus-specific T-cell proliferative responses were low.The live attenuated SIVmacC8 vaccine was able to induce long-term protection against heterologous intrarectal SIVsm challenge in a proportion of macaques but not against the more divergent HIV-2, which was given intravenously.

Infection of rhesus macaques with attenuated SIVmac is, at present, the only strategy which confers significant protection from challenge with wild-type SIVmac grown in monkey PBMC. However, initial results suggest that the protective mechanism does not develop until late after “vaccination” (approx 10 months). As part of a European study using the C8 variant of SIVmac251-32H(containing an in-frame 12-bp deletion in thenefgene), we wished to determine (a) if protection could be achieved against challenge with a “swarm” of SIVmac251-32Hproduced in monkey cells and (b) if protection could be demonstrated after a short period of infection with the attenuated virus. Eight Indian rhesus macaques were infected with C8 and four were challenged after 10 weeks with 50 MID50of an uncloned stock of SIVmac251-32Hgrown in rhesus cells, and the other four were challenged after 20 weeks. Four animals served as naive controls. Three of the four monkeys challenged at 10 weeks and three of those challenged at 20 weeks were protected from productive superinfection. From one monkey in each group it was, however, possible to demonstrate the presence of the wild-type provirus in monkey PBMC by diagnostic PCR and anamnestic immune response. There was no apparent correlation between the levels of binding or neutralizing antibodies on the day of challenge and subsequent protection. Approximately 1 year after infection with the attenuated virus all monkeys were rechallenged with the heterologous SIVsm strain, first with 10–20 MID50and then with 1000 MID50. Although not all of the SIVsm-inoculated naive controls became productively infected, PCR analysis failed to reveal any evidence for infection of the “immunized” monkeys.

The noncytotoxic soluble factor produced by CD8+ T cells inhibits replication of HIV and SIV in vitro and is thought to play a crucial role in combatting infection in vivo. We determined the effect of human CD8+ lymphocytes on the in vitro replication potential of both wild-type and nef-defective mutants of the simian immunodeficiency virus SIVmac251. Although replication of wild-type SIVmac251 in unstimulated human PBMC supplemented with IL-2 was unaffected by the presence of CD8+ T cells, the nef mutants were susceptible to the inhibitory effects. The effect of exogenous IL-2 depended upon the culture conditions: (i) in nonstimulated human PBMC depleted of CD8+ T cells, addition of IL-2 had a positive effect on the growth of the nef-defective viruses; (ii) in total human PBMC, IL-2 appeared to reinforce the CD8+ T-cell-dependent inhibition of the same mutant viruses. This strongly suggests that IL-2 stimulates the noncytotoxic anti-HIV/SIV response of CD8+ cells present in PBMC cultures. PHA stimulation of unfractionated human PBMC overrode the suppression of viral replication by CD8+ T cells. Depletion of activated T cells expressing the IL-2 receptor alpha-chain (CD25+ T cells), present in small amounts in these primary T cell cultures, dramatically reduced viral replication, indicating that the depleted cell population harbors the target cells permissive for viral replication. Furthermore, using neutralizing antibodies we could show that inhibition by the beta-chemokines MIP-1alpha, MIP-1beta, and RANTES and the inhibitory effect of CD8+ lymphocytes on nef mutant SIVmac viruses are harbored on different levels.