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A major obstacle to development of an effective AIDS vaccine is that along with the intended beneficial responses, the immunization regimen may activate CD4 + T cells that can facilitate acquisition of human immunodeficiency virus (HIV) by serving as target cells for the virus. Lu et al. (W. Lu et al., Cell Rep 2: 1736–1746, 2012, https://doi.org/10.1016/j.celrep.2012.11.016 ) reported that intragastric administration of chemically inactivated simian immunodeficiency virus SIV mac239 and Lactobacillus plantarum (iSIV- L. plantarum ) protected 15/16 Chinese-origin rhesus macaques (RMs) from high-dose intrarectal SIV mac239 challenge at 3 months postimmunization. They attributed the observed protection to induction of immune tolerance, mediated by “MHC-Ib/E-restricted CD8 + regulatory T cells that suppressed SIV-harboring CD4 + T cell activation and ex vivo SIV replication in 15/16 animals without inducing SIV-specific antibodies or cytotoxic T.” J.-M. Andrieu et al. (Front Immunol 5:297, 2014, https://doi.org/10.3389/fimmu.2014.00297 ) subsequently reported protection from infection in 23/24 RMs immunized intragastrically or intravaginally with iSIV and Mycobacterium bovis BCG, L. plantarum , or Lactobacillus rhamnosus , which they ascribed to the same tolerogenic mechanism. Using vaccine materials obtained from our coauthors, we conducted an immunization and challenge experiment with 54 Indian RMs and included control groups receiving iSIV only or L. plantarum only as well as unvaccinated animals. Intrarectal challenge with SIV mac239 resulted in rapid infection in all groups of vaccinated RMs as well as unvaccinated controls. iSIV- L. plantarum- vaccinated animals that became SIV infected showed viral loads similar to those observed in animals receiving iSIV only or L. plantarum only or in unvaccinated controls. The protection from SIV transmission conferred by intragastric iSIV- L. plantarum administration reported previously for Chinese-origin RMs was not observed when the same experiment was conducted in a larger cohort of Indian-origin animals. IMPORTANCE Despite an increased understanding of immune responses against HIV, a safe and effective AIDS vaccine is not yet available. One obstacle is that immunization may activate CD4 + T cells that may act as target cells for acquisition of HIV. An alternative strategy may involve induction of a tolerance-inducing response that limits the availability of activated CD4 + T cells, thus limiting the ability of virus to establish infection. In this regard, exciting results were obtained for Chinese-origin rhesus macaques by using a “tolerogenic” vaccine, consisting of intragastric administration of Lactobacillus plantarum and 2,2′-dithiodipyridine-inactivated SIV, which showed highly significant protection from virus transmission. In the present study, we administered iSIV- L. plantarum to Indian-origin rhesus macaques and failed to observe any protective effect on virus acquisition in this experimental setting. This work is important because it contributes to the overall assessment of the clinical potential of a new candidate AIDS vaccine platform based on iSIV- L. plantarum .