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Review
. 2024 Sep 6;16(9):1423.
doi: 10.3390/v16091423.

Exploring HIV-1 Maturation: A New Frontier in Antiviral Development

Aidan McGraw  1 , Grace Hillmer  1 , Stefania M Medehincu  1 , Yuta Hikichi  2 , Sophia Gagliardi  1 , Kedhar Narayan  1 , Hasset Tibebe  1 , Dacia Marquez  1 , Lilia Mei Bose  1 , Adleigh Keating  1 , Coco Izumi  1 , Kevin Peese  3 , Samit Joshi  3 , Mark Krystal  3 , Kathleen L DeCicco-Skinner  1 , Eric O Freed  2 , Luca Sardo  3 , Taisuke Izumi  1   4
Affiliations
Review

Exploring HIV-1 Maturation: A New Frontier in Antiviral Development

Aidan McGraw et al. Viruses. .

Abstract

HIV-1 virion maturation is an essential step in the viral replication cycle to produce infectious virus particles. Gag and Gag-Pol polyproteins are assembled at the plasma membrane of the virus-producer cells and bud from it to the extracellular compartment. The newly released progeny virions are initially immature and noninfectious. However, once the Gag polyprotein is cleaved by the viral protease in progeny virions, the mature capsid proteins assemble to form the fullerene core. This core, harboring two copies of viral genomic RNA, transforms the virion morphology into infectious virus particles. This morphological transformation is referred to as maturation. Virion maturation influences the distribution of the Env glycoprotein on the virion surface and induces conformational changes necessary for the subsequent interaction with the CD4 receptor. Several host factors, including proteins like cyclophilin A, metabolites such as IP6, and lipid rafts containing sphingomyelins, have been demonstrated to have an influence on virion maturation. This review article delves into the processes of virus maturation and Env glycoprotein recruitment, with an emphasis on the role of host cell factors and environmental conditions. Additionally, we discuss microscopic technologies for assessing virion maturation and the development of current antivirals specifically targeting this critical step in viral replication, offering long-acting therapeutic options.

Keywords: Förster resonance energy transfer (FRET); Gag; Gag-Pol; allosteric integrase inhibitor (ALLINI); capsid; capsid inhibitor (CAI); human immunodeficiency virus type I (HIV-1); maturation; maturation inhibitor (MI); protease inhibitor (PI).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
HIV Replication Cycle. Schematic representation of the HIV replication cycle. (A) HIV-1 Env binds to plasma membrane receptors, CD4, and CCR5 or CXCR4 coreceptors. (B) Upon interactions between Env and host receptors, viral and host membrane fusion occurs, releasing the viral core into the host cell cytoplasm. (C) Reverse transcription is initiated shortly after virus entry. The HIV-1 CA core is transported toward the nucleus through the host cell’s microtubule network by dynein and kinesin motor proteins. (D) Reverse-transcribed intermediate products inside the intact core are imported into the nucleus through the nuclear pore. (E) Upon completion of reverse transcription, viral DNA induces uncoating of the core structure in the nucleus, and IN mediates viral DNA integration into the host genome. (F) Proviral DNA is transcribed by the host machinery, enhanced by HIV-1 Tat. (G) Viral mRNAs are translated by free ribosomes or ER-associated ribosomes specific for spliced forms encoding the env gene. (H) Gag and Gag-Pol polyproteins assemble at the plasma membrane and recruit Env in progeny virions. (I) Full-length viral RNAs migrate to the plasma membrane and are packaged into progeny virions. (J) Progeny virions bud from virus-producer cells. (K) PR cleaves Gag and Gag-Pol in immature virions, releasing CA proteins that form the conical core harboring viral gRNA. Viral Env distribution changes during maturation. The currently developed antivirals disrupt multiple steps of the viral replication cycle, including (B) Fusion, (C) Reverse Transcription, (D) Nuclear Transport/Import, (E) Integration, (H) Assembly, and (K) Maturation.
Figure 2
Figure 2
Gag and Gag-Pol polyprotein processing by PR. Schematic representation of (A) Gag and (B) Gag-Pol polyprotein cleavage pattern by PR. (A) The first cleavage occurs between the SP1-NC region within the RQA|NFLG protease recognition sequence, followed by cleavages between MA-CA within SQNY|PIV and SP2-p6 within PGNF|LQS. Finally, SP1 and SP2 short peptides are removed from CA and NC, respectively, within the ARVL|AEA and RQAN|FLG protease recognition sequences. (B) The Gag-Pol polyprotein is formed by a frameshifting event at the NC/SP1 boundary, which translates the p6 domain in an alternative reading frame (Transframe/TF). The initial cleavage events separate Gag and Pol regions by cleaving between TF and PR within the SFNF|PQIT protease recognition sequence, carried out by the poorly active PR precursor. This process frees the protease from the rest of the precursor, enabling the ordered processing of the Gag polyprotein. (C) FRET indicator fluorescent proteins inserted between the MA and CA domains, bridged by the SQNY|PIV protease cleavage sequence. CFP and YFP separate when MA-CA is cleaved by PR.
Figure 3
Figure 3
Structural representation of the HIV-1 CA Core. Approximately 250 hexamers and exactly 12 pentamers of CA assemble into a conical core (PDB: 3J3Y) [43,44]. The N-terminal domain from residues 1–145, the linker between residues 146–150, and the C-terminal domain from residues 151–231 of CA are colored in brown, gray, and bright orange, respectively. Twelve pentamers are specifically highlighted in sky blue. IP6 (green) is incorporated into both capsid hexamers (PDB: 7ZUD) [44,45] and pentamers (PDB: 7URN) [45]. In the absence of IP6, IP5 (blue) is incorporated into the capsid hexamers (PDB: 6R8C) [46]. NUP153 (pink in PDB: 4U0C) [47,48]), CPSF6 (pale green in PDB: 7ZUD), and LEN (green in PDB: 6V2F) [49] associated with the capsid hexamer are highlighted. To dynamically visualize these host proteins and small molecule interactions with the CA hexamer, the angles are rotated by 90 degrees from the outer surface angle on the x-axis.
Figure 4
Figure 4
Schematic, TEM, and fluorescence images of HIV-1 Gag-iFRET viruses. While immature virions, depicted by both schematic and TEM images, exhibit a higher FRET signal (red in the ratio color; yellow arrow), mature virions show a low FRET signal (blue in the ratio color; white arrow). Under electron microscopy, HIV-1 immature virions are characterized by an incomplete, spherical structure, while mature virions display a conical core indicative of successful proteolytic processing and proper assembly of the capsid proteins. Under fluorescence microscopy, immature virions express a red signal, which is reduced in mature virions in ratio view. This results in mature virions emitting a blue and green signal. Several drugs, including PIs, MIs, CAIs, and ALLINIs, interrupt virion maturation.
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