Simian-human immunodeficiency virus SHIV.CH505 infection of rhesus macaques results in persistent viral replication and induces intestinal immunopathology

Katharine J. Bar, Ernesto Coronado, Tiffany Hensley-McBain, Megan A. O’Connor, Jessica M. Osborn, Charlene Miller, Toni M. Gott, Solomon Wangari, Naoto Iwayama, Chul Y. Ahrens, Jeremy Smedley, Cassie Moats, Rebecca M. Lynch, Elias K. Haddad, Nancy Haigwood, Deborah H. Fuller, George M. Shaw, Nichole R. Klatt, Jennifer A. Manuzakb

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Abstract

Simian-human immunodeficiency viruses (SHIVs) have been utilized to test vaccine efficacy and characterize mechanisms of viral transmission and pathogenesis. However, the majority of SHIVs currently available have significant limitations in that they were developed using sequences from chronically HIV-infected individuals or uncommon HIV subtypes or were optimized for the macaque model by serially passaging the engineered virus in vitro or in vivo. Recently, a newly developed SHIV, SHIV.C.CH505.375H.dCT (SHIV.CH505), which incorporates vpu-env (gp140) sequences from a transmitted/founder HIV-1 subtype C strain, was shown to retain attributes of primary HIV-1 strains. However, a comprehensive analysis of the immunopathology that results from infection with this virus, especially in critical tissue compartments like the intestinal mucosa, has not been completed. In this study, we evaluated the viral dynamics and immunopathology of SHIV.CH505 in rhesus macaques. In line with previous findings, we found that SHIV.CH505 is capable of infecting and replicating efficiently in rhesus macaques, resulting in peripheral viral kinetics similar to that seen in pathogenic SIV and HIV infection. Furthermore, we observed significant and persistent depletions of CCR5+ and CCR6+ CD4+ T cells in mucosal tissues, decreases in CD4+ T cells producing Th17 cell-associated cytokines, CD8+ T cell dysfunction, and alterations of B cell and innate immune cell function, indicating that SHIV.CH505 elicits intestinal immunopathology typical of SIV/HIV infection. These findings suggest that SHIV.CH505 recapitulates the early viral replication dynamics and immunopathogenesis of HIV-1 infection of humans and thus can serve as a new model for HIV-1 pathogenesis, treatment, and prevention research. IMPORTANCE The development of chimeric SHIVs has been instrumental in advancing our understanding of HIV-host interactions and allowing for in vivo testing of novel treatments. However, many of the currently available SHIVs have distinct drawbacks and are unable to fully reflect the features characteristic of primary SIV and HIV strains. Here, we utilize rhesus macaques to define the immunopathogenesis of the recently developed SHIV.CH505, which was designed without many of the limitations of previous SHIVs. We observed that infection with SHIV.CH505 leads to peripheral viral kinetics and mucosal immunopathogenesis comparable with those caused by pathogenic SIV and HIV. Overall, these data provide evidence of the value of SHIV.CH505 as an effective model of SIV/HIV infection and an important tool that can be used in future studies, including preclinical testing of new therapies or prevention strategies.

Original languageEnglish (US)
Article numbere00372-19
JournalJournal of virology
Volume93
Issue number18
DOIs
StatePublished - Sep 1 2019

Fingerprint

immunopathology
Simian Immunodeficiency Virus
Human immunodeficiency virus
virus replication
Macaca mulatta
HIV
Infection
infection
Human immunodeficiency virus 1
HIV infections
HIV Infections
HIV-1
T-lymphocytes
pathogenesis
T-Lymphocytes
kinetics
viruses
testing
intestinal mucosa

Keywords

  • Immunopathogenesis
  • Mucosal immunity
  • Nonhuman primate
  • SHIV

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Bar, K. J., Coronado, E., Hensley-McBain, T., O’Connor, M. A., Osborn, J. M., Miller, C., ... Manuzakb, J. A. (2019). Simian-human immunodeficiency virus SHIV.CH505 infection of rhesus macaques results in persistent viral replication and induces intestinal immunopathology. Journal of virology, 93(18), [e00372-19]. https://doi.org/10.1128/JVI.00372-19

