Virus­es hijack a pletho­ra of host fac­tors to ensure effi­cient viral repli­ca­tion. For exam­ple, HIV1 and relat­ed lentivirus­es exploit cel­lu­lar tran­scrip­tion fac­tors such as NF-κB for the expres­sion of their own genes. These tran­scrip­tion fac­tors are fre­quent­ly acti­vat­ed upon infec­tion and medi­ate the expres­sion of sev­er­al antivi­ral and pro-inflam­ma­to­ry host fac­tors. Since chron­ic inflam­ma­tion dri­ves dis­ease pro­gres­sion in HIV-infect­ed indi­vid­u­als, a bet­ter under­stand­ing of tran­scrip­tion fac­tor acti­va­tion will pro­vide impor­tant insights into retro­vi­ral path­o­genic­i­ty. Notably, tran­scrip­tion fac­tor acti­va­tion is also an impor­tant deter­mi­nant of viral laten­cy, which rep­re­sents a major obsta­cle in cur­ing HIV/​AIDS.
With­in the first fund­ing peri­od of this SPP, we showed that pri­mate lentivirus­es evolved sev­er­al inde­pen­dent mech­a­nisms to inter­fere with tran­scrip­tion fac­tor acti­va­tion. For exam­ple, we demon­strate that the viral pro­tein U (Vpu) of HIV‑1 is a potent inhibitor of NF-κB-elicit­ed immune respons­es, sup­press­ing the tran­scrip­tion of mul­ti­ple restric­tion fac­tors and pro-inflam­ma­to­ry cytokines (Langer et al., 2019, eLife; Hot­ter et al., 2017, PLoS Pathogens). Stud­ies in human­ized mice con­firmed that this immuno-sup­pres­sive activ­i­ty is rel­e­vant for retro­vi­ral repli­ca­tion in vivo (Yama­da et al., 2018, Cell Host and Microbe). Fur­ther­more, we uncov­ered a tem­po­ral reg­u­la­tion of NF-κB acti­va­tion enabling effi­cient ini­ti­a­tion of viral gene expres­sion ear­ly upon infec­tion, while lim­it­ing antivi­ral immune respons­es dur­ing lat­er stages of the repli­ca­tion cycle (Hot­ter et al., 2017, PLoS Pathogens; Sauter et al., 2015, Cell Reports).
Intrigu­ing­ly, bind­ing sites for pro-inflam­ma­to­ry tran­scrip­tion fac­tors such as IRFs and STATs are often retained in LTR pro­mot­ers of endoge­nous retro­virus­es (ERVs). Accu­mu­lat­ing evi­dence sug­gests that these LTRs are in turn exploit­ed by the host to reg­u­late the expres­sion of antivi­ral genes. In the sec­ond fund­ing peri­od, we will there­fore elu­ci­date the role of ERVs in induc­ing innate immune respons­es and lim­it­ing retro­vi­ral repli­ca­tion. Our tran­scrip­tome analy­ses revealed that spe­cif­ic ERV fam­i­lies (e.g. LTR12C) are acti­vat­ed in HIV‑1 infect­ed pri­ma­ry T cells. Inter­est­ing­ly, LTR12C pro­mot­er ele­ments have been shown to bind IRFs and STATs, and may deter­mine the expres­sion and IFN-inducibil­i­ty of anti­retro­vi­ral fac­tors such as GBP2 and GBP5 (Braun et al., 2019, Cell Reports). We will com­bine in vit­ro and in vivo tran­scrip­tomics and pro­teomics approach­es to mon­i­tor the induc­tion of endoge­nous retroele­ments in HIV‑1 infect­ed cells in an unbi­ased man­ner. Fur­ther­more, col­lab­o­ra­tive in sil­i­co analy­ses will com­ple­ment LTR reporter assays and muta­tion­al analy­ses to iden­ti­fy the mech­a­nisms that under­lie the acti­va­tion of retroele­ments upon HIV‑1 infec­tion. Final­ly, we aim to iden­ti­fy cel­lu­lar antivi­ral genes that are reg­u­lat­ed by endoge­nous LTRs and to deci­pher the role of LTR12C ele­ments and oth­er ERV lin­eages in restrict­ing retro­vi­ral replication.
The results will help to under­stand a sophis­ti­cat­ed host-virus arms race, in which host cells exploit the abil­i­ty of endoge­nous retro­vi­ral pro­mot­ers to hijack cel­lu­lar tran­scrip­tion factors.