Dr. Frauke Mücksch

Frauke.Muecksch
(at)med.uni-heidelberg.de
Phone: +49 6221 56–35643

HIV‑1 Infection and Latency

Projects

The Mücksch lab is inter­est­ed in gain­ing a bet­ter under­stand­ing of the inter­play between HIV‑1 and its host cells dur­ing HIV‑1 infec­tion and laten­cy at the cel­lu­lar and mol­e­c­u­lar lev­el. HIV infec­tion remains one of the world’s most rel­e­vant infec­tious dis­eases with more than 38 mil­lion peo­ple world­wide liv­ing with HIV. Since the begin­ning of the HIV epi­dem­ic, more than 84 mil­lion peo­ple have been infect­ed with HIV and about 40 mil­lion have died of HIV. Inten­sive research has led to the devel­op­ment of anti­retro­vi­ral ther­a­py (ART), which has since been applied to con­trol HIV infec­tion in peo­ple liv­ing with HIV. How­ev­er, despite avail­able ther­a­pies, HIV infec­tion still can­not be cured, result­ing in a need for life-long ART. This impos­es severe chal­lenges on peo­ple liv­ing with HIV, such as lim­it­ed access to ART, strict med­ica­tion sched­ule, stig­ma, side-effects, and inflam­ma­tion-asso­ci­at­ed co-mor­bidi­ties. The absence of a cure for HIV infec­tion results from the for­ma­tion of a latent reser­voir which can­not be tar­get­ed by cur­rent ther­a­pies. HIV inte­grates into the host cell genome where it can per­sist as a latent provirus dur­ing anti­retro­vi­ral treat­ment. Treat­ment inter­rup­tion inevitably leads to viral rebound. With this, the latent reser­voir presents the main chal­lenge to the devel­op­ment of a cure for HIV infec­tion and cure can thus only result from a detailed under­stand­ing of these process­es. The over­all aim of the Mücksch lab is to study and under­stand the mech­a­nisms under­ly­ing latent HIV‑1 infec­tion. Our research goals are to char­ac­ter­ize the het­ero­gene­ity of HIV‑1 laten­cy in cell mod­els and pri­ma­ry cells, inves­ti­gate how HIV enters and revers­es from laten­cy, and define the viral and host fac­tors respon­si­ble for these processes.

We believe that a process as het­ero­ge­neous and mul­ti-fac­to­r­i­al as HIV‑1 laten­cy can only be stud­ied using diverse tools and mod­els. We are apply­ing a provi­ral laten­cy reporter, which allows for rapid sep­a­ra­tion of cells har­bor­ing tran­scrip­tion­al­ly active vs. inac­tive provirus­es. This reporter enabled us to estab­lish excep­tion­al­ly large and diverse libraries of hun­dreds of latent­ly infect­ed T cell lines. Togeth­er with human pri­ma­ry cell mod­els, we are using these tools com­bined with mol­e­c­u­lar virol­o­gy, genet­ics, immunol­o­gy, and microscopy tech­niques to dis­sect HIV-host inter­ac­tions and under­stand the mech­a­nisms under­ly­ing laten­cy estab­lish­ment, main­te­nance, and rever­sal. Through this we expect to gain a bet­ter under­stand­ing of the reg­u­la­tion of HIV‑1 laten­cy to get one step clos­er to achiev­ing a cure for HIV.

Com­plete Pub­li­ca­tion List (PubMed)

