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.
Bibliographical noteFunding Information:
This work was supported by grant 5R01AI120712 to N.R.K. and grant UM1AI100645 to G.M.S. K.J.B. was supported by the Penn Center for AIDS Research Viral and Molecular Core (P30 AI045008), the BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (UM1AI126620), and CARE: Delaney Collaboratory for AIDS Eradication (UM1AI126619). J.A.M. was supported by grant K01OD024876. M.A.O. was supported by grant T32-AI007140. Research reported in this publication was additionally supported in part by WaNPRC NIH core grant P51OD010425.
We thank all veterinary staff of the Washington National Primate Research Center (WaNPRC) for their aid with this animal study. We thank Philip Barnette for technical assistance with the neutralization assays. This work was supported by grant 5R01AI120712 to N.R.K. and grant UM1AI100645 to G.M.S. K.J.B. was supported by the Penn Center for AIDS Research Viral and Molecular Core (P30 AI045008), the BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (UM1AI126620), and CARE: Delaney Collaboratory for AIDS Eradication (UM1AI126619). J.A.M. was supported by grant K01OD024876. M.A.O. was supported by grant T32-AI007140. Research reported in this publication was additionally supported in part by WaNPRC NIH core grant P51OD010425. J. A. Manuzak performed and analyzed experiments and wrote the paper. N. R. Klatt conceived of the study. K. J. Bar, M. A. O?Connor, R. M. Lynch, D. H. Fuller, E. K. Haddad, and G. M. Shaw assisted with data interpretation and manuscript preparation. E. Coronado, T. Hensley-McBain, J. M. Osborn, C. Miller, and T. M. Gott assisted with tissue processing and flow cytometry. N. L. Haigwood performed antibody and neutralization assays. S. Wangari, N. Iwayama, and C. Y. Ahrens provided research support for animals. J. Smedley and C. Moats provided veterinary support for animals.
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- Mucosal immunity
- Nonhuman primate