Antagonism of host cell restriction and sensing by HIV‑1 Nef

Project Member

Prof. Dr. Oliv­er Till Fackler

Project Leader

Prof. Dr. Oliver Till Fackler

Phone: +49 6221 56 – 1322

Research Group Fackler

Depart­ment of Infec­tious Diseases
Inte­gra­tive Virology
Uni­ver­si­ty Hos­pi­tal Heidelberg
Im Neuen­heimer Feld 344
69120 Heidelberg

Leon Dani­au,
PhD Student

Project Summary

The puta­tive Ser­ine Incor­po­ra­tors SERINC3 (S3) and SERINC5 (S5) were recent­ly described as potent inhibitors of the infec­tiv­i­ty of HIV par­ti­cles that are effi­cient­ly coun­ter­act­ed by HIV‑1 Nef. The cur­rent mech­a­nis­tic mod­el of S3/​5 as anti-retro­vi­ral restric­tion fac­tors pre­dicts that viri­on incor­po­ra­tion of S3/​5 is a pre­req­ui­site for restric­tion and that Nef reroutes the restric­tion fac­tors away from the plas­ma mem­brane of virus pro­duc­ing cells to exclude them from viri­ons and thus main­tain their infec­tiv­i­ty. Our pre­lim­i­nary results obtained in prepa­ra­tion of this pro­pos­al defined a com­plex set of mol­e­c­u­lar deter­mi­nants in Nef that gov­ern S5 antag­o­nism and sug­gest that intra­cel­lu­lar rerout­ing of the restric­tion fac­tor may be dis­pens­able for antagonism.
Build­ing on these ini­tial find­ings, we now aim at defin­ing mol­e­c­u­lar prin­ci­ples of the S3/​5‑mediated restric­tion of HIV‑1 par­ti­cle infec­tiv­i­ty and Nef antag­o­nism there­of and at assess­ing in which phys­i­o­log­i­cal­ly rel­e­vant pri­ma­ry cells the SERINC restric­tion is at work. In addi­tion to struc­ture-func­tion analy­ses in cell lines and pri­ma­ry cells, this will include the analy­sis of viri­on mor­phol­o­gy and lipid com­po­si­tion as well as the iden­ti­fi­ca­tion of involved host cell machin­ery. Our pre­lim­i­nary evi­dence also sug­gests that S5 sen­si­tizes HIV par­ti­cles to innate immune recog­ni­tion and that Nef also antag­o­nizes this activ­i­ty. A sec­ond line of inves­ti­ga­tion of this project will there­fore address the immuno­log­i­cal con­se­quences of the SERINC restriction.
These analy­ses will focus on defin­ing the speci­fici­ty and antivi­ral poten­cy of this response, iden­ti­fy­ing viral and host cell com­po­nents elic­it­ing this response, and dis­sect­ing the mech­a­nisms by which Nef antag­o­nizes this effect. Togeth­er, these stud­ies will yield insight into the mol­e­c­u­lar mech­a­nisms of SERINC restric­tion and Nef antag­o­nism as well as the patho-phys­i­o­log­i­cal con­se­quences of the SERINC restriction.

Fig. 1: Cyto­plas­mic host cell restric­tions to human immun­od­e­fi­cien­cy virus types 1 (HIV‑1) infec­tion and viral­ly encod­ed antag­o­nists. Schemat­ic depic­tion of the HIV‑1 life cycle in the cyto­plasm of a tar­get cell with some restric­tion fac­tors (RF) and their viral antag­o­nists indi­cat­ed. Ear­ly post entry steps of HIV‑1 repli­ca­tion are par­tic­u­lar­ly tar­get­ed by host cell restric­tion fac­tors includ­ing TRIM5α and Mx2 that rec­og­nize viral cores and may affect their sta­bil­i­ty. Uncoat­ing of viral cap­sids ren­ders viral RNA genomes acces­si­ble to host cell nucle­as­es such as TREX1 that reduce innate immune recog­ni­tion by the host cell and thus ben­e­fit HIV repli­ca­tion. Such a strat­e­gy may be exploit­ed by the HIV‑1 Vpr pro­tein that acti­vates the SLX4 endonu­cle­ase com­plex. Reverse tran­scrip­tion of viral RNA genomes into DNA is tar­get­ed by the cyti­dine deam­i­nase activ­i­ty of the apolipopro­tein B mRNA edit­ing enzyme, cat­alyt­ic polypep­tide-like (APOBEC) pro­teins and the triphos­pho­hy­dro­lase SAMHD1, which are antag­o­nized by the viral pro­teins Vif and Vpx (Vpx is only encod­ed bythe human immun­od­e­fi­cien­cy virus type 2 (HIV‑2) and the simi­an immun­od­e­fi­cien­cy virus (SIV) and is lack­ing in HIV‑1). Reverse tran­scrip­tion prod­ucts are rec­og­nized by cyto­plas­mic DNA sen­sors such as cGAS and Ifi-16 to trig­ger innate immune respons­es. Dur­ing virus pro­duc­tion, trans­la­tion of viral mRNA can be restrict­ed by Schlafen11 (SLFN11). At the late stages of par­ti­cle pro­duc­tion, viral prog­e­ny is trapped at the cell sur­face by teth­erin (THN), a restric­tion antag­o­nized by Vpu. The infec­tiv­i­ty of released par­ti­cles can be sig­nif­i­cant­ly com­pro­mised by the new­ly described restric­tion fac­tors ser­ine incor­po­ra­tor 3 and 5 (SERINC3/​5) and their antivi­ral activ­i­ty is antag­o­nized by Nef.

From: Fack­ler, O.T. (2015). Spot­light on HIV‑1 Nef: SERINC3 and SERINC5 iden­ti­fied as restric­tion fac­tors antag­o­nized by the patho­gen­e­sis fac­tor. Virus­es, 7: 6730 — 6738.