Effective treatment of SIVcpz-induced immunodeficiency in a captive western chimpanzee

Hannah J Barbian,Katharine J Bar,Frederic Bibollet-Ruche,Beatrice H Hahn,Corrine S Brown,Gerald H Learn,Thomas N Denny,Raven Jackson-Jewett,Paul M Sharp,George M Shaw,Jeffrey Lifson,Michael S Saag,Edward F Kreider,Yingying Li,Edward P Acosta,Timothy Decker

doi:10.1186/s12977-017-0359-0

Abstract

BackgroundSimian immunodeficiency virus of chimpanzees (SIVcpz), the progenitor of human immunodeficiency virus type 1 (HIV-1), is associated with increased mortality and AIDS-like immunopathology in wild-living chimpanzees (Pan troglodytes). Surprisingly, however, similar findings have not been reported for chimpanzees experimentally infected with SIVcpz in captivity, raising questions about the intrinsic pathogenicity of this lentivirus.FindingsHere, we report progressive immunodeficiency and clinical disease in a captive western chimpanzee (P. t. verus) infected twenty years ago by intrarectal inoculation with an SIVcpz strain (ANT) from a wild-caught eastern chimpanzee (P. t. schweinfurthii). With sustained plasma viral loads of 105 to 106 RNA copies/ml for the past 15 years, this chimpanzee developed CD4+ T cell depletion (220 cells/μl), thrombocytopenia (90,000 platelets/μl), and persistent soft tissue infections refractory to antibacterial therapy. Combination antiretroviral therapy consisting of emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and dolutegravir (DTG) decreased plasma viremia to undetectable levels (<200 copies/ml), improved CD4+ T cell counts (509 cell/μl), and resulted in the rapid resolution of all soft tissue infections. However, initial lack of adherence and/or differences in pharmacokinetics led to low plasma drug concentrations, which resulted in transient rebound viremia and the emergence of FTC resistance mutations (M184V/I) identical to those observed in HIV-1 infected humans.ConclusionsThese data demonstrate that SIVcpz can cause immunodeficiency and other hallmarks of AIDS in captive chimpanzees, including P. t. verus apes that are not naturally infected with this virus. Moreover, SIVcpz-associated immunodeficiency can be effectively treated with antiretroviral therapy, although sufficiently high plasma concentrations must be maintained to prevent the emergence of drug resistance. These findings extend a growing body of evidence documenting the immunopathogenicity of SIVcpz and suggest that experimentally infected chimpanzees may benefit from clinical monitoring and therapeutic intervention.

Highlights

Simian immunodeficiency virus of chimpanzees (SIVcpz), the progenitor of human immunodeficiency virus type 1 (HIV-1), is associated with increased mortality and acquired immunodeficiency syndrome (AIDS)-like immunopathology in wild-living chimpan‐ zees (Pan troglodytes)
SIVcpz-associated immunodeficiency can be effectively treated with antiretroviral therapy, sufficiently high plasma concentra‐ tions must be maintained to prevent the emergence of drug resistance
These findings extend a growing body of evidence documenting the immunopathogenicity of SIVcpz and suggest that experimentally infected chimpanzees may benefit from clinical monitoring and therapeutic intervention

Summary

Introduction

Simian immunodeficiency virus of chimpanzees (SIVcpz), the progenitor of human immunodeficiency virus type 1 (HIV-1), is associated with increased mortality and AIDS-like immunopathology in wild-living chimpan‐ zees (Pan troglodytes). Other mutations known to be associated with TFV and DVG resistance were not observed in any of the post-treatment sequences, and the most recent plasma sample, which was RT-qPCR negative (1/17/17), failed to yield pol amplicons, suggesting complete virus suppression.

Results

Conclusion