A unique spumavirus Gag N-terminal domain with functional properties of orthoretroviral matrix and capsid.

The Spumaretrovirinae, or foamyviruses (FVs) are complex retroviruses that infect many species of monkey and ape. Although FV infection is apparently benign, trans-species zoonosis is commonplace and has resulted in the isolation of the Prototypic Foamy Virus (PFV) from human sources and the potential for germ-line transmission. Despite little sequence homology, FV and orthoretroviral Gag proteins perform equivalent functions, including genome packaging, virion assembly, trafficking and membrane targeting. In addition, PFV Gag interacts with the FV Envelope (Env) protein to facilitate budding of infectious particles. Presently, there is a paucity of structural information with regards FVs and it is unclear how disparate FV and orthoretroviral Gag molecules share the same function. Therefore, in order to probe the functional overlap of FV and orthoretroviral Gag and learn more about FV egress and replication we have undertaken a structural, biophysical and virological study of PFV-Gag. We present the crystal structure of a dimeric amino terminal domain from PFV, Gag-NtD, both free and in complex with the leader peptide of PFV Env. The structure comprises a head domain together with a coiled coil that forms the dimer interface and despite the shared function it is entirely unrelated to either the capsid or matrix of Gag from other retroviruses. Furthermore, we present structural, biochemical and virological data that reveal the molecular details of the essential Gag-Env interaction and in addition we also examine the specificity of Trim5α restriction of PFV. These data provide the first information with regards to FV structural proteins and suggest a model for convergent evolution of gag genes where structurally unrelated molecules have become functionally equivalent.

Foamy virus envelope protein is a substrate for signal peptide peptidase-like 3 (SPPL3).

Signal peptide peptidase (SPP), its homologs, the SPP-like proteases SPPL2a/b/c and SPPL3, as well as presenilin, the catalytic subunit of the γ-secretase complex, are intramembrane-cleaving aspartyl proteases of the GxGD type. In this study, we identified the 18-kDa leader peptide (LP18) of the foamy virus envelope protein (FVenv) as a new substrate for intramembrane proteolysis by human SPPL3 and SPPL2a/b. In contrast to SPPL2a/b and γ-secretase, which require substrates with an ectodomain shorter than 60 amino acids for efficient intramembrane proteolysis, SPPL3 cleaves mutant FVenv lacking the proprotein convertase cleavage site necessary for the prior shedding. Moreover, the cleavage product of FVenv generated by SPPL3 serves as a new substrate for consecutive intramembrane cleavage by SPPL2a/b. Thus, human SPPL3 is the first GxGD-type aspartyl protease shown to be capable of acting like a sheddase, similar to members of the rhomboid family, which belong to the class of intramembrane-cleaving serine proteases.

Simian foamy virus prevalence in Macaca mulatta and zookeepers.

The simian foamy virus (SFV) has been reported to be transmissible among humans occupationally exposed to nonhuman primates. Nevertheless, epidemiological and genotypic data on the SFV in Macaca mulatta and zookeepers in China are limited. In the present study, SFV proviral DNA was detected in 74 blood samples from M. mulatta and 12 saliva specimens from zookeepers by nested polymerase chain reaction. A total of 29 blood samples from M. mulatta (29/74, 39.19%) and two saliva specimens from zookeepers (2/12, 16.67%) were positive. The phylogenetic analysis indicated that these SFV strains shared the highest homology with Macaca fascicularis (93.4%). The two SFV strains infected human beings, and shared the highest homology of 98.6% with each other as well as 90.8-99.5% with M. mulatta. The investigation revealed the high prevalence of the SFV in M. mulatta in China and its zoonotic transmission to humans.

Foamy retrovirus integrase contains a Pol dimerization domain required for protease activation.

Unlike orthoretroviruses, foamy retroviruses (FV) synthesize Pol independently of Gag. The FV Pol precursor is cleaved only once between reverse transcriptase (RT) and integrase (IN) by the protease (PR), resulting in a PR-RT and an IN protein. Only the Pol precursor, not the cleaved subunits, is packaged into virions. Like orthoretroviral PRs, FV PR needs to dimerize to be active. Previously, we showed that a Pol mutant lacking IN has defects in PR activity and Pol packaging into virions. We now show that introduction of a leucine zipper (zip) dimerization motif in an IN truncation mutant can restore PR activity, leading to Pol processing in cells. However, these zip mutants neither cleave Gag nor incorporate Pol into virions. We propose that IN is required for Pol dimerization, which is necessary for the creation of a functional PR active site.

On the general theory of the origins of retroviruses.

BACKGROUND: The order retroviridae comprises viruses based on ribonucleic acids (RNA). Some, such as HIV and HTLV, are human pathogens. Newly emerged human retroviruses have zoonotic origins. As far as has been established, both repeated infections (themselves possibly responsible for the evolution of viral mutations (Vm) and host adaptability (Ha)); along with interplay between inhibitors and promoters of cell tropism, are needed to effect retroviral cross-species transmissions. However, the exact modus operandi of intertwine between these factors at molecular level remains to be established. Knowledge of such intertwine could lead to a better understanding of retrovirology and possibly other infectious processes. This study was conducted to derive the mathematical equation of a general theory of the origins of retroviruses. METHODS AND RESULTS: On the basis of an arbitrarily non-Euclidian geometrical "thought experiment" involving the cross-species transmission of simian foamy virus (sfv) from a non-primate species Xy to Homo sapiens (Hs), initially excluding all social factors, the following was derived. At the port of exit from Xy (where the species barrier, SB, is defined by the Index of Origin, IO), sfv shedding is (1) enhanced by two transmitting tensors (Tt), (i) virus-specific immunity (VSI) and (ii) evolutionary defenses such as APOBEC, RNA interference pathways, and (when present) expedited therapeutics (denoted e2D); and (2) opposed by the five accepting scalars (At): (a) genomic integration hot spots, gIHS, (b) nuclear envelope transit (NMt) vectors, (c) virus-specific cellular biochemistry, VSCB, (d) virus-specific cellular receptor repertoire, VSCR, and (e) pH-mediated cell membrane transit, (downward arrow pH CMat). Assuming As and Tt to be independent variables, IO = Tt/As. The same forces acting in an opposing manner determine SB at the port of sfv entry (defined here by the Index of Entry, IE = As/Tt). Overall, If sfv encounters no unforeseen effects on transit between Xy and Hs, then the square root of the combined index of sfv transmissibility (radical |RTI|) is proportional to the product IO* IE (or approximately Vm* Ha* sum Tt* sum As*Omega), where Omega is the retrovirological constant and summation operator is a function of the ratio Tt/As or As/Tt for sfv transmission from Xy to Hs. CONCLUSIONS: I present a mathematical formalism encapsulating the general theory of the origins of retroviruses. It summarizes the choreography for the intertwined interplay of factors influencing the probability of retroviral cross-species transmission: Vm, Ha, Tt, As, and Omega.