Persistent Zoonotic Infection of a Human with Simian Foamy Virus in the Absence of an Intactorf-2Accessory Gene

Abstract

Although foamy viruses (FVs) are endemic among nonhuman primates, FV infection among humans is rare. Recently, simian foamy virus (SFV) infection was reported in 4 of 231 individuals occupationally exposed to primates (1.8%). Secondary transmission to spouses has not been seen, suggesting that while FV is readily zoonotic, humans may represent dead-end hosts. Among different simian species, SFV demonstrates significant sequence diversity within the U3 region of the long terminal repeat (LTR) and 3′ accessory open reading frames (ORFs). To examine if persistent human SFV infection and apparent lack of secondary transmission are associated with genetic adaptations in FV regulatory regions, we conducted sequence analysis of the LTR, internal promoter, ORF-1, and ORF-2 on a tissue culture isolate and peripheral blood mononuclear cell samples from a human infected with SFV of African green monkey origin (SFV-3). Compared to the prototype SFV-3 sequence, the LTR, internal promoter, and FV transactivator (ORF-1) showed sequence conservation, suggesting that FV zoonosis is not dependent on host-specific adaptation to these transcriptionally important regions. However, ORF-2 contains a number of deleterious mutations predicted to result in premature termination of protein synthesis. ORF-2 codes in part for the 60-kDa Bet fusion protein, proposed to be involved in the establishment of persistent cellular SFV infections. These results suggest that persistent human infection by SFV and reduced transmissibility may be influenced by the absence of a functional ORF-2.

Origin, evolution and innate immune control of simian foamy viruses in humans

“…In the blood, the cellular targets of SFV remain poorly studied. Preliminary studies, performed mostly in small series of chimpanzees, African green monkeys, and in few humans, have shown SFV DNA in lymphocytes, especially CD8+ T cells [25,26]. By studying a larger cohort of humans infected with a gorilla strain of SFV in Cameroon, we demonstrated that CD8+, CD4+ T cells and CD19+ B lymphocytes were preferentially infected, compared to monocytes and NK cells ( Table 1).…”

“…SFV DNA loads in this sorted cell population is 1/10 5 cells (in the 7/9 positive samples from AGM) and 1/10 5 cells (in the 3/4 samples from CPZ). b In the study from Callahan et al [25], only one dilution of leucocytes DNA was shown, corresponding to a viral load of >70 SFV DNA copies/10 5 cells, assuming the usual sensitivity of 1 SFV DNA copies/10 5 cells.…”

“…Genetic stability was also found in SFV-infected humans, with less than 1% divergence in the nucleotide sequence over several years [13,24]. Several groups also reported genetic modifications including mutations in the Bet accessory gene [25,31], deletion in the U3 sequence of the LTR which improves FV replication in vitro [31,32] and deletions in the Tas sequence, which might be linked with the chronicity of the infection [31]. However, most of these modifications are not a unifying trait of zoonotic strains, and can also be found in NHP or experimentally infected animals [31].…”

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

“…Based on available data, SFV transmission among humans has not been yet demonstrated. Indeed, only around 40 family members (mostly spouses) of men infected by SFV have been studied and scored negative Callahan et al, 1999;Heneine et al, 1998;Switzer et al, 2004;Boneva et al, 2007) suggesting that SFV transmission does not occur frequently through sexual contacts or saliva exposure. The persistence of infectious virus in PBMCs, and the identification of infected blood donor (CDC study conducted in North America (Boneva et al, 2002)) had raised safety concerns regarding a potential viral transmission through blood transfusion.…”

“…Several groups also reported genetic modifications including deleterious mutations in the Bet accessory gene in one SFVinfected human (Callahan et al, 1999). Some other features were also reported in humans infected with FVs, although they are probably not specific to human infection.…”