Pathogenic features associated with increased virulence upon Simian immunodeficiency virus cross-species transmission from natural hosts.
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.


OBJECTIVE
We 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.
Division of Microbiology, Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
Daniel T
DT
Mandell
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Jan
J
Kristoff
Division of Microbiology, Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
Thaidra
T
Gaufin
Division of Microbiology, Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
Rajeev
R
Gautam
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Dongzhu
D
Ma
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Netanya
N
Sandler
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
George
G
Haret-Richter
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Cuiling
C
Xu
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Hadega
H
Aamer
Division of Veterinary Medicine, Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
Jason
J
Dufour
Division of Laboratory Animal Resources, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Anita
A
Trichel
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Daniel C
DC
Douek
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
Brandon F
BF
Keele
Division of Microbiology, Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Departments of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA pandrea@pitt.edu apetreic@pitt.edu.
Cristian
C
Apetrei
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Division of Comparative Pathology, Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA pandrea@pitt.edu apetreic@pitt.edu.
Ivona
I
Pandrea
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002522:Chlorocebus aethiops; D006678:HIV / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D015658:HIV Infections / Q000276:immunology / Q000635:transmission / Q000821:virology; D058507:Host Specificity; D006801:Humans; D008254:Macaca nemestrina; D012692:Serial Passage; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000635:transmission* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D014774:Virulence; D014779:Virus Replication