Emerging Roles of Cyclophilin A in Regulating Viral Cloaking

Mamatis, John E.; Pellizzari-Delano, Isabella E.; Gallardo-Flores, Carla E.; Colpitts, Che C.

doi:10.3389/fmicb.2022.828078

Cited by 15 publications

(10 citation statements)

References 84 publications

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“…Conversely, we observed significantly decreased expression of IL32 , which blocks latency reversal ( 12 , 13 ); APOBEC3G , which inhibits HIV-1 replication ( 31 ); SERINC3 , which reduces viral infectivity ( 32 , 33 ); and BST2 (tetherin), which inhibits release of virions from the host cell ( 34 ). PPIA (cyclophilin A), which has cell type–specific effects on HIV-1 ( 35 ), was also significantly downregulated in the GFP + and GFP – cells compared with mock-infected cells. The overall transcriptional response in the GFP – cells was in a similar direction but less robust than in the GFP + cells and differed with respect to several interferon-associated transcripts ( RSAD2 , MX2 , OAS1 , and IFIT5 ), which were significantly upregulated in the GFP – compared with GFP + and mock-infected cells ( Figure 4C ).…”

Section: Resultsmentioning

confidence: 99%

HSV-2 triggers upregulation of MALAT1 in CD4+ T cells and promotes HIV latency reversal

Pierce¹,

Loh²,

Steach³

et al. 2023

Journal of Clinical Investigation

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HSV-2 coinfection is associated with increased HIV-1 viral loads and expanded tissue reservoirs, but the mechanisms are not well-defined. HSV-2 recurrences result in an influx of activated CD4+ T cells to sites of viral replication and an increase in activated CD4+ T cells in peripheral blood. We hypothesized that HSV-2 induces changes in these cells that facilitate HIV-1 reactivation and replication and tested this hypothesis in human CD4+ T cells and 2D10 cells, a model of HIV-1 latency. HSV-2 promoted latency reversal in HSV-2 infected and bystander 2D10 cells. Bulk and single-cell RNA sequencing studies of activated primary human CD4+ T cells identified decreased expression of HIV-1 restriction factors and increased expression of transcripts including MALAT1 that could drive HIV replication in both the HSV-2-infected and bystander cells. Transfection of 2D10 cells with VP16, an HSV-2 protein that regulates transcription, significantly upregulated MALAT1 expression, decreased trimethylation of lysine 27 on histone H3 protein, and triggered HIV latency reversal. Knockout of MALAT1 from 2D10 cells abrogated the response to VP16 and reduced the response to HSV-2 infection. These results demonstrate that HSV-2 contributes to HIV-1 reactivation through diverse mechanisms including upregulation of MALAT1 to release epigenetic silencing. Brief summary: HSV-2 triggers transcriptional changes in CD4+ T cells including upregulation of the long noncoding RNA MALAT to promote HIV reactivation and replication.frequency of CCR5+, CXCR4+, PD-1+, and CD69+ and decreased frequency of CCR10+ and CCR6+ CD4+ T-cells. These changes were associated with higher levels of cell-associated HIV-1 DNA. Paradoxically, IL-32, a proinflammatory cytokine, was lower in subpopulations of CD4+ T-cells in HSV-2 + versus HSV-2women and the addition of recombinant IL-32γ blocked HIV reactivation in CD4+ T-cells treated with phytohemagglutinin (PHA) (12,13). Other studies found that siRNA targeting IL-32 resulted in an increase in HIV replication (13). Together these findings suggested that the phenotypic changes in CD4+ T cells including the decrease in IL-32γ associated with HSV-2 may promote HIV-1 reactivation and/or replication. However, the molecular mechanisms underlying these changes and their effects on HIV-1 reactivation are not known.Activated CD4+ T cells are susceptible to HSV-2 infection in vitro ( 14) and virus has been detected in CD4+ T cells isolated from vesicle fluid of genital lesions and within biopsies of HSV-2 skin lesions (15). The recruitment and persistence of activated CD4+ T cells to the genital mucosa during HSV-2 reactivation (5) and potential for activated peripheral blood CD4+ T cells to be exposed to HSV during episodes of transient prompted us to postulate that HSV-2 might have direct or indirect bystander effects on CD4+ T cells to promote HIV-1 reactivation and/or replication. We therefore analyzed the effects of HSV-2 infection of activated primary CD4+ T cells and an immortalized human CD4+ T cell line model o...

