The antiviral activity of rodent and lagomorph SERINC3 and SERINC5 is counteracted by known viral antagonists.

A first step towards the development of a human immunodeficiency virus (HIV) animal model has been the identification and surmounting of species-specific barriers encountered by HIV along its replication cycle in cells from small animals. Serine incorporator proteins 3 (SERINC3) and 5 (SERINC5) were recently identified as restriction factors that reduce HIV-1 infectivity. Here, we compared the antiviral activity of SERINC3 and SERINC5 among mice, rats and rabbits, and their susceptibility to viral counteraction to their human counterparts. In the absence of viral antagonists, rodent and lagomorph SERINC3 and SERINC5 displayed anti-HIV activity in a similar range to human controls. Vesicular stomatitis virus G protein (VSV-G) pseudotyped virions were considerably less sensitive to restriction by all SERINC3/5 orthologs. Interestingly, HIV-1 Nef, murine leukemia virus (MLV) GlycoGag and equine infectious anemia virus (EIAV) S2 counteracted the antiviral activity of all SERINC3/5 orthologs with similar efficiency. Our results demonstrate that the antiviral activity of SERINC3/5 proteins is conserved in rodents and rabbits, and can be overcome by all three previously reported viral antagonists

HIV-1 Antagonism of CD317 is species specific and involves Vpu-mediated proteasomal degradation of the restriction factor

SummaryMammals encode proteins that inhibit viral replication at the cellular level. In turn, certain viruses have evolved genes that can functionally counteract these intrinsic restrictions. Human CD317 (BST-2/HM1.24/tetherin) is a restriction factor that blocks release of human immunodeficiency virus type 1 (HIV-1) from the cell surface and can be overcome by HIV-1 Vpu. Here, we show that mouse and rat CD317 potently inhibit HIV-1 release but are resistant to Vpu. Interspecies chimeras reveal that the rodent-specific resistance and human-specific sensitivity to Vpu antagonism involve all three major structural domains of CD317. To promote virus release, Vpu depletes cellular pools of human CD317, but not of the rodent orthologs, by accelerating its degradation via the 20S proteasome. Thus, HIV-1 Vpu suppresses the expression of the CD317 antiviral factor in human cells, and the species-specific resistance to this suppression may guide the development of small animal models of HIV infection

HIV-1 Vpu affects the anterograde transport and the glycosylation pattern of NTB-A.

HIV-1 Vpu induces downregulation of cell surface NTB-A to evade lysis of HIV-1 infected cells by NK cells. Here we show that Vpu affects the anterograde transport and the glycosylation pattern of NTB-A by a mechanism that is distinct from the Vpu induced downregulation of CD4 and tetherin. In the presence of Vpu, only the high mannose form of NTB-A was detectable, suggesting that Vpu prevented the formation of the mature form of NTB-A. This phenomenon is associated with the ability of Vpu to downregulate cell surface NTB-A by retention of NTB-A within the Golgi-compartment. Furthermore, the Vpu-mediated effect on NTB-A glycosylation is highly conserved among Vpu proteins derived from HIV-1 and SIV and corresponds to the level of downregulation of NTB-A. Together, these results suggest that the reduction of NTB-A from the cell surface is associated with the Vpu-mediated effect on the glycosylation pattern of newly synthesized NTB-A molecules

The biology of A20-binding inhibitors of NF-κB activation (ABINs)

The family of A20‑Binding Inhibitors of NF‑kB (ABINs) consists of three proteins, ABIN‑1, ABIN‑2 and ABIN‑3, which were originally identified as A20‑binding proteins and inhibitors of cytokines and Lipopolysaccharide (LPS) induced NF‑kB activation. ABIN family members have limited sequence homology in a number of short regions that mediate A20‑binding, ubiquitin‑binding, and NF‑kB inhibition. The functional role of A20 binding to ABINs remains unclear, although an adaptor function has been suggested. ABIN‑1 and ABIN‑3 expression is upregulated when cells are triggered by NF‑kB‑activating stimuli, suggesting a role for these ABINs in a negative feedback regulation of NF‑kB signaling. Additional ABIN functions have been reported such as inhibition of TNF‑induced hepatocyte apoptosis, regulation of HIV‑1 replication for ABIN‑1, and Tumor Progression Locus 2 (TPL‑2)‑mediated Extracellular signal‑Regulated Kinase (ERK) activation for ABIN‑2. In mice, ABIN‑1 overexpression reduces allergic airway inflammation and TNF‑mediated liver injury, ABIN‑2 overexpression delays liver regeneration, and ABIN‑3 overexpression partially protects against LPS‑induced acute liver failure. Analysis of mice deficient in ABIN‑1 or ABIN‑2 demonstrates the important immune regulatory function of ABINs. Future studies should clarify the functional implication of the A20‑ABIN interaction in supporting ABINs’ mechanisms of action