Using a mul­ti­dis­ci­pli­nary approach com­bin­ing mol­e­c­u­lar virol­o­gy, func­tion­al genomics, immunol­o­gy, and advanced imag­ing, we inves­ti­gate how viral and host fac­tors inter­act to con­trol laten­cy and reac­ti­va­tion. In par­al­lel, we study how immune respons­es and tis­sue-spe­cif­ic envi­ron­ments, includ­ing the cen­tral ner­vous sys­tem, influ­ence viral per­sis­tence and the acces­si­bil­i­ty of the reservoir.

Ulti­mate­ly, our goal is to define the prin­ci­ples that gov­ern HIV‑1 per­sis­tence and to trans­late these insights into strate­gies that either elim­i­nate the viral reser­voir or achieve durable con­trol of infection.

1 | Regulation of HIV‑1 latency establishment and reversal

We study how the estab­lish­ment, main­te­nance, and rever­sal of HIV‑1 laten­cy are reg­u­lat­ed. Our work focus­es on iden­ti­fy­ing path­ways that deter­mine whether an inte­grat­ed provirus remains silent or becomes tran­scrip­tion­al­ly active, and how these process­es dif­fer across cell types and cel­lu­lar states. A key unre­solved ques­tion is why laten­cy-revers­ing agents (LRAs) reac­ti­vate only a sub­set of infect­ed cells with­in the reser­voir. We are there­fore par­tic­u­lar­ly inter­est­ed in defin­ing the bar­ri­ers to drug-induced laten­cy reversal.

To address these ques­tions, we com­bine well-defined laten­cy mod­els with pri­ma­ry cell sys­tems and apply a range of mol­e­c­u­lar and func­tion­al approach­es to dis­sect HIV–host inter­ac­tions. In par­tic­u­lar, we lever­age reporter sys­tems that allow us to dis­tin­guish and iso­late cells har­bor­ing tran­scrip­tion­al­ly active or inac­tive provirus­es, enabling sys­tem­at­ic analy­sis of the cel­lu­lar states asso­ci­at­ed with laten­cy. We are espe­cial­ly inter­est­ed in the role of the provi­ral inte­gra­tion site for HIV laten­cy and laten­cy reversal.

By defin­ing the mech­a­nisms that gov­ern HIV‑1 laten­cy and reac­ti­va­tion, we aim to iden­ti­fy nov­el tar­gets for ther­a­peu­tic inter­ven­tion and con­tribute to strate­gies that enable durable con­trol or elim­i­na­tion of the viral reservoir.

Part of this work is fund­ed through SFB1129 “Inte­gra­tive Analy­sis of Pathogen Repli­ca­tion and Spread”.

2 | HIV infection and latency in monocytes and macrophages

While HIV‑1 laten­cy has been stud­ied pre­dom­i­nant­ly in CD4+ T cells, increas­ing evi­dence high­lights the role of cells of the myeloid lin­eage, includ­ing mono­cytes and macrophages, as addi­tion­al reser­voirs of viral per­sis­tence. These cells dif­fer fun­da­men­tal­ly from T cells in their biol­o­gy, lifes­pan, and immune func­tions, cre­at­ing a dis­tinct envi­ron­ment for HIV infec­tion and laten­cy that remains incom­plete­ly understood.

We study how HIV‑1 infects, per­sists, and estab­lish­es laten­cy in mono­cytes and macrophages. Our work focus­es on defin­ing the mech­a­nisms that reg­u­late viral tran­scrip­tion and laten­cy in these cells and on under­stand­ing how they dif­fer from clas­si­cal T cell models.

To address these ques­tions, we have devel­oped a diverse set of mono­cyt­ic laten­cy mod­els that cap­ture vari­a­tion in provi­ral inte­gra­tion sites, tran­scrip­tion­al states, and respon­sive­ness to laten­cy-revers­ing agents. These mod­els pro­vide a ver­sa­tile plat­form to study the het­ero­gene­ity of laten­cy in myeloid cells and to direct­ly com­pare it with T cell–based mod­els. We fur­ther lever­age these mod­els in func­tion­al screen­ing approach­es to inter­ro­gate HIV–host inter­ac­tions in this cel­lu­lar context.

Through this work, we aim to define the con­tri­bu­tion of myeloid cells to the latent reser­voir and to inform cure strate­gies that effec­tive­ly tar­get HIV across dif­fer­ent cel­lu­lar compartments.

