HUMAN FOAMY VIRUS (HFV)

 

 

The human foamy virus (HFV) was first isolated and identified in 1971 from cells released from a human nasopharyngeal carcinoma (NPC) in a Kenyan patient. At the time it was called SFVcpz(hu) because of its origin and its marked similarity to the Simian Foamy Virus found in chimpanzees. The origin of SFVcpz(hu) was debated until 1994, when SFVcpz was cloned and sequenced; the 86 to 95% amino acid identity between SFVcpz and SFVcpz(hu) suggested that SFVcpz(hu) is likely a variant of SFVcpz and not a unique isolate. Recently, sequence comparisons between the original SFVcpz(hu) isolate and SFV from four distinct subspecies of chimpanzee demonstrate that SFVcpz(hu) is most closely related to foamy viruses found in Pan troglodytes schweinfurthii, whose natural habitat includes Kenya. Since the original HFV isolate came from a man who might have had contact with P. troglodytes schweinfurthii in Kenya, the virus was probably acquired as a zoonotic infection.


HFV belongs to the genus of spumaviruses. Although it has been isolated from patients with various neoplastic and degenerative diseases such as myasthenia gravis, multiple sclerosis, thyroditis de Quervain and Graves’ disease, an etiological role for the virus has yet to be identified and little is known about its prevalence in human populations. There is also a lot of controversy about the criteria used to identify the isolate as HFV in most of these early studies, and so it may be that HFV is really an orphan virus and is just coincidentally associated with these disorders.


Like other Foamy Viruses, HFV has many characteristics that set it apart from the other well-known retroviruses, including a distinct morphology, budding from the endoplasmic reticulum rather than the plasma membrane and a unique replication strategy.

 

HFV particles shown budding from the ER (note immature particle appearance and characteristic envelope spikes)

Foamy Viruses are considered complex retroviruses because they encode viral proteins that are not incorporated into viral particles. The HFV genome encodes the canonical retroviral gag, pol, and env genes, as well as at least two additional genes termed tas (bel-1) and bet. Although a number of putative functions have been proposed for the bet gene, its role in vivo is still unknown. The tas gene (transactivator of spumavirus) is however, known to be required for viral replication. It encodes a protein that transactivates a long terminal repeat (LTR) promoter, which remains transcriptionally silent in the absence of Tas. HFV is also known to have a second promoter, termed the internal promoter (IP) located within the env gene, which drives tas and bet gene expression and is also transactivated by Tas protein. During the early stages of infection, the IP directs the synthesis of tas and bet mRNAs. Once the Tas protein is synthesized, transcription begins from the LTR, leading to the accumulation of gag, pol, and env mRNAs and ultimately to new viral particles.


The retroviral structural genes also behave in a distinctive way in HFV. The virus particle has an immature appearance because the Gag protein is not efficiently cleaved into the mature viral proteins seen in most other retroviruses. The Pol precursor protein is only partially cleaved, and after protease cleaves the integrase domain, it leaves the protease and reverse transcriptase domains in the same molecule. The Env protein is cleaved into surface and transmembrane domains, as in other retroviruses, but it contains an endoplasmic reticulum retention signal as a result of which HFV has the distinction of budding from the ER.

 

HFV Life Cycle

HFV replication also differs from conventional retroviruses, and in many ways resembles that of the Hepadnaviridae more closely. The figure shows an outline of HFV replication, with the unique aspects in red text and arrows, and non-unique stages in black. Reverse transcription occurs at a late step in the replication cycle, resulting in infectious HFV particles with DNA not RNA which has raised the question of whether HFV is a DNA or an RNA virus. Incomplete cleavage of the Gag protein by viral protease during maturation means that HFV doesn’t contain matrix, capsid, and nucleocapsid proteins, only two large Gag proteins. Particles bud from cells primarily through the endoplasmic reticulum. HFV’s cellular receptor hasn’t yet been identified, but must be ubiquitous, since HFV has a wide tropism.

Source:  Historical Perspective of Foamy Virus Epidemiology and Infection (Meiering et al. Clinical Microbiology Reviews, January 2001)