93 : Role of cytokines in the natural resistance of baboons to SIV infection

Abstract

The establishment of human immunodeficiency virus type 1 (HIV-1) and HIV-2 infections in humans is the consequence of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) from chimpanzees (SIVcpz) and sooty mangabeys (SIVsmm), respectively. While over 40 African nonhuman primate (NHP) species carry their unique strain of SIV, many of which resulted from simian-to-simian transmissions, these natural SIV infections are chronic and productive but not associated with immunodeficiency. Baboons ( Papio hamadryas ssp. ), one of the most widely distributed African NHP species, do not seem to be naturally infected with SIV, even though their home ranges overlap those of many SIV-infected NHP species. Despite some serological evidence for SIV infection in very few wild-living baboons, isolation of a replicating virus from these animals has not been reported. The reasons for this apparent natural resistance to SIV infection are not known. Baboons have been shown to be susceptible to experimental infections with some HIV-1, HIV-2 or SHIVs strains. Further, in our hands, baboon lymphocytes support productive infection with SIVmac and SIVagm, indicating that intracellular antiviral factors like APOBEC3 proteins, Trim-5 α , and Tetherin probably do not contribute to this resistance. Our long-term goal is to identify the factors responsible for natural resistance to SIV infection in baboons. We hypothesized that cytokines and cytotoxic factors from cells from the innate immune system are involved in this natural resistance. As a first step towards testing this hypothesis, we performed in vitro infections with SIV of lymphocytes from baboons and Indian rhesus macaques. We determined kinetics of viral replication, and measured cytokine production and cell activation in order to identify differences between these NHP species. While all the rhesus PBMC preparations supported SIV replication, there were PBMC from some baboons that were refractory to SIV infection; this difference was more pronounced for infections with SIVagm than with SIVmac. We also observed that in vitro stimulation of rhesus cells resulted in higher levels of CD4 T cell activation in comparison to stimulated cells from baboons; however, the concentration of cytokines that compete with SIV for binding to CCR5 (such as RANTES, MIP-1 α , and MIP-1 β ) was higher for stimulated baboon cells than for macaque cells. Taken together, these differences in T cell activation status and cytokine levels could explain the natural immunity of baboons to SIV infection. Further work is underway to identify genes associated with this natural immunity. Identification of these genes ultimately may help inform the development of new therapeutic or preventive approaches to AIDS.