Abstract
Since 1985, we have tested several immunological approaches to suppressing HIV replication in HIV-infected patients and to prevent HIV acquisition in uninfected people. Here, after briefly reviewing our studies on immunosuppressive treatments and therapeutic dendritic cell-based therapies, we examine in more detail our work on the tolerogenic vaccines we developed against AIDS in Chinese macaques. The vaccine consisted of inactivated SIVmac239 particles adjuvanted with the Bacillus of Calmette and Guerin (BCG), Lactobacillus plantarum (LP), or Lactobacillus rhamnosus (LR). Without adjuvant, the vaccine administered by the intragastric route induced the usual simian immunodeficiency virus (SIV)-specific humoral immune responses but no post-challenge protection. In contrast, out of 24 macaques that were immunized with the adjuvanted vaccine and challenged intrarectally with SIVmac239 or SIVB670, 23 were sterilely protected for up to 5 years, while all control macaques were infected. On the other hand, all macaques of Indian origin that were immunized with the same adjuvanted vaccine were not protected. We then discovered that vaccinated Chinese macaques developed a previously unrecognized class of non-cytolytic MHC-Ib/E-restricted CD8+ T cells (or CD8+ T-Regs) that suppressed the activation of SIV RNA-infected CD4+ T cells and thereby inhibited the (activation-dependent) reverse transcription of the virus and prevented the establishment of SIV infection. Finally, we found a similar population of HLA-E-restricted CD8+ T-Regs in human elite controllers (a small group of HIV-infected patients whose viral replication is naturally inhibited). Ex vivo, their CD8+ T-Regs suppressed viral replication in the same manner as those of vaccinated Chinese macaques. It is noteworthy that all of these elite controllers had a homo- or heterozygous HLA-Bw4-80I genotype. Taking into account the longevity and the high percentage of vaccine-protected Chinese macaques together with the concomitant identification of a robust ex vivo correlate of protection and the discovery of similar CD8+ T-Regs in human elite controllers, preventive and therapeutic HIV vaccines should be envisaged in humans.
Highlights
Human immunodeficiency virus (HIV) infection occurs mainly via the sexual and anal mucosa
Vaccine-induced non-classical MHC-Ib/Erestricted CD8+ T-Regs prevented the activation of simian immunodeficiency virus (SIV)-RNA-infected CD4+ T cells, which in turn prevented the reverse transcription of SIV RNA into SIV DNA and the subsequent cascade of events ending in virus replication and release
We started with the discovery by serendipity of an effective mucosal vaccine made of iSIV particles adjuvanted with Bacillus of Calmette and Guerin (BCG) in the Chinese rhesus macaque (RM) model
Summary
Human immunodeficiency virus (HIV) infection occurs mainly via the sexual and anal mucosa. A central question was how a mucosal vaccine made of iSIV particles adjuvanted with BCG, LP or LR induced, both SIV-specific tolerance (defined by the absence of SIV-specific CD4+ T-cell activation and antibody production) and a post-challenge sterile protection in Chinese RMs, while the same vaccine administered without adjuvant induced a classical immune response and no post-challenge protection. To measure the antiviral activity of the vaccine, we established a virus suppression assay where we measured SIV concentrations in supernatants of infected C D4+ T cells (from healthy RMs) cultivated for 5 days in the presence or absence of fresh CD8+ T cells collected at several time points before and after vaccination of RMs. In our second series of eight vaccinated RMs, seven were protected (Fig. 1, left, green line); all seven showed a strong pre-challenge C D8+ T-Reg-mediated antiviral activity that remained stable until 5 years post-vaccination (Fig. 1, right, green lines). The results of such preliminary trials will provide the information required for considering whether further preventive and therapeutic efficacy trials should be undertaken
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