# HIV-host interactions driving virus integration

> **NIH NIH U54** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $448,495

## Abstract

Abstract
Results from the HIVE Center and from others have transformed the way that we think about the mechanistic
basis of HIV DNA integration. Until quite recently, the consensus view was that an integrase tetramer, working
in the context of the intasome nucleoprotein complex, catalyzed retroviral integration into chromatin. However,
over the past year, the tetramer-centric view of retroviral integration has been exposed as overly simplistic. Work
in part funded by this grant revealed that beta-retroviral integration is promoted by an integrase octamer. More
recently, cryo-electron microscopy revealed that the structure of the HIV-1 strand transfer complex, the final
intasome complex in the integration pathway, is polymorphic, containing both simple tetramer arrangements as
well as higher-order dodecamers/hexadecamers. Higher-order complex formation moreover depended on the
presence of the integrase-binding domain of the common integration co-factor LEDGF. These observations lead
to several new questions in the field, which will be addressed in this grant application. For example, do intasome
complexes that precede the strand transfer complex also comprise a mixture of different multimers, or, by its
nature, does integration pathway maturation necessitate higher-order multimer formation? Several cutting edge
approaches, including single-particle cryo-electron microscopy and single-molecule fluorescence imaging, will
be used to characterize the mechanistic basis of intasome assembly and function as the complexes mature
along the HIV-1 integration pathway. In addition to assessing the role of LEDGF in pathway maturation, the
LEDGF structure will be determined bound to nucleosomes, and as the tether that links the intasome to the
nucleosome. In addition to directing integration into active genes, LEDGF has recently been implicated in the
regulation of HIV latency. Although the capsid binding CPSF6 factor plays a greater role than LEDGF to direct
integration to active chromatin, a potential role for CPSF6 in regulating HIV latency is unknown. Here, we will
comprehensively address the roles of the two main integration targeting cofactors, LEDGF and CPSF6, in the
establishment and regulation of HIV-1 latency in cell line models as well as in primary T cells. The completion of
this project will provide for the structural basis of HIV-1 integration into chromatin and the consequences of
disrupting these pathways on the establishment and regulation of HIV proviral latency.

## Key facts

- **NIH application ID:** 10242908
- **Project number:** 5U54AI150472-11
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Alan N. Engelman
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $448,495
- **Award type:** 5
- **Project period:** 2012-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242908

## Citation

> US National Institutes of Health, RePORTER application 10242908, HIV-host interactions driving virus integration (5U54AI150472-11). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10242908. Licensed CC0.

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