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Section: Resultsmentioning

confidence: 99%

HSV-2 triggers upregulation of MALAT1 in CD4+ T cells and promotes HIV latency reversal

Pierce¹,

Loh²,

Steach³

et al. 2023

Journal of Clinical Investigation

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“…Cyclophilin A (CypA) belongs to the cellular cyclophilin family, essential for viral replication in a variety of viruses, such as hepatitis C virus (HCV), coronaviruses (CoVs) and HIV, and its polymorphisms affect viral susceptibility and disease progression ( Le Sage et al, 2014 ; Mamatis et al, 2022 ). CypA interacts with CypA binding loops at the N-terminal of HIV-1 CA, as described above.…”

Section: Human Immunodeficiency Virus Capsidmentioning

confidence: 99%

Human immunodeficiency virus-1 core: The Trojan horse in virus–host interaction

Wang

Zhang

et al. 2022

Front. Microbiol.

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Human immunodeficiency virus-1 (HIV-1) is the major cause of acquired immunodeficiency syndrome (AIDs) worldwide. In HIV-1 infection, innate immunity is the first defensive line for immune recognition and viral clearance to ensure the normal biological function of the host cell and body health. Under the strong selected pressure generated by the human body over thousands of years, HIV has evolved strategies to counteract and deceive the innate immune system into completing its lifecycle. Recently, several studies have demonstrated that HIV capsid core which is thought to be a protector of the cone structure of genomic RNA, also plays an essential role in escaping innate immunity surveillance. This mini-review summarizes the function of capsid in viral immune evasion, and the comprehensive elucidation of capsid-host cell innate immunity interaction could promote our understanding of HIV-1’s pathogenic mechanism and provide insights for HIV-1 treatment in clinical therapy.

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“…The mechanisms by which Cyps contribute to viral replication remain obscure, however they have been proposed to both induce conformational changes in target proteins (as a result of isomerase activity), and/or regulate protein complex formation [13]. An emerging theme is that Cyps protect either viral particles or replication complexes from cellular antiviral factors such as innate immune sensors [13]. Notably, both CypA and CypB are targets of the immunosuppressive drug cyclosporin A (CsA), and consequently CsA was demonstrated to inhibit HCV genome replication [14].…”

Section: Introductionmentioning

confidence: 99%

“…Cyps are one of the most abundant proteins in the cytoplasm (0.1-0.4 % of total protein content) and are expressed in all tissues [12]. The mechanisms by which Cyps contribute to viral replication remain obscure, however they have been proposed to both induce conformational changes in target proteins (as a result of isomerase activity), and/or regulate protein complex formation [13]. An emerging theme is that Cyps protect either viral particles or replication complexes from cellular antiviral factors such as innate immune sensors [13].…”

Section: Introductionmentioning

confidence: 99%

Mutational analysis reveals a novel role for hepatitis C virus NS5A domain I in cyclophilin-dependent genome replication

Chen,

Harris

2023

Journal of General Virology

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The hepatitis C virus (HCV) NS5A protein is comprised of three domains (D1–3). Previously, we observed that two alanine substitutions in D1 (V67A, P145A) abrogated replication of a genotype 2a isolate (JFH-1) sub-genomic replicon (SGR) in Huh7 cells, but this phenotype was partially restored in Huh7.5 cells. Here we demonstrate that five additional residues, surface-exposed and proximal to V67 or P145, exhibited the same phenotype. In contrast, the analogous mutants in a genotype 3a isolate (DBN3a) SGR exhibited different phenotypes in each cell line, consistent with fundamental differences in the functions of genotypes 2 and 3 NS5A. The difference between Huh7 and Huh7.5 cells was reminiscent of the observation that cyclophilin inhibitors are more potent against HCV replication in the former and suggested a role for D1 in cyclophilin dependence. Consistent with this, all JFH-1 and DBN3a mutants exhibited increased sensitivity to cyclosporin A treatment compared to wild-type. Silencing of cyclophilin A (CypA) in Huh7 cells inhibited replication of both JFH-1 and DBN3a. However, in Huh7.5 cells CypA silencing did not inhibit JFH-1 wild-type, but abrogated replication of all the JFH-1 mutants, and both DBN3a wild-type and all mutants. CypB silencing in Huh7 cells had no effect on DBN3a, but abrogated replication of JFH-1. CypB silencing in Huh7.5 cells had no effect on either SGR. Lastly, we confirmed that JFH-1 NS5A D1 interacted with CypA in vitro. These data demonstrate both a direct involvement of NS5A D1 in cyclophilin-dependent genome replication and functional differences between genotype 2 and 3 NS5A.

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Emerging Roles of Cyclophilin A in Regulating Viral Cloaking

Cited by 15 publications

References 84 publications

HSV-2 triggers upregulation of MALAT1 in CD4+ T cells and promotes HIV latency reversal

HSV-2 triggers upregulation of MALAT1 in CD4+ T cells and promotes HIV latency reversal

Human immunodeficiency virus-1 core: The Trojan horse in virus–host interaction

Mutational analysis reveals a novel role for hepatitis C virus NS5A domain I in cyclophilin-dependent genome replication

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