3 | Identifying host cell regulators of HIV‑1 latency

We aim to sys­tem­at­i­cal­ly iden­ti­fy host cell deter­mi­nants that reg­u­late HIV‑1 laten­cy using large-scale, unbi­ased approach­es. A cen­tral focus of our work is the gen­er­a­tion and analy­sis of exten­sive libraries of latent­ly infect­ed cells, which cap­ture the diver­si­ty and het­ero­gene­ity of provi­ral states. These sys­tems allow us to study laten­cy not as a sin­gle enti­ty, but as a spec­trum of dis­tinct cel­lu­lar and tran­scrip­tion­al configurations.

Impor­tant­ly, we extend these approach­es beyond our T cell mod­els by incor­po­rat­ing diverse mono­cyt­ic laten­cy mod­els estab­lished in our lab. This enables us to inves­ti­gate cell type–specific reg­u­la­tion of laten­cy and to cap­ture aspects of HIV per­sis­tence that are not rep­re­sent­ed in T cell sys­tems alone.

Build­ing on these mod­els, we per­form large-scale func­tion­al genom­ic screens to iden­ti­fy host fac­tors that influ­ence whether a provirus remains silent or becomes reac­ti­vat­ed, there­by defin­ing path­ways that con­trol laten­cy estab­lish­ment, sta­bil­i­ty, and reversal.

Through this approach, we aim to define key reg­u­la­to­ry net­works of HIV‑1 laten­cy and to uncov­er nov­el tar­gets for ther­a­peu­tic strate­gies aimed at desta­bi­liz­ing or per­ma­nent­ly silenc­ing the viral reservoir.

4 | Targeting the CNS HIV‑1 reservoir in HIV cure approaches

The cen­tral ner­vous sys­tem (CNS) rep­re­sents a unique and under­stud­ied reser­voir of HIV‑1. In con­trast to periph­er­al infec­tion, the CNS is char­ac­ter­ized by lim­it­ed immune sur­veil­lance, spe­cial­ized res­i­dent cell types such as microglia, and a high risk of inflam­ma­tion-dri­ven tis­sue dam­age. These fea­tures cre­ate a dis­tinct envi­ron­ment in which HIV can per­sist and evade both immune respons­es and ther­a­peu­tic interventions.

We study how HIV‑1 estab­lish­es and main­tains infec­tion with­in the CNS, with a par­tic­u­lar focus on myeloid cells such as microglia. Our work aims to under­stand how viral laten­cy and immune eva­sion are reg­u­lat­ed in this com­part­ment and why infect­ed cells in the brain are par­tic­u­lar­ly dif­fi­cult to eliminate.

To address these ques­tions, we com­bine com­ple­men­tary approach­es. On the one hand, we inves­ti­gate strate­gies to tar­get the CNS reser­voir by pro­mot­ing viral reac­ti­va­tion and enhanc­ing immune-medi­at­ed clear­ance. On the oth­er hand, we imple­ment advanced organ­otyp­ic human brain mod­els that allow us to study HIV infec­tion, laten­cy, and immune con­trol in a phys­i­o­log­i­cal­ly rel­e­vant tis­sue context.

Part of this work is fund­ed through DZIF

Part of this project is embed­ded with­in the Syn­thIm­mune Clus­ter of Excel­lence. https://synthimmune.de/

5 | Elite cytotoxic T cells and immune control of HIV‑1

A small sub­set of peo­ple liv­ing with HIV can con­trol viral repli­ca­tion with­out ther­a­py. This rare phe­nom­e­non is linked to high­ly effec­tive HIV-spe­cif­ic CD8 T cells, yet the mol­e­c­u­lar fea­tures that define these “elite” immune respons­es remain poor­ly under­stood. At the same time, latent­ly infect­ed reser­voir cells large­ly evade immune recog­ni­tion, pos­ing a major chal­lenge for cura­tive strategies.

In this project, we inves­ti­gate what dis­tin­guish­es high­ly potent HIV-spe­cif­ic CD8 T cells from less effec­tive respons­es. We focus on how these cells rec­og­nize and elim­i­nate infect­ed tar­get cells, includ­ing dif­fi­cult-to-tar­get reser­voir pop­u­la­tions such as myeloid cells. By com­par­ing immune cells from indi­vid­u­als with nat­ur­al viral con­trol to those from typ­i­cal dis­ease cours­es, we aim to iden­ti­fy key func­tion­al and mol­e­c­u­lar deter­mi­nants of effec­tive antivi­ral immunity.

To achieve this, we com­bine advanced imag­ing approach­es with sin­gle-cell analy­ses to cap­ture dynam­ic inter­ac­tions between cyto­tox­ic T cells and infect­ed tar­get cells. This allows us to link func­tion­al behav­ior to under­ly­ing mol­e­c­u­lar sig­na­tures and define fea­tures asso­ci­at­ed with supe­ri­or antivi­ral activity.

This project is part of the Syn­thIm­mune Clus­ter of Excel­lence. https://synthimmune.de/