Pathogenic Features Associated with Increased Virulence upon Simian Immunodeficiency Virus Cross-Species Transmission from Natural Hosts

Abstract

While simian immunodeficiency viruses (SIVs) are generally nonpathogenic in their natural hosts, dramatic increases in pathogenicity may occur upon cross-species transmission to new hosts. Deciphering the drivers of these increases in virulence is of major interest for understanding the emergence of new human immunodeficiency viruses (HIVs). We transmitted SIVsab from the sabaeus species of African green monkeys (AGMs) to pigtailed macaques (PTMs). High acute viral replication occurred in all SIVsab-infected PTMs, yet the outcome of chronic infection was highly variable, ranging from rapid progression to controlled infection, which was independent of the dynamics of acute viral replication, CD4؉ T cell depletion, or preinfection levels of microbial translocation. Infection of seven PTMs with plasma collected at necropsy from a rapid-progressor PTM was consistently highly pathogenic, with high acute and chronic viral replication, massive depletion of memory CD4 ؉ T cells, and disease progression in all PTMs. The plasma inoculum used for the serial passage did not contain adventitious bacterial or viral contaminants. Single-genome amplification showed that this inoculum was significantly more homogenous than the inoculum directly derived from AGMs, pointing to a strain selection in PTMs. In spite of similar peak plasma viral loads between the monkeys in the two passages, immune activation/inflammation levels dramatically increased in PTMs infected with the passaged virus. These results suggest that strain selection and a massive cytokine storm are major factors behind increased pathogenicity of SIV upon serial passage and adaptation of SIVs to new hosts following cross-species transmission. IMPORTANCEWe report here that upon cross-species transmission and serial passage of SIVsab from its natural host, the sabaeus African green monkey (AGM), to a new host, the pigtailed macaque (PTM), viral adaptation and increased pathogenicity involve strain selection and a massive cytokine storm. These results permit the design of strategies aimed at preventing cross-species transmission from natural hosts of SIVs to humans in areas of endemicity. Furthermore, our study describes a new animal model for SIV infection. As the outcomes of SIVsab infection in PTMs, African green monkeys, and rhesus macaques are different, the use of these systems enables comparative studies between pathogenic, nonpathogenic, and elite-controlled infections, to gain insight into the mechanisms of SIV immunodeficiency and comorbidities.

Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

“…All the animals were males, aged 4 to 9 years old. They were infected with plasma equivalent to 300 50% tissue culture infectious doses (TCID 50 ) of SIVsab (49). The follow-up was for 180 days postinfection (dpi) or until progression to AIDS.…”

“…Notably, the vast majority of these studies focused on T cells from peripheral blood. Since progressive HIV/SIV infections are characterized by profound mucosal dysfunction caused by increased cell death associated with high virus replication and inflammatory responses (3,22,(49)(50)(51), we studied the changes in CD39 and CD73 expression on Tregs from the gut of SIV-infected nonhuman primates (NHPs). We also aimed to better understand the role of the ADO pathway in modulating immune activation/inflammation during HIV/SIV infection.…”

“…We assessed CD39 and CD73 expression on CD4 ϩ and CD8 ϩ Tregs isolated from blood, lymph node (LN), and intestine from progressor pigtailed macaques (PTMs) (10,24,49) and nonprogressor AGMs (17,52,53) infected with the same SIVsab strain. We report that CD39 and CD73 are coexpressed predominantly at mucosal sites and that the coexpression levels of these two molecules on CD4 ϩ and CD8 ϩ Tregs are higher in AGMs than in PTMs.…”

Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

“…To this end, we used SIVsab-infected pigtailed macaques (PTMs), a new animal model of pathogenic SIV infection developed in our laboratory. The advantage of SIVsab-infected PTMs over the conventional AIDS macaque models is that SIVsab infection in PTMs is more suited for the study of AIDS-related comorbidities, being characterized by a robust viral replication, consistent high levels of microbial translocation associated with dramatic increases in the immune activation/ inflammation, and a high rate of cardiovascular comorbidities, i.e., hypercoagulopathy (9,14).…”

Simian Immunodeficiency Virus SIVsab Infection of Rhesus Macaques as a Model of Complete Immunological Suppression with Persistent Reservoirs of Replication-Competent Virus: Implications for Cure Research

“…Eleven RMs were inoculated intravenously with plasma samples equivalent to 300 tissue culture infectious doses at 50% (TCID 50 ) of SIVsab92018. The same virus strain induces a persistent nonprogressive infection in the natural African green monkey (AGM) host (13,15) and a pathogenic progressive infection in pigtailed macaques (16)(17)(18). The remaining two RMs were inoculated with plasma samples collected from SIVsab92018 controllers collected at 4 years postinfection (p.i.…”