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”. 

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.

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.

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/

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/

Complete publication list

Selected publications:

• 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

Dr. Frauke Mücksch, Principal Investigator
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Eva Müller, Post doc
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Claudia Bastl, PhD student
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Xinyi Cui, PhD student
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Luca Menges, PhD student
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Tetyana Murdza, PhD student
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Hana Ostir, medical PhD student
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