HTLV-3/4 and simian foamy retroviruses in humans: discovery, epidemiology, cross-species transmission and molecular virology

Abstract

Non-human primates are considered to be likely sources of viruses that can infect humans and thus pose a significant threat to human population. This is well illustrated by some retroviruses, as the simian immunodeficiency viruses and the simian T lymphotropic viruses, which have the ability to cross-species, adapt to a new host and sometimes spread. This leads to a pandemic situation for HIV-1 or an endemic one for HTLV-1. Here, we present the available data on the discovery, epidemiology, cross-species transmission and molecular virology of the recently discovered HTLV-3 and HTLV-4 deltaretroviruses, as well as the simian foamy retroviruses present in different human populations at risk, especially in central African hunters. We discuss also the natural history in humans of these retroviruses of zoonotic origin (magnitude and geographical distribution, possible inter-human transmission). In Central Africa, the increase of the bushmeat trade during the last decades has opened new possibilities for retroviral emergence in humans, especially in immuno-compromised persons.

Fig. 1

Schematic representation of PTLV-1, -2, -3 and -4 genomic organization and coding potential. PTLVs are complex retroviruses displaying a conserved genomic arrangement. Grey: colored boxes indicating Open Reading Frame (ORF) encoding structural and enzymatic proteins (gag, pro, pol and env); Red: ORF encoding regulatory proteins (Tax, Rex, sHBZ (HTLV-1), APH-2, -3 and -4 (HTLV-2, -3 and -4, respectively)). Blue: ORF encoding auxiliary proteins: p8/p12, p13, p30 for HTLV-1; p10, p11, p28 for HTLV-2 and p8, p9, RoRFII for PTLV-3. The presence of ORFs encoding auxiliary proteins in HTLV-4 sequence was reported from in silico analyses only.

Fig. 2

Schematic representation of HTLV-1, -2 and -3, receptor complexes on T cells. HTLV-1 binding and entry require the presence of heparan sulphate proteoglycans (HSPGs), Neuropilin 1 (NRP-1) and glucose transporter type 1 (GLUT-1) on the surface of activated CD4⁺ cells. On the other hand HTLV-2 preferentially targets CD8+ cells and is more dependent on the level of GLUT-1 and does not require HSPGs. Unlike HTLV-1 and HTLV-2, HTLV-3 binds to primary resting cells that do not express detectable levels of HSPGs, NRP-1 or GLUT-1. GLUT-1 may participate in the final fusion step of entry (Jones et al., 2011). −: cells cannot be infected, +: cells can be infected. Figure was made using Servier Medical Art.

Fig. 3

SFV open reading frames and transcription map. A scheme of SFV genome (chimpanzee strain) and proteins encoded by each mRNA are shown. ORFs are indicated by boxes. The SFV genome includes the canonical retroviral gag, pol and env genes and is flanked by two large LTRs which contain elements crucial for FV transcription. Two additional genes tas and bet encode proteins having regulatory functions. Indeed, the transactivator Tas binds to the 5'LTR and is responsible for the transcription of the structural genes gag, pol and env.

Fig. 4

Observation of foamy virus and foamy viral infected cells. BHK cells were infected with a primary chimpanzee SFV strain (isolated from an SFV-infected hunter, Betsem et al., 2011) (A) and (B) or by the prototypic strain of SFV (C) and (D) at a multiplicity of infection of 10 and fixed 4 days post-infection. (A) Observation of the SFV-infected cells was performed under light microscopy and shows a large FV-induced syncytium with a “foamy” aspect. (B) An immunofluorescent staining was performed as previously described (Calattini et al., 2007). FV antigens are revealed in the green channel and nuclei are stained with DAPI. (C) and (D) Results of the electron microscopy performed on the FV-infected BHK cells. Sections represent FV viral particles at the proximity of the nucleus (C) or near the microtubule network (D). Scale bars represent 10 μm (A), 3 μm (B) or 300 nm (C) and (D).

Fig. 6

Common scenes in villages of rural areas of South and East Cameroon showing possible human exposure to simian retroviruses. (A) Full basket of wild-monkey game for sale. (B) Hunted monkey (C. neglectus) for consumption. (C) Hunted monkey (C. cephus) for sale. (D) Hunter and a monkey (C. nictitans) he just killed. (E) Captive mandrill (M. leucophaeus) used as a pet.

Fig. 5

Schematic representation of the different steps leading to possible retroviral emergence from non-human primates to Humans. Such viral emergence is a multi-step process involving mostly viral transmission per se to Humans by different possible contacts with infected body fluids (initial spill-over) and then spread in the human population. For HTLV-3/4 and simian foamy viruses, the inter-human population diffusion has not been yet demonstrated and the zoonotic strains seems to be mainly restricted in the few persons having been directly in contact with infected NHPs. This is totally different to the situation with the other human retroviruses of zoonotic origin as HIV-1 and HTLV-1, which have became largely epidemic and endemic, respectively.