Dynamic Regulation of Host Restriction Factor Expression over the Course of HIV-1 Infection
            <i>In Vivo</i>

Raposo, Rui André Saraiva; Abdel‐Mohsen, Mohamed; Deng, Xutao; Hecht, Frederick M.; Pilcher, Christopher D.; Pillai, Satish K.; Nixon, Douglas F.

doi:10.1128/jvi.01771-14

Cited by 15 publications

(17 citation statements)

References 16 publications

(18 reference statements)

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“…In chronic HIV‐1 infection, CD4+ T cell activation is elevated in viremic non‐controller patients and it gradually decreases from ART‐suppressed to elite controllers; it is low in HIV‐1 seronegative individuals . We have previously reported a strong correlation between the levels of CD4+ T‐cell activation and the expression of antiviral genes . Curiously, we did not observe elevated antiviral gene expression in psoriatic peripheral blood, despite the increased activation levels previously shown in psoriatic PBMCs .…”

Section: Discussioncontrasting

confidence: 63%

“…22 We have previously reported a strong correlation between the levels of CD4+ Tcell activation and the expression of antiviral genes. 10,23 Curiously, we did not observe elevated antiviral gene expression in psoriatic peripheral blood, despite the increased activation levels previously shown in psoriatic PBMCs. 24 It is possible that psoriatic autoantigens are expressed primarily in the skin and thus the observed antiviral immune responses localize preferentially in skin.…”

Section: Discussioncontrasting

confidence: 43%

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Antiviral gene expression in psoriasis

Raposo

Gupta

Abdel‐Mohsen

et al. 2015

Acad Dermatol Venereol

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Background Psoriasis patients have relatively infrequent cutaneous viral infections compared to atopic dermatitis patients. Increased expression of four antiviral proteins (MX1, BST2, ISG15, and OAS2) has been reported in psoriatic skin and genetic studies of psoriasis have identified susceptibility genes in antiviral pathways. Objective To determine if psoriasis is associated with pervasive expression of antiviral genes in skin and blood. Methods We performed RNA-sequencing on skin samples of 18 subjects with chronic plaque psoriasis and 16 healthy controls. We examined the expression of a pre-defined set of 42 antiviral genes, each of which has been shown in previous studies to inhibit viral replication. In parallel, we examined antiviral gene expression in atopic dermatitis, non-lesional psoriatic skin, and psoriatic blood. We performed HIV-1 infectivity assays in CD4+ peripheral blood T cells from psoriatic and healthy individuals. Results We observed significant overexpression of 16 antiviral genes in lesional psoriatic skin, with a greater than two-fold increase in ISG15, RSAD2, IRF7, MX2, and TRIM22 (p<1E-07). None of these genes was overexpressed in atopic dermatitis skin (p<0.0001) or non-lesional psoriatic skin. In contrast to the skin compartment, no differences in antiviral gene expression were detected in the peripheral blood of psoriasis cases compared to healthy controls. CD4+ T cells from both psoriatic and healthy patients supported HIV-1 infection at a similar rate. Conclusion Our findings highlight psoriasis as an inflammatory disease with cutaneous but not systemic immune activation against viral pathogens.

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Section: Discussioncontrasting

confidence: 63%

Section: Discussioncontrasting

confidence: 43%

Antiviral gene expression in psoriasis

Raposo

Gupta

Abdel‐Mohsen

et al. 2015

Acad Dermatol Venereol

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“…Cell-based measurements of viral persistence are consistently associated with markers of immune activation and the frequency of PD-1-expressing CD4+ T cells [5]. In contrast to previously published data on ART-untreated individuals revealing positive correlations between restriction factor expression, viral load and T cell activation [30, 58, 59], the expression of several restriction factors during ART exhibited significant negative correlations with percentage of CD4+ T cells expressing markers of T-cell activation and exhaustion. Our data therefore suggest that ART may perturb the biology and regulation of restriction factors, which may have important implications for the development of HIV curative strategies.…”

Section: Discussionmentioning

confidence: 99%

Select host restriction factors are associated with HIV persistence during antiretroviral therapy

