Cellular and molecular mechanisms of HIV-1 integration targeting

Abstract

Integration is central to HIV-1 replication and helps mold the reservoir of cells that persists in AIDS patients. HIV-1 interacts with specific cellular factors to target integration to interior regions of transcriptionally active genes within gene-dense regions of chromatin. The viral capsid interacts with several proteins that are additionally implicated in virus nuclear import, including cleavage and polyadenylation specificity factor 6, to suppress integration into heterochromatin. The viral integrase protein interacts with transcriptional co-activator lens epithelium-derived growth factor p75 to principally position integration within gene bodies. The integrase additionally senses target DNA distortion and nucleotide sequence to help fine-tune the specific phosphodiester bonds that are cleaved at integration sites. Research into virus-host interactions that underlie HIV-1 integration targeting has aided the development of a novel class of integrase inhibitors and may help to improve the safety of viral-based gene therapy vectors.

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

“…Although integration occurs largely throughout animal cell genomes (45,46), host DNA sequences that contort to fit the target DNA-binding interface within the CSC are preferred targets (37,44,(47)(48)(49) (for a detailed review, see Ref. 50). Thus, Figure 2.…”

“…This targeting preference is largely dictated through specific interactions of two PIC-associated proteins, IN and capsid, with respective host factors LEDGF/p75 and cleavage and polyadenylation specificity factor 6 (173, 174) (for a recent review, see Ref. 50). LEDGF/p75 is a chromosome-associated (59,175,176) transcriptional co-activator (177) that harbors two globular domains, an N-terminal PWWP (for Pro-Trp-Trp-Pro) chromatin reader with affinity for histone 3 Lys-36 trimethylation (178 -180), and a downstream region that was termed the IN-binding domain (IBD) because it mediated the binding of LEDGF/p75 to HIV-1 IN in vitro (181).…”

Cone-shaped HIV-1 capsids are transported through intact nuclear pores

“…The capsid shell encases two copies of genomic single stranded RNA associated in a condensed ribonucleoprotein (RNP) complex with the NC (nucleocapsid) protein, the replication enzymes reverse transcriptase (RT) and integrase (IN) as well as other components (Welker et al, 2000). Following cytosolic entry, the viral replication complex undergoes reverse transcription of the RNA genome into double-stranded DNA and transport into the nucleus, where the viral genome integrates into that of the host cell (Engelman and Singh, 2018;Hu and Hughes, 2012).…”

Discovery of novel 1,4-disubstituted 1,2,3-triazole phenylalanine derivatives as HIV-1 capsid inhibitors

“…11 If the formation of CA is inhibited, the viral replication process will be disturbed and the ability to infect host cells will be almost lost. 12 Due to its high sequence conservation (around 70%) and multiple functions in replication, HIV-1 CA protein has become an attractive therapeutic target for anti-HIV drug research. 13,14 Due to its importance as an anti-HIV target, several chemotypes of HIV-1 CA protein inhibitors have been found.…”