Evidence of a tolerogenic vaccine against AIDS in the Chinese macaque prefigures a potential human vaccine

Abstract

In 2006 we discovered a new type of mucosal vaccine against simian immunodeficiency virus (SIV) in Chinese macaques. Here, we review 15 years of our published work on this vaccine, which consists of inactivated SIVmac239 particles adjuvanted with Bacillus Calmette-Guérin, Lactobacillus plantarum, or Lactobacillus rhamnosus. Without adjuvant, the vaccine administered by the intragastric route induced the usual SIV-specific humoral and cellular immune responses but provided no protection against intrarectal challenge with SIVmac239. In contrast, out of 24 macaques immunized with the adjuvanted vaccine and challenged intrarectally with SIVmac239 or SIVB670, 23 were sterilely protected for up to five years, while all control macaques were infected. This protection was confirmed by an independent group from the Pasteur Institute. During the past 15 years, we have identified the mechanism of action of the vaccine and discovered that the vaccinated macaques produced a previously unrecognized class of MHC-Ib/E-restricted CD8⁺ T cells (which we refer to as tolerogenic CD8⁺ T cells) that suppressed the activation of SIV-RNA-infected CD4⁺ T cells and thereby inhibited the (activation-dependent) reverse transcription of the virus, which in turn prevented the establishment of SIV infection. Importantly, we discovered also that the tolerogenic CD8⁺ T cell subset observed in vaccinated Chinese macaques could also be found in human elite controllers, a small group of HIV-infected patients in whom these tolerogenic CD8⁺ T cells were shown to naturally suppress viral replication. Given that SIV and HIV require activated immune cells in which to replicate, the specific prevention of activation of SIV-RNA-containing CD4⁺ T cells by a tolerogenic vaccine approach offers an exciting new avenue in HIV vaccine research.

Fig. 1

The evolution of the plasma SIV RNA load in ChRMs repeatedly receiving the iiSIV/LP vaccine. The eight vaccinated macaques were euthanized at month 15, and no trace of SIV DNA or RNA was found at autopsy

Fig. 2

Plasma SIV RNA and PBMC-associated SIV DNA loads in control macaques (C1-C4) and in vaccinated macaques (E9, E11-E16) after challenge with SIVMac239. (A) All control animals became infected, and RNA levels increased exponentially, peaking at day 10 after infection and then decreasing gradually. No viral RNA was detected in the plasma of vaccinated animals. The quantification limit for this assay was 100 RNA copies/ml. (B) DNA levels in control animals were already over the quantification threshold at day 7 postinfection and increased in three animals until days 14-23. Six of the seven vaccinated animals had extremely low levels of viral DNA that were below the limit of quantification. In most cases, PCR was positive only in one out of two replicate wells, except for E9, E11, E13 and E16 at day 14 and E12 at day 7. Values corresponding to positive replicate wells were arbitrarily set to 10 copies, and values corresponding to only one positive well were arbitrarily set to 3 copies. The quantification limit of the assay was 100 DNA copies/ml.

Fig. 3

Percentage of activated cells (Ki-67⁺) among SIVp27⁺CD4⁺ T cells without or with depletion of CD8⁺ cells or CD25⁺ cells. In vaccinated macaques, SIV⁺CD4⁺ T cell activation was suppressed. Activation of SIVp27⁺CD4⁺ T cells was re-established when CD8⁺ T cells were withdrawn.

Fig. 4

Ex vivo antiviral activity (SIV RNA suppression) of CD8⁺ T cells taken from vaccinated ChRMs. The data show the anti-SIV activity of CD8⁺ T cells 60 days after immunization in a delayed (A), insert (B), or allogenic (C) culture system in the presence of MHC-la/ABC or MCH-Ib/E antibodies (D).

Fig. 5

Antiviral activity (fold SIV suppression) of CD8⁺ T cells taken from vaccinated ChRMs