Simian-human immunodeficiency virus SHIV.CH505 infection of rhesus macaques results in persistent viral replication and induces intestinal immunopathology. / Bar, Katharine J.; Coronado, Ernesto; Hensley-McBain, Tiffany; O’Connor, Megan A.; Osborn, Jessica M.; Miller, Charlene; Gott, Toni M.; Wangari, Solomon; Iwayama, Naoto; Ahrens, Chul Y.; Smedley, Jeremy; Moats, Cassie; Lynch, Rebecca M.; Haddad, Elias K.; Haigwood, Nancy; Fuller, Deborah H.; Shaw, George M.; Klatt, Nichole R.; Manuzakb, Jennifer A.

In: Journal of virology, Vol. 93, No. 18, e00372-19, 01.09.2019.

Research output: Contribution to journalArticle

Bar, KJ, Coronado, E, Hensley-McBain, T, O’Connor, MA, Osborn, JM, Miller, C, Gott, TM, Wangari, S, Iwayama, N, Ahrens, CY, Smedley, J, Moats, C, Lynch, RM, Haddad, EK, Haigwood, N, Fuller, DH, Shaw, GM, Klatt, NR & Manuzakb, JA 2019, 'Simian-human immunodeficiency virus SHIV.CH505 infection of rhesus macaques results in persistent viral replication and induces intestinal immunopathology', Journal of virology, vol. 93, no. 18, e00372-19. https://doi.org/10.1128/JVI.00372-19
Bar, Katharine J. ; Coronado, Ernesto ; Hensley-McBain, Tiffany ; O’Connor, Megan A. ; Osborn, Jessica M. ; Miller, Charlene ; Gott, Toni M. ; Wangari, Solomon ; Iwayama, Naoto ; Ahrens, Chul Y. ; Smedley, Jeremy ; Moats, Cassie ; Lynch, Rebecca M. ; Haddad, Elias K. ; Haigwood, Nancy ; Fuller, Deborah H. ; Shaw, George M. ; Klatt, Nichole R. ; Manuzakb, Jennifer A. / Simian-human immunodeficiency virus SHIV.CH505 infection of rhesus macaques results in persistent viral replication and induces intestinal immunopathology. In: Journal of virology. 2019 ; Vol. 93, No. 18.
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abstract = "Simian-human immunodeficiency viruses (SHIVs) have been utilized to test vaccine efficacy and characterize mechanisms of viral transmission and pathogenesis. However, the majority of SHIVs currently available have significant limitations in that they were developed using sequences from chronically HIV-infected individuals or uncommon HIV subtypes or were optimized for the macaque model by serially passaging the engineered virus in vitro or in vivo. Recently, a newly developed SHIV, SHIV.C.CH505.375H.dCT (SHIV.CH505), which incorporates vpu-env (gp140) sequences from a transmitted/founder HIV-1 subtype C strain, was shown to retain attributes of primary HIV-1 strains. However, a comprehensive analysis of the immunopathology that results from infection with this virus, especially in critical tissue compartments like the intestinal mucosa, has not been completed. In this study, we evaluated the viral dynamics and immunopathology of SHIV.CH505 in rhesus macaques. In line with previous findings, we found that SHIV.CH505 is capable of infecting and replicating efficiently in rhesus macaques, resulting in peripheral viral kinetics similar to that seen in pathogenic SIV and HIV infection. Furthermore, we observed significant and persistent depletions of CCR5+ and CCR6+ CD4+ T cells in mucosal tissues, decreases in CD4+ T cells producing Th17 cell-associated cytokines, CD8+ T cell dysfunction, and alterations of B cell and innate immune cell function, indicating that SHIV.CH505 elicits intestinal immunopathology typical of SIV/HIV infection. These findings suggest that SHIV.CH505 recapitulates the early viral replication dynamics and immunopathogenesis of HIV-1 infection of humans and thus can serve as a new model for HIV-1 pathogenesis, treatment, and prevention research. IMPORTANCE The development of chimeric SHIVs has been instrumental in advancing our understanding of HIV-host interactions and allowing for in vivo testing of novel treatments. However, many of the currently available SHIVs have distinct drawbacks and are unable to fully reflect the features characteristic of primary SIV and HIV strains. Here, we utilize rhesus macaques to define the immunopathogenesis of the recently developed SHIV.CH505, which was designed without many of the limitations of previous SHIVs. We observed that infection with SHIV.CH505 leads to peripheral viral kinetics and mucosal immunopathogenesis comparable with those caused by pathogenic SIV and HIV. Overall, these data provide evidence of the value of SHIV.CH505 as an effective model of SIV/HIV infection and an important tool that can be used in future studies, including preclinical testing of new therapies or prevention strategies.",
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T1 - Simian-human immunodeficiency virus SHIV.CH505 infection of rhesus macaques results in persistent viral replication and induces intestinal immunopathology

