Cellular and Viral Determinants of Innate HIV Recognition in Macrophages

Project Member

Prof. Dr. Oliv­er T. Kep­pler

Project Leader

Prof. Dr. Oliver T. Keppler

Phone: +49 89 2180 – 72901
Keppler@mvp.uni-muenchen.de

Max von Pet­tenkofer-Insti­tut
Lud­wig-Max­i­m­il­ians-Uni­ver­sität München
Pet­tenkofer­str. 9a
80336 München
Ger­many

Prof. Dr. Veit Hor­nung

Project Leader

Prof. Dr. Veit Hornung

Phone: +49 89 2180 – 71110
Hornung@genzentrum.lmu.de

Gene Cen­ter Munich
and Depart­ment of Bio­chem­istry
Lud­wig-Max­i­m­il­ians-Uni­ver­sität München
Bute­nandt­str. 1
81377 München
Ger­many

Project Summary

Besides CD4 T‑cells, macrophages con­sti­tute the major tar­get cells for HIV infec­tion. Macrophages com­prise a crit­i­cal in vivo-reser­voir and play an impor­tant role in shap­ing the immune response. Lit­tle is known about their innate sens­ing mech­a­nisms to detect HIV and the down­stream con­se­quences. Study­ing mono­cyte-derived macrophages (MDMs), we observed that HIV elic­its antivi­ral gene expres­sion at a step post-inte­gra­tion. More­over, deple­tion of the nucle­ic acid pat­tern recog­ni­tion recep­tors (PRRs) IFI16 or AIM2 marked­ly enhanced infec­tion and ear­ly HIV gene expres­sion. Notably, expres­sion of inter­fer­on-stim­u­lat­ed genes (ISGs) was upreg­u­lat­ed in HIV-infect­ed MDMs deplet­ed of IFI16 or AIM2, call­ing into ques­tion a direct role of these PRRs in the ini­ti­a­tion of antivi­ral respons­es. Employ­ing a nov­el macrophage trans-dif­fer­en­ti­a­tion sys­tem that is amenable to com­plex genet­ic manip­u­la­tion side-by-side with stud­ies in MDMs, we aim at deter­min­ing (i) the PRRs that are involved in the recog­ni­tion of HIV, (ii) the stages of the repli­ca­tion cycle at which engage­ment occurs, (iii) the viral nucle­ic acid and pro­tein com­po­nents that are rec­og­nized, and (iv) the func­tion­al con­se­quences of this innate pathogen sens­ing. Col­lec­tive­ly, these stud­ies will con­tribute to our under­stand­ing of the mech­a­nisms and func­tion­al con­se­quences of HIV recog­ni­tion by the innate immune sys­tem in macrophages.

Fig. 1: Mod­el of emerg­ing com­plex­i­ty of HIV recog­ni­tion in pri­ma­ry human cells. (a) Inef­fi­cient HIV‑1 infec­tion of MDD­Cs and MDMs due to SAMHD1 restric­tion. (b) Viri­on-pack­aged or arti­fi­cial­ly VLP-deliv­ered Vpx over­come the SAMHD1 restric­tion in MDD­Cs and MDMs and allow recog­ni­tion of HIV‑1 cDNA pri­or to inte­gra­tion in a CA-CypA-depen­dent man­ner via cGAS and/​or IFI16 (Gao et al., 2013; Jakob­sen et al., 2013; Lahaye et al., 2013). It has been pro­posed that sens­ing requires spe­cif­ic muta­tions in the HIV‑1 CA (Lahaye et al., 2013; Rasaiyaah et al., 2013). © Vpx co-deliv­ery over­comes the MDDC resis­tance to pro­duc­tive HIV‑1 infec­tion and unmasks a post-inte­gra­tion recog­ni­tion through a still unknown sen­sor that may depend on CypA and de novo-syn­the­sis of CA (Manel et al., 2010). (d) IFI16-depen­dent pyrop­to­sis in rest­ing CD4 T‑cells in ton­sil his­to­cul­tures (Mon­roe et al., 2014).