  • Schae­fer-Baba­jew D*, Wang Z*, Muecksch F*, Cho A*, Loewe M, Cipol­la M, Raspe R, John­son B, Can­is M, DaSil­va J, Ramos V, Tur­ro­ja M, Mil­lard KG, Schmidt F, Witte L, Dizon J, Shime­liovich I, Yao KH, Oliveira TY, Gazumyan A, Gae­bler C, Bieni­asz PD, Hatzi­ioan­nou T, Caskey M, Nussen­zweig MC (2023) Anti­body feed­back reg­u­lates immune mem­o­ry after SARS-CoV­‑2 mRNA vac­ci­na­tion. Nature. 613(7945):735–742
  • Schmidt F*, Muecksch F*, Weis­blum Y, Da Sil­va J, Bed­nars­ki E, Cho A, Wang Z, Gae­bler C, Caskey M, Nussen­zweig MC, Hatzi­ioan­nou T, Bieni­asz PD (2022) Plas­ma Neu­tral­iza­tion of the SARS-CoV­‑2 Omi­cron Vari­ant. N Engl J Med. 386(6):599–601
  • Muecksch F, Wise H, Tem­ple­ton K, Batch­e­lor B, Squires M, McCance K, Jarvis L, Mal­loy K, Fur­rie E, Richard­son C, MacGuire J, God­ber I, Burns A, Mavin S, Zhang F, Schmidt F, Bieni­asz PD, Jenks S, Hatzi­ioan­nou T (2022) Lon­gi­tu­di­nal vari­a­tion in SARS-CoV­‑2 anti­body lev­els and emer­gence of viral vari­ants: a sero­log­i­cal analy­sis. Lancet Microbe. 3(7):e493-e502
  • Muecksch F*, Wang Z*, Cho A*, Gae­bler C, Ben Tan­fous T, DaSil­va J, Bed­nars­ki E, Ramos V, Zong S, John­son B, Raspe R, Schae­fer-Baba­jew D, Shime­liovich I, Daga M, Yao KH, Schmidt F, Mil­lard KG, Tur­ro­ja M, Jankovic M, Oliveira TY, Gazumyan A, Caskey M, Hatzi­ioan­nou T, Bieni­asz PD, Nussen­zweig MC (2022) Increased mem­o­ry B cell poten­cy and breadth after a SARS-CoV­‑2 mRNA boost. Nature. 607(7917):128–134
  • Wang Z*, Muecksch F*, Schae­fer-Baba­jew D*, Finkin S*, Viant C*, Gae­bler C*, Hoff­mann HH, Barnes CO, Cipol­la M, Ramos V, Oliveira TY, Cho A, Schmidt F, Da Sil­va J, Bed­nars­ki E, Agua­do L, Yee J, Daga M, Tur­ro­ja M, Mil­lard KG, Jankovic M, Gazumyan A, Zhao Z, Rice CM, Bieni­asz PD, Caskey M, Hatzi­ioan­nou T, Nussen­zweig MC (2021) Nat­u­ral­ly enhanced neu­tral­iz­ing breadth against SARS-CoV­‑2 one year after infec­tion. Nature. 595(7867):426–431
  • Muecksch F*, Weis­blum Y*, Barnes CO*, Schmidt F*, Schae­fer-Baba­jew D, Wang Z, JC CL, Fly­ak AI, DeLaitsch AT, Huey-Tub­man KE, Hou S, Schif­fer CA, Gae­bler C, Da Sil­va J, Pos­ton D, Finkin S, Cho A, Cipol­la M, Oliveira TY, Mil­lard KG, Ramos V, Gazumyan A, Rutkows­ka M, Caskey M, Nussen­zweig MC, Bjork­man PJ, Hatzi­ioan­nou T, Bieni­asz PD (2021) Affin­i­ty mat­u­ra­tion of SARS-CoV­‑2 neu­tral­iz­ing anti­bod­ies con­fers poten­cy, breadth, and resilience to viral escape muta­tions. Immu­ni­ty. 54(8):1853–1868 e1857
  • Cho A*, Muecksch F*, Schae­fer-Baba­jew D*, Wang Z*, Finkin S*, Gae­bler C, Ramos V, Cipol­la M, Men­doza P, Agude­lo M, Bed­nars­ki E, DaSil­va J, Shime­liovich I, Dizon J, Daga M, Mil­lard KG, Tur­ro­ja M, Schmidt F, Zhang F, Tan­fous TB, Jankovic M, Oliv­e­ria TY, Gazumyan A, Caskey M, Bieni­asz PD, Hatzi­ioan­nou T, Nussen­zweig MC (2021) Anti-SARS-CoV­‑2 recep­tor-bind­ing domain anti­body evo­lu­tion after mRNA vac­ci­na­tion. Nature. 600(7889):517–522
  • Bou-Nad­er C*, Muecksch F*, Brown JB, Gor­don JM, York A, Peng C, Ghirlan­do R, Sum­mers MF, Bieni­asz PD, Zhang J (2021) HIV‑1 matrix-tRNA com­plex struc­ture reveals basis for host con­trol of Gag local­iza­tion. Cell Host Microbe. 29(9):1421–1436 e1427
  • Rob­biani DF*, Gae­bler C*, Muecksch F*, Loren­zi JCC*, Wang Z*, Cho A*, Agude­lo M*, Barnes CO*, Gazumyan A*, Finkin S*, Hag­glof T*, Oliveira TY*, Viant C*, Hur­ley A, Hoff­mann HH, Mil­lard KG, Kost RG, Cipol­la M, Gor­don K, Bian­chi­ni F, Chen ST, Ramos V, Patel R, Dizon J, Shime­liovich I, Men­doza P, Hartweger H, Nogueira L, Pack M, Horowitz J, Schmidt F, Weis­blum Y, Michai­lidis E, Ash­brook AW, Wal­tari E, Pak JE, Huey-Tub­man KE, Koran­da N, Hoff­man PR, West AP, Jr., Rice CM, Hatzi­ioan­nou T, Bjork­man PJ, Bieni­asz PD, Caskey M, Nussen­zweig MC (2020) Con­ver­gent anti­body respons­es to SARS-CoV­‑2 in con­va­les­cent indi­vid­u­als. Nature. 584(7821):437–442
  • Mucksch F*, Citir M*, Lucht­en­borg C, Glass B, Traynor-Kaplan A, Schultz C, Brug­ger B, Kraus­slich HG (2019) Quan­tifi­ca­tion of phos­pho­inosi­tides reveals strong enrich­ment of PIP2 in HIV‑1 com­pared to pro­duc­er cell mem­branes. Sci Rep. 9(1):17661
  • Mucksch F, Lake­ta V, Muller B, Schultz C, Kraus­slich HG (2017) Syn­chro­nized HIV assem­bly by tun­able PIP2 changes reveals PIP2 require­ment for sta­ble Gag anchor­ing. Elife. 6