Differential Innate Immune Responses to Low or High Dose Oral SIV Challenge in Rhesus Macaques

Abstract

Mucosal transmission of HIV predominately occurs during sexual intercourse or breast-feeding and generally results in a successful infection from just one or few founder virions. Here we assessed the impact of viral inoculum size on both viral and immune events within two groups of Rhesus macaques that were non-traumatically, orally inoculated with either multiple low (1000 to 4000 TCID50) or high (100,000 TCID50) doses of SIV. In agreement with previous studies, more diverse SIV variants were observed in macaques following infection with high dose oral SIV compared to a low dose challenge. In peripheral blood cells, the immune gene transcript levels of CXCL9, IFNγ, TNFα and IL10 remained similar to uninfected macaques. In contrast, OAS and CXCL10 were upregulated following SIV infection in both the high and low dosed macaques, with a more rapid kinetics (detectable by 7 days) following the high SIV dose challenge. In peripheral lymph nodes, an increase in CXCL10 was observed irrespective of viral dose while CXCL9 and OAS were differentially regulated in the two SIV dosed groups. Magnetic bead sorting of CD3+, CD14+ and CD3−/CD14− cells from peripheral blood identified the increase in OAS expression primarily within CD14+ monocytes, whereas the CXCL10 expression was primarily in CD3+ T cells. These findings provide insights into the impact of SIV challenge dose on viral and innate immune factors, which has the potential to inform future SIV/HIV vaccine efficacy trials in which vaccinated hosts have the potential to be infected with a range of viral challenge doses.

Metabolomic Profiling in Cattle Experimentally Infected with Mycobacterium avium subsp. paratuberculosis

“…Although the same metabolites discriminated LD and HD infected cattle from negative controls; therefore, dose did not affect metabolomic changes, it is noteworthy that immune-related outcomes are typically influenced by dose in parasitic [31], viral [32] and bacterial [33] infections. Moreover, whereas all treatment groups of this trial were purposely allocated into 2 independent runs, differentiation of infected and non-infected animals was still possible despite added seasonal variation to the metabolite profiles.…”

Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+T-Cell Responses

“…Although we cannot exclude subtle differences in the fitness of the viruses, all low-dose controllers carried replication-competent viruses that are able to infect heterologous CD4 ϩ T cells to the same extent as the original SIVmac 251 . Low-dose SIV exposure in macaques has also been associated with lower plasma proinflammatory cytokine levels during the early phases of infection (45), which may provide an optimal context for the development of adaptive responses.…”

Impact of Mucosal Inflammation on Oral Simian Immunodeficiency Virus Transmission

“…Five weeks after inserting ligatures, and when all animals in the treated group had clear signs of inflammation, animals in both groups were exposed to cellfree SIVmac251 by the oral route. The initial viral dose (1,833 TCID 50 ) and delivery method (needleless syringe applying the virus to the boundary between the teeth and gums) had previously been shown to infect 50% of untreated rhesus macaques (26); in this study, this challenge resulted in three out of four animals in each group becoming infected (Table 1). Since our goal was to evaluate the infectivity of the virus at the site of gingivitis, we designed a second exper-iment in which 5 macaques (the single uninfected macaque from each group plus four new macaques for each group) again were administered the same amount of virus (1,833 TCID 50 ), but this time the virus was deposited in a piece of Whatman 3-mm paper placed at the junction of teeth and gingiva.…”

“…In a first study, one group of 4 control animals and a second group of 4 gingivitis macaques were challenged by depositing 1 ml (1,833 50% tissue culture infectious doses [TCID 50 ]) of SIVmac251 suspension over the gingiva, at the location of the ligatures, or in equivalent areas in control macaques; this procedure was repeated on two occasions, 48 and 96 h after the first challenge. This viral dose and type of delivery was previously determined to infect approximately 50% of control animals (26). In a second study, two groups of 5 animals each were exposed to virus by placing a strip of Whatman 3-mm paper soaked in virus on the same area of the gum used in the first study and leaving the strip for at least 10 min; the procedure was repeated 48 and 96 h later.…”