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

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.

CD4 receptor diversity in chimpanzees protects against SIV infection

“…Thus, the requirement to interact with different CD4 alleles may curb SIVcpz transmission and/or reduce viral replication in infected individuals. Interestingly, of three captive chimpanzees that were infected with the same SIVcpz strain (ANT) at the same time over 20 y ago, only the two that were homozygous for the QQNVT allele developed high viral loads and progressed to AIDS (30, 63, 64). The third individual, who is heterozygous for QQNVT and QQNVP alleles, exhibited much lower viral loads and has remained healthy ( SI Appendix , Table S4).…”

“…Even members of chimpanzee subspecies that do not naturally harbor SIVcpz are susceptible to infection and disease. Examples include the transmission of SIVcpz Ptt from a central chimpanzee to a Nigeria-Cameroonian cage mate (29) and the experimental infection of a western chimpanzee with SIVcpz Pts that resulted in high titer viremia, CD4 T cell depletion, and clinical AIDS requiring antiretroviral therapy (30).…”

CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses

“…In HIV-infected humans and SIVmac-infected macaques, continuous high level viral replication leads to CD4 + T cell depletion, systemic immune activation, T cell exhaustion, and the development of AIDS (35,36). Naturally occurring SIVs can also cause immunodeficiency and disease, as shown for chimpanzees and mandrills (37)(38)(39)(40), indicating that these viruses are intrinsically pathogenic (41)(42)(43). However, a number of primate species with presumed longstanding SIV infections, such as African green monkeys, sooty mangabeys, and Ugandan red colobus monkeys (Piliocolobus tephrosceles), have evolved unique mechanisms that prevent disease progression despite continuous high viral replication (44)(45)(46)(47)(48).…”

Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses

“…This pattern held for four diverse SIVcpz isolates representing both subspecies of chimpanzees infected in the wild, including the SIVcpz Ptt lineage that crossed into humans to found the HIV-1 pandemic [ 1 ]. SIVcpz was initially thought to be nonpathogenic in chimpanzees, but subsequent study of wild-living populations and captive primates revealed increased mortality and AIDS-like disease in infected apes [ 10 , 61 , 62 ]. While SIVsmm/SM and SIVagm/AGM infections are well-studied and typically nonprogressive (although a rare case of AIDS-like disease in a very old SIV+ SM has been reported [ 63 ]), the consequences of SIV infection in naturally-infected GSN/MUS/MON monkeys has not been investigated directly.…”