Simian Retrovirus Infections: Potential Confounding Variables in Primate Toxicology Studies

Mucosal transmission is the predominant mode of human immunodeficiency virus (HIV) infection world-wide, and the mucosal innate interferon response represents an important component of the earliest host response to the infection. Our goal here was to assess the changes in mRNA expression of innate mucosal genes after oral simian immunodeficiency virus (SIV) inoculation of rhesus macaques (Macaca mulatta) that were followed throughout their course of disease progression. The SIV plasma viral load was highest in the macaque that progressed rapidly to simian AIDS (99 days) and lowest in the macaque that progressed more slowly (>700 days). The mRNA levels of six innate/effector genes in the oral mucosa indicated that slower disease progression was associated with increased expression of these genes. This distinction was most evident when comparing the slowest-progressing macaque to the intermediate and rapid progressors. Expression levels of alpha and gamma interferons, the antiviral interferon-stimulated gene product 2-5 oligoadenylate synthetase (OAS), and the chemokines CXCL9 and CXCL10 in the slow progressor were elevated at each of the three oral mucosal biopsy time points examined (day 2 to 4, 14 to 21, and day 70 postinfection). In contrast, the more rapidly progressing macaques demonstrated elevated levels of these cytokine/chemokine mRNA at lymph nodes, coincident with decreased levels at the mucosal sites, and a decreased ability to elicit an effective anti-SIV antibody response. These data provide evidence that a robust mucosal innate/effector immune response is beneficial following lentiviral exposure; however, it is likely that the anatomical location and timing of the response need to be coordinated to permit an effective immune response able to delay progression to simian AIDS.

Section: Methodsmentioning

confidence: 99%

Mucosal Innate Immune Response Associated with a Timely Humoral Immune Response and Slower Disease Progression after Oral Transmission of Simian Immunodeficiency Virus to Rhesus Macaques

Milush

Stefano-Cole

Schmidt

et al. 2007

“…We have used this strategy to evaluate activation of endogenous retroviral sequences in Vero cells, which, although known to contain numerous copies of endogenous retroviral sequences due to their AGM species of origin (5,8,10,26,31,36,42,57,68,81), were not expected to contain an inducible virus, based upon the extensive testing history and broad use of the cell line (29,74). Here, we report that treatment of Vero cells with 5-azacytidine (AzaC) and with 5Ј-iodo-2Ј-deoxyuridine (IUdR) induced endogenous retroviral particles related to ancient sim-ian endogenous type D betaretrovirus (SERV) sequences that are present in all Old World monkeys (83) and distinct from pathogenic, type D simian retroviruses (SRVs) (46). Additionally, particles containing baboon endogenous virus (BaEV)-related type C gammaretrovirus sequences were also induced from AzaC-treated Vero cells.…”

mentioning

confidence: 99%

Chemical Induction of Endogenous Retrovirus Particles from the Vero Cell Line of African Green Monkeys

et al. 2011

“…Currently, there are five serotypes (SRV-1 to SRV-5) and two additional genotypes (SRV-6 and SRV-7) of SRVs reported (14)(15)(16). SRV-1, -2, and -3 induce immunodeficiency-like diseases in macaques; however, symptoms are generally mild and chronic (14).…”

Section: Discussionmentioning

confidence: 99%

Simian Retrovirus 4 Induces Lethal Acute Thrombocytopenia in Japanese Macaques

Yoshikawa

Okamoto

Sakaguchi

et al. 2015

In 2001-2002, six of seven Japanese macaques (Macaca fuscata) died after developing hemorrhagic syndrome at the Kyoto University Primate Research Institute (KUPRI). While the cause of death was unknown at the time, we detected simian retrovirus 4 (SRV-4) in samples obtained from a similar outbreak in 2008-2011, during which 42 of 43 Japanese macaques died after exhibiting hemorrhagic syndrome. In this study, we isolated SRV-4 strain PRI-172 from a Japanese macaque showing severe thrombocytopenia. When inoculated into four Japanese macaques, the isolate induced severe thrombocytopenia in all within 37 days. We then constructed an infectious molecular clone of strain PRI-172, termed pSR415, and inoculated the clone-derived virus into two Japanese macaques. These animals also developed severe thrombocytopenia in just 31 days after inoculation, and the virus was reisolated from blood, bone marrow, and stool. At necropsy, we observed bleeding from the gingivae and subcutaneous bleeding in all animals. SRV-4 infected a variety of tissues, especially in digestive organs, including colon and stomach, as determined by real-time reverse transcription-PCR (RT-PCR) and immunohistochemical staining. Furthermore, we identified the SRV-4 receptor as ASCT2, a neutral amino acid transporter. ASCT2 mRNA was expressed in a variety of tissues, and the distribution of SRV-4 proviruses in infected Japanese macaques correlated well with the expression levels of ASCT2 mRNA. From these results, we conclude that the causative agent of hemorrhagic syndrome in KUPRI Japanese macaques was SRV-4, and its receptor is ASCT2.