Coelacanth SERINC2 Inhibits HIV-1 Infectivity and Is Counteracted by Envelope Glycoprotein from Foamy Virus

Abstract

SERINC5 restricts nef-defective HIV-1 by affecting early steps of the virus life cycle. Distant retroviruses with a wide host-range encode virulent factors in response to the challenge by SERINC5. Yet, the evolutionary origins of this anti-retroviral activity, its prevalence among the paralogs, and its ability to target retroviruses remain understudied. In agreement with previous studies, we find that four human SERINC paralogs inhibit nef-defective HIV-1, with SERINC2 being an exception. Here, we demonstrate that this lack of activity in human SERINC2 is associated with its post-whole genome duplication (WGD) divergence, as evidenced by the ability of pre-WGD orthologs from yeast, fly, and a post-WGD-proximate SERINC2 from coelacanth to inhibit the virus. Intriguingly, Nef is unable to counter coelacanth SERINC2, indicating that such activity was directed towards other retroviruses found in coelacanth (like foamy viruses). However, foamy-derived vectors are intrinsically resistant to the action of SERINC2, and we show that the foamy virus envelope confers this resistance by affecting its steady-state levels. Our study highlights an ancient origin of anti-retroviral activity in SERINCs and a hitherto unknown interaction with a foamy virus. Importance SERINC5 constitutes a critical barrier to the propagation of retroviruses as highlighted by parallel emergence of anti-SERINC5 activities among distant retroviral lineages. Therefore, understanding the origin and evolution of these host factors will provide key information about virus-host relationships that can be exploited for future drug development. Here we show that SERINC5-mediated nef-defective HIV-1 infection inhibition is evolutionarily conserved. SERINC2 from coelacanth restricts HIV-1 and it was functionally adapted to target foamy viruses. Our findings provide insights into the evolutionary origin of anti-retroviral activity in SERINC gene family and uncover the role of SERINCs in shaping the long-term conflicts between retroviruses and their hosts.

Improved loss-of-function CRISPR-Cas9 genome editing in human cells concomitant with inhibition of TGF-β signaling

“…To infect CD4 + primary T cells, we generated HIV-1 particles using HEK293T as a virus producer cells by co-transfecting 7 μg pNL4-3 Env − Nef − and 1 μg pHXB2 X4-tropic envelope 48 in a 10 cm 2 cell culture dish using the calcium phosphate transfection method. The next morning, after 12–15 h, the medium was replaced with fresh medium, and cells were maintained for the next 48 h. Post-incubation, virus-containing supernatant was clarified using centrifugation at 300 × g for 5 min.…”

HIV-1 Vpr induces ciTRAN to prevent transcriptional silencing of the provirus

“…Virus incorporation assay was done as described previously(43). Virus particles (HIV-1 Luc) were produced by transfecting HEK293T cells using calcium phosphate transfection reagent in a 10 cm2 plate, NL4-3 Env-R-Luc, pMD2.G (VSVG) along with 2μg Vpr expressing construct (pEGFP-C2-Vpr) or vector alone.…”

“…Next, the samples were added to a 2mm-gap electroporation cuvette (Bio-Rad, USA). The sample was pulsed at 140V and 1,000 μF with an exponential decay on a Bio-Rad GenePulserXcell module as described previously (43). Warm RPMI (~600 l) with 20% fetal bovine serum (FBS) was immediately added to the electroporated cells, which were then transferred to a 6-well plate containing pre-warmed 10% FBS containing RPMI.…”

The Emerging Role of the Serine Incorporator Protein Family in Regulating Viral Infection

“…However, the antiviral effect of SERINC2 is lost with evolution. This loss in human SERINC2 is associated with its post-whole-genome duplication (post-WGD) divergence (Ramdas et al, 2021). However, HIV Nef and MLV glycoGag do not restrict coelacanth SERINC2.…”