Tough Way In, Tough Way Out: The Complex Interplay of Host and Viral Factors in Nucleocytoplasmic Trafficking during HIV-1 Infection

Sarkar, Satarupa; Balakrishnan, Kannan; Chintala, Kumaraswami; Mohareer, Krishnaveni; Luedde, Tom; Vasudevan, Ananda Ayyappan Jaguva; Münk, Carsten; Banerjee, Sharmistha

doi:10.3390/v14112503

Cited by 6 publications

(3 citation statements)

References 170 publications

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“…Since these T-cells are the regulators of the adaptive immune system, their depletion effectively weakens the immune system, leading to acquired immune deficiency syndrome (AIDS) (113). Several host factors have been shown to play an essential role in the HIV life cycle (114). PIN1 is one of these factors, enhancing HIV infection by being involved in three vital stages of the HIV replication cycle: Cell entry, reverse transcription and host genome integration (115,116).…”

Section: Human Immunodeficiency Virus (Hiv)mentioning

confidence: 99%

Role of PIN1 in human pathology: Cellular regulation, pathogenesis and therapeutic implications (Review)

Maggio,

Armando,

Balcone

et al. 2023

World Acad Sci J

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Peptidyl-prolyl isomerase NIMA-interacting 1 (PIN1) plays a crucial regulatory role in cells, and it is the only enzyme capable of selectively binding to phosphorylated proline-directed serine/threonine (pSer/Thr-Pro) residues in target proteins and catalyzing their isomerization. The change in the conformational status of the protein, transitioning between cis and trans, affects its three-dimensional structure and, therefore, alters its function and stability. In this manner, PIN1 plays a role in the development of several human pathologies by regulating essential proteins. In cancer, the enzymatic activity of PIN1 induces conformational changes in essential proteins, promoting oncogenic processes and fostering aggressive tumor characteristics and resistance to chemotherapies. Moreover, the effects of PIN1 on viral infections are notable, as it interacts with viral proteins, enhancing their replication and infection mechanisms. In addition, PIN1 participates in autoimmune, cardiovascular, metabolic, neurodegenerative diseases and osteoporosis. These diverse functions render PIN1 as an attractive therapeutic target, leading to the development of PIN1 inhibitors. The critical role of PIN1 in human pathology is further underscored by its relevance to various diseases, rendering it a potential nexus for novel interventions in human pathologies.

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Section: Human Immunodeficiency Virus (Hiv)mentioning

confidence: 99%

Role of PIN1 in human pathology: Cellular regulation, pathogenesis and therapeutic implications (Review)

Maggio,

Armando,

Balcone

et al. 2023

World Acad Sci J

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“…These steps include docking of the capsid (CA) onto NPC (NUP358), import of viral DNA (NUP153), integration of viral DNA into the host genome (NUP62, NUP98), and export of viral RNA (NUP98, NUP214, NUP62) ( 22 – 29 ). Furthermore, evidence shows that NUPs such as NUP358 and NUP153 are shown to be important for the HIV-1 integration site selection in the genome ( 26 , 30 , 31 ). Given their essential participation during HIV-1 replication, several proteomic studies have focused on and identified many NUPs that are dysregulated during HIV-1 infection ( 28 , 32 , 33 ).…”

Section: Introductionmentioning

confidence: 99%

The nuclear pore protein NUP98 impedes LTR-driven basal gene expression of HIV-1, viral propagation, and infectivity

Chintala,

Yandrapally,

Faiz

et al. 2024

Front. Immunol.

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Nucleoporins (NUPs) are cellular effectors of human immunodeficiency virus-1 (HIV-1) replication that support nucleocytoplasmic trafficking of viral components. However, these also non-canonically function as positive effectors, promoting proviral DNA integration into the host genome and viral gene transcription, or as negative effectors by associating with HIV-1 restriction factors, such as MX2, inhibiting the replication of HIV-1. Here, we investigated the regulatory role of NUP98 on HIV-1 as we observed a lowering of its endogenous levels upon HIV-1 infection in CD4+ T cells. Using complementary experiments in NUP98 overexpression and knockdown backgrounds, we deciphered that NUP98 negatively affected HIV-1 long terminal repeat (LTR) promoter activity and lowered released virus levels. The negative effect on promoter activity was independent of HIV-1 Tat, suggesting that NUP98 prevents the basal viral gene expression. ChIP-qPCR showed NUP98 to be associated with HIV-1 LTR, with the negative regulatory element (NRE) of HIV-1 LTR playing a dominant role in NUP98-mediated lowering of viral gene transcription. Truncated mutants of NUP98 showed that the attenuation of HIV-1 LTR-driven transcription is primarily contributed by its N-terminal region. Interestingly, the virus generated from the producer cells transiently expressing NUP98 showed lower infectivity, while the virus generated from NUP98 knockdown CD4+ T cells showed higher infectivity as assayed in TZM-bl cells, corroborating the anti-HIV-1 properties of NUP98. Collectively, we show a new non-canonical function of a nucleoporin adding to the list of moonlighting host factors regulating viral infections. Downregulation of NUP98 in a host cell upon HIV-1 infection supports the concept of evolutionary conflicts between viruses and host antiviral factors.

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“…Recent studies suggest that the core remains fully or mostly intact during nuclear entry, thereby ensuring completion of reverse transcription within the nucleus 3,4 . It is presently unclear how the core passes through the nuclear pore 6–8 while remaining intact. Docking of the HIV-1 core at the NPC and subsequent nuclear entry are effected by interactions between the capsid and cellular factors, including cyclophilin A, CPSF6, and nucleoporins (e.g.…”

mentioning

confidence: 99%

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection

Deshpande,

Bryer,

Andino

et al. 2023

Preprint

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HIV-1 infection requires passage of the viral core through the nuclear pore of the cell, a process that depends on functions of the viral capsid1,2. Recent studies have shown that HIV- 1 cores enter the nucleus prior to capsid disassembly3–5. Interactions with the nuclear pore complex are necessary but not sufficient for nuclear entry, and the mechanism by which the viral core traverses the comparably sized nuclear pore is unknown. Here we show that the HIV-1 core is highly elastic and that this property is linked to nuclear entry and infectivity. Using atomic force microscopy-based approaches, we found that purified wild type cores rapidly returned to their normal conical morphology following a severe compression. Results from independently performed molecular dynamic simulations of the mature HIV-1 capsid also revealed its elastic property. Analysis of four HIV-1 capsid mutants that exhibit impaired nuclear entry revealed that the mutant viral cores are brittle. Suppressors of the mutants restored elasticity and rescued infectivity and nuclear entry. Elasticity was also reduced by treatment of cores with the capsid-targeting compound PF74 and the antiviral drug lenacapavir. Our results indicate that capsid elasticity is a fundamental property of the HIV-1 core that enables its passage through the nuclear pore complex, thereby facilitating infection. These results provide new insights into the mechanisms of HIV-1 nuclear entry and the antiviral mechanisms of HIV-1 capsid inhibitors.

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Tough Way In, Tough Way Out: The Complex Interplay of Host and Viral Factors in Nucleocytoplasmic Trafficking during HIV-1 Infection

Cited by 6 publications

References 170 publications

Role of PIN1 in human pathology: Cellular regulation, pathogenesis and therapeutic implications (Review)

Role of PIN1 in human pathology: Cellular regulation, pathogenesis and therapeutic implications (Review)

The nuclear pore protein NUP98 impedes LTR-driven basal gene expression of HIV-1, viral propagation, and infectivity

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection

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