Abdel‐Mohsen

Wang

Strain

et al. 2015

Aids

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Objective The eradication of HIV necessitates elimination of the HIV latent reservoir. Identifying host determinants governing latency and reservoir size in the setting of antiretroviral therapy (ART) is an important step in developing strategies to cure HIV infection. We sought to determine the impact of cell-intrinsic immunity on the HIV latent reservoir. Design We investigated the relevance of a comprehensive panel of established anti-HIV-1 host restriction factors to multiple established virologic and immunologic measures of viral persistence in HIV-1-infected, ART-suppressed individuals. Methods We measured the mRNA expression of 42 anti-HIV-1 host restriction factors, levels of cell-associated HIV-1 RNA, levels of total pol and 2-LTR circle HIV-1 DNA, and immunophenotypes of CD4+ T cells in 72 HIV-1-infected subjects on suppressive ART (23 subjects initiated ART <1 year post-infection, and 49 subjects initiated ART >1 year post-infection). Correlations were analyzed using non-parametric tests. Results The enhanced expression of a few select host restriction factors, p21, schlafen 11, and PAF1, was strongly associated with reduced CD4+ T cell-associated HIV RNA during ART (p<0.001). In addition, our data suggested that ART perturbs the regulatory relationship between CD4+ T cell activation and restriction factor expression. Lastly, cell-intrinsic immune responses were significantly enhanced in subjects who initiated ART during early versus chronic infection, and may contribute to the reduced reservoir size observed in these individuals. Conclusions Intrinsic immune responses modulate HIV persistence during suppressive ART, and may be manipulated to enhance the efficacy of ART and promote viral eradication through reversal of latency in vivo.

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“…A customized RNA expression array (1,13,14) was used to measure the baseline expression levels of antiviral genes and restriction factors in fetal and adult monocytes and MDMs. Compared with fetal monocytes, adult monocytes had significantly higher levels of expression of the following genes: APOBEC3A ( p < 0.05), CDKN1A ( p < 0.01), EI-F2AK2 ( p < 0.01), HERC5 ( p < 0.05), ISG15 ( p < 0.01), MX2 ( p < 0.001), PML/TRIM19 ( p < 0.01), RSAD2 ( p < 0.001), and TRIM22 ( p < 0.01) (Mann-Whitney t-test) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previous work by our group led to the development of a quantitative polymerase chain reaction (PCR)-based array capable of examining the expression of a predefined set of antiviral genes in primary cells from adults who were healthy (15), HIV-infected (14), and psoriatic (16). Here, we hypothesized that differential transcriptional patterns found in adult versus fetal monocytes and monocyte-derived macrophages (MDMs) might lead to differential expression of restriction factors and other antiviral genes, as detected by this assay.…”

Section: Introductionmentioning

confidence: 99%

Relative mRNA Expression Levels of Restriction Factors and Antiviral Genes in Fetal and Adult Human Monocytes and Monocyte-Derived Macrophages

et al. 2017

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Among untreated HIV-infected pregnant women, the frequency of mother-to-child transmission of HIV is low (5-10%), with most infections occurring at or after birth. Given findings that fetal and adult monocytes are distinct from one another in terms of basal transcriptional profiles, and in phosphorylation of signal transducer and activators of transcription in response to cytokines, we hypothesized that fetal CD14+CD16-monocyte and monocyte-derived macrophages (MDMs) might, compared to their adult counterparts, express higher levels of transcripts for restriction factors and antiviral factors at baseline and/or after stimulation with cytokines that might be induced upon transmission of HIV in utero, for example, IFNa, IFNc, and IL-6. We carried out these experiments and noted that a few genes, including APOBEC3B, APOBEC3C, and IFITM2, were expressed to a greater degree in fetal monocytes compared to adults. Similarly, the expression levels of APOBEC3F and TRIM32 were greater in fetal MDMs. However, most of these differences were not observed after stimulation with cytokines and the vast majority of antiviral genes were more highly expressed in adults. Therefore, the results of this study are not consistent with the hypothesis that increased expression of antiviral genes in fetal myeloid cells confers immune protection to fetuses in utero.

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Dynamic Regulation of Host Restriction Factor Expression over the Course of HIV-1 Infection In Vivo

Cited by 15 publications

References 16 publications

Antiviral gene expression in psoriasis

Antiviral gene expression in psoriasis

Select host restriction factors are associated with HIV persistence during antiretroviral therapy

Relative mRNA Expression Levels of Restriction Factors and Antiviral Genes in Fetal and Adult Human Monocytes and Monocyte-Derived Macrophages

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