Intragastric Administration of Lactobacillus plantarum and 2,2′-Dithiodipyridine-Inactivated Simian Immunodeficiency Virus (SIV) Does Not Protect Indian Rhesus Macaques from Intrarectal SIV Challenge…

Diane G. Carnathan, Joseph J. Mackel, Shelby L. Sweat, Chiamaka A. Enemuo, Etse H. Gebru, Pallavi Dhadvai, Sailaja Gangadhara, Sakeenah Hicks, Thomas H. Vanderford, Rama R. Amara, José Esparza, Wei Lu, Jean-Marie Andrieu, Guido Silvestri

A major obstacle to development of an effective AIDS vaccine is that along with intended beneficial responses, immunization regimen may activate CD4+ T cells that can facilitate acquisition of HIV by serving as target cells for the virus. Lu et al. reported that intra-gastric administration of chemically inactivated SIVmac239(iSIV) andLactobacillus plantarum(LP) (iSIV+LP) protected 15/16 Chinese-origin rhesus macaques (RMs) from high-dose intra-rectal SIVmac239challenge at three months post-immunization. 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". Andrieu et al subsequently reported protection from infection in 23/24 RM immunized intragastrically or intravaginally with iSIV and BCG, LP orLactobacillus rhamnosus, which they ascribed to the same tolerogenic mechanism. Using vaccine materials obtained from our co-authors, we conducted an immunization and challenge experiment in 54 Indian RMs, and included control groups receiving iSIV only or LP only, as well as unvaccinated animals. Intra-rectal challenge with SIVmac239resulted in rapid infection in all groups of vaccinated RMs as well as unvaccinated controls. iSIV+LP vaccinated animals that became SIV infected showed viral loads similar to those observed in animals receiving iSIV only, LP only, and unvaccinated controls. The protection from SIV transmission conferred by intra-gastric iSIV+LP 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 increased understanding in 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 could act as target cells for acquisition of HIV. An alternative strategy could involve induction of a tolerizing 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 in Chinese-origin rhesus macaques by using a "tolerogenic" vaccine consisting of intra-gastric administration of Lactobacillus plantarum and AT-2-inactivated SIV (iSIV+LP) which showed highly significant protection from virus transmission. Here, we administered iSIV+LP immunizations to Indian-origin rhesus macaques, and failed to observe any protective effect from virus acquisition in this experimental setting. This work is important as it contributes to the overall assessment of the clinical potential of a new candidate AIDS vaccine platform based on the iSIV+LP.