A gorilla reservoir for human T-lymphotropic virus type 4

OPEN Emerging Microbes and Infections (2014) 3, e7; doi:10.1038/emi.2014.7 ß 2014 SSCC. All rights reserved 2222-1751/14 www.nature.com/emi ORIGINAL ARTICLE A gorilla reservoir for human T-lymphotropic virus type 4 Matthew LeBreton1,2,3,*, William M Switzer4,*, Cyrille F Djoko2, Amethyst Gillis2,3, Hongwei Jia4, Michele M Sturgeon4, Anupama Shankar4, Haoqiang Zheng4, Gerard Nkeunen2, Ubald Tamoufe2,3, Ahmadou Nana2, Joseph Le Doux Diffo2, Babila Tafon5, John Kiyang6, Bradley S Schneider3, Donald S Burke7 and Nathan D Wolfe3,8,9 Of the seven known species of human retroviruses only one, human T-cell lymphotropic virus type 4 (HTLV-4), lacks a known animal reservoir. We report the largest screening for simian T-cell lymphotropic virus (STLV-4) to date in a wide range of captive and wild non-human primate (NHP) species from Cameroon. Among the 681 wild and 426 captive NHPs examined, we detected STLV-4 infection only among gorillas by using HTLV-4-specific quantitative polymerase chain reaction. The large number of samples analyzed, the diversity of NHP species examined, the geographic distribution of infected animals relative to the known HTLV-4 case, as well as detailed phylogenetic analyses on partial and full genomes, indicate that STLV-4 is endemic to gorillas, and that rather than being an ancient virus among humans, HTLV-4 emerged from a gorilla reservoir, likely through the hunting and butchering of wild gorillas. Our findings shed further light on the importance of gorillas as keystone reservoirs for the evolution and emergence of human infectious diseases and provide a clear course for preventing HTLV-4 emergence through management of human contact with wild gorillas, the development of improved assays for HTLV-4/STLV-4 detection and the ongoing monitoring of STLV-4 among gorillas and for HTLV-4 zoonosis among individuals exposed to gorilla populations. Emerging Microbes and Infections (2014) 3, e7; doi:10.1038/emi.2014.7; published online 22 January 2014 Keywords: gorilla; human T-lymphotropic virus; primate; retrovirus; simian T-lymphotropic virus; zoonoses INTRODUCTION Human infection with a plethora of simian retroviruses is well documented and has led to global pandemics, exemplified by the human immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV), and local outbreaks, as occurs with simian foamy virus (SFV), simian T-lymphotropic virus (STLV) and occasionally simian immunodeficiency virus (SIV).1–3 Given the demonstrated pandemic potential of retroviruses, a full understanding of the epidemiology and animal reservoirs of zoonotic primate retroviruses is of importance for monitoring and preventing future retrovirus pandemics. The primate origin of these zoonotic infections has been identified by detailed epidemiological and phylogenetic analyses of both human and non-human primate (NHP) retroviruses. Through detailed examination of SIV infections in over 45 NHP species, it has been demonstrated that HIV-1 arose from multiple cross-species transmissions of SIVcpz and SIVgor from chimpanzees and gorillas, to people in west Central Africa.1,2 Similarly, HIV-2 in West Africa originated from multiple introductions of related SIVs from sooty mangabeys.1,2 Many studies have described ongoing zoonotic infection of primate workers, hunters and butchers with SFV from a variety of monkeys and apes and phylogenetic analysis showing that the co-evolution of SFV with NHPs has facilitated accurate identification of the simian origin of infection.3–10 Likewise, phylogenetic analysis has 1 demonstrated that at least three of the four major HTLV lineages, HTLV-1, HTLV-2 and HTLV-3, originated from multiple introductions of their simian virus counterparts in monkeys and apes, STLV-1, STLV-2, and STLV-3, respectively.3,6–8 Thus, STLV and HTLV lineages are called primate T-lymphotropic viruses (PTLVs). Of the four major HTLV lineages, the majority of human infections are caused by HTLV-1, which is conservatively estimated to be responsible for 5–10 million global human infections.11 HTLV2, while less frequent, has also spread globally and like HTLV-1, is transmitted from mother to child through breast feeding, sexual contact and contaminated blood products during transfusion or injection drug use.11 HTLV-1 causes adult T-cell leukemia, HTLVassociated myelopathy/tropical spastic paraperesis and other inflammatory diseases in 2%–5% of infected persons.12,13 HTLV2 is less pathogenic, but is increasingly associated with HTLVassociated myelopathy/tropical spastic paraperesis and some inflammatory diseases.14 HTLV-3 is much less frequent and has only been found in people in Cameroon who have direct contact with NHPs from which they were likely infected.6–8,15,16 No direct evidence of disease or secondary transmission of HTLV-3 has been reported.3,6–8 The fourth HTLV lineage, HTLV-4, was discovered in 2005 in a 48year-old male hunter (1863LE) from rural Cameroon who reported Mosaic (Environment, Health, Data, Technology), Yaoundé, Cameroon; 2Global Viral Cameroon, BP 7039 Yaounde, Cameroon; 3Metabiota, San Francisco, CA 94104, USA; Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA; 5Ape Action Africa, Cameroon, BP 20072 Yaounde, Cameroon; 6Limbe Wildlife Centre, Limbe, Cameroon; 7Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA; 8Program in Human Biology, Stanford University, Stanford, CA 94305, USA and 9Global Viral, San Francisco, CA 94104, USA *These authors contributed equally to this work. Correspondence: M LeBreton; WM Switzer, E-mail: ; Received 3 October 2013; revised 5 December 2013; accepted 10 December 2013 4 A gorilla reservoir for HTLV-4 M LeBreton et al 2 hunting monkeys, chimpanzees, gorillas and other animals.15 The infection of individual 1863LE currently represents the only known human or simian virus in this lineage. As for HTLV-3, person-toperson transmission and disease have yet to be reported for HTLV-4, though both viruses possess genes and motifs believed to be associated with disease potential in HTLV-1 and HTLV-2.8,16–18 Molecular dating suggests that HTLV-4 is the oldest PTLV lineage, having originated some 200 000 years ago (ya).16 The ancient age of the HTLV-4 lineage led to the hypothesis that HTLV-4 is a descendent of an ancestral PTLV that infected humans during their evolutionary history and frequent NHP contact in Africa and represents a rare strain circulating within people in the central African region.16 Alternatively, it has been hypothesized that HTLV-4 originated from a more recent zoonotic infection with a divergent STLV also present in NHPs cohabitating the forests of Cameroon.16 Identification of the simian origin of HTLV-4 would help determine the validity of each hypothesis. While STLV has been found in at least 30 African and Asian NHPs, discovery of (...truncated)