AU - Bar, Katharine J.

AU - Coronado, Ernesto

AU - Hensley-McBain, Tiffany

AU - O’Connor, Megan A.

AU - Osborn, Jessica M.

AU - Miller, Charlene

AU - Gott, Toni M.

AU - Wangari, Solomon

AU - Iwayama, Naoto

AU - Ahrens, Chul Y.

AU - Smedley, Jeremy

AU - Moats, Cassie

AU - Lynch, Rebecca M.

AU - Haddad, Elias K.

AU - Haigwood, Nancy

AU - Fuller, Deborah H.

AU - Shaw, George M.

AU - Klatt, Nichole R.

AU - Manuzakb, Jennifer A.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Simian-human immunodeficiency viruses (SHIVs) have been utilized to test vaccine efficacy and characterize mechanisms of viral transmission and pathogenesis. However, the majority of SHIVs currently available have significant limitations in that they were developed using sequences from chronically HIV-infected individuals or uncommon HIV subtypes or were optimized for the macaque model by serially passaging the engineered virus in vitro or in vivo. Recently, a newly developed SHIV, SHIV.C.CH505.375H.dCT (SHIV.CH505), which incorporates vpu-env (gp140) sequences from a transmitted/founder HIV-1 subtype C strain, was shown to retain attributes of primary HIV-1 strains. However, a comprehensive analysis of the immunopathology that results from infection with this virus, especially in critical tissue compartments like the intestinal mucosa, has not been completed. In this study, we evaluated the viral dynamics and immunopathology of SHIV.CH505 in rhesus macaques. In line with previous findings, we found that SHIV.CH505 is capable of infecting and replicating efficiently in rhesus macaques, resulting in peripheral viral kinetics similar to that seen in pathogenic SIV and HIV infection. Furthermore, we observed significant and persistent depletions of CCR5+ and CCR6+ CD4+ T cells in mucosal tissues, decreases in CD4+ T cells producing Th17 cell-associated cytokines, CD8+ T cell dysfunction, and alterations of B cell and innate immune cell function, indicating that SHIV.CH505 elicits intestinal immunopathology typical of SIV/HIV infection. These findings suggest that SHIV.CH505 recapitulates the early viral replication dynamics and immunopathogenesis of HIV-1 infection of humans and thus can serve as a new model for HIV-1 pathogenesis, treatment, and prevention research. IMPORTANCE The development of chimeric SHIVs has been instrumental in advancing our understanding of HIV-host interactions and allowing for in vivo testing of novel treatments. However, many of the currently available SHIVs have distinct drawbacks and are unable to fully reflect the features characteristic of primary SIV and HIV strains. Here, we utilize rhesus macaques to define the immunopathogenesis of the recently developed SHIV.CH505, which was designed without many of the limitations of previous SHIVs. We observed that infection with SHIV.CH505 leads to peripheral viral kinetics and mucosal immunopathogenesis comparable with those caused by pathogenic SIV and HIV. Overall, these data provide evidence of the value of SHIV.CH505 as an effective model of SIV/HIV infection and an important tool that can be used in future studies, including preclinical testing of new therapies or prevention strategies.

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KW - Immunopathogenesis

KW - Mucosal immunity

KW - Nonhuman primate

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