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Combination antiretroviral therapy (cART) restores HIV-1 infection-mediated impairment of JAK-STAT signaling pathway.

ABSTRACT: JAK-STAT signaling pathway has a crucial role in host innate immunity against viral infections, including HIV-1. We therefore examined the impact of HIV-1 infection and combination antiretroviral therapy (cART) on JAK-STAT signaling pathway. Compared to age-matched healthy donors (n = 18), HIV-1-infected subjects (n = 18) prior to cART had significantly lower expression of toll-like receptors (TLR-1/4/6/7/8/9), the IFN regulatory factors (IRF-3/7/9), and the antiviral factors (OAS-1, MxA, A3G, PKR, and Tetherin). Three months' cART partially restores the impaired functions of JAK-STAT-mediated antiviral immunity. We also found most factors had significantly positive correlations (p < 0.05) between each two factors in JAK-STAT pathway in healthy donors (98.25%, 168/171), but such significant positive associations were only found in small part of HIV-1-infected subjects (43.86%, 75/171), and stably increased during the cART (57.31%, 98/171 after 6 months' cART). With regard to the restoration of some HIV-1 restriction factors, HIV-1-infected subjects who had CD4+ T cell counts > 350//?l responded better to cART than those with the counts < 350/?l. These findings indicate that the impairment of JAK-STAT pathway may play a role in the immunopathogenesis of HIV-1 disease.

SUBMITTER: Liu MQ

PROVIDER: S-EPMC5410242 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Combination antiretroviral therapy (cART) restores HIV-1 infection-mediated impairment of JAK-STAT signaling pathway.

Liu Man-Qing MQ Zhao Min M Kong Wen-Hua WH Tang Li L Wang Fang F Zhu Ze-Rong ZR Wang Xia X Qiu Hong-Yan HY Zhou Dun-Jin DJ Wang Xu X Ho Wen-Zhe WZ Zhou Wang W

Oncotarget 20170401 14

JAK-STAT signaling pathway has a crucial role in host innate immunity against viral infections, including HIV-1. We therefore examined the impact of HIV-1 infection and combination antiretroviral therapy (cART) on JAK-STAT signaling pathway. Compared to age-matched healthy donors (n = 18), HIV-1-infected subjects (n = 18) prior to cART had significantly lower expression of toll-like receptors (TLR-1/4/6/7/8/9), the IFN regulatory factors (IRF-3/7/9), and the antiviral factors (OAS-1, MxA, A3G, P ...[more]

PMID: 28186978

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Project description:Jak-STAT, Ras, Notch pathway genes and CD44 are frequently mutated in HIV-associated PBL, and together with transcriptomic features distinguish the disease from closely related B-cell cancers. Plasmablastic lymphoma (PBL) is an aggressive B-cell non-Hodgkin lymphoma associated with immunodeficiency in the context of human immunodeficiency virus (HIV) infection or iatrogenic immunosuppression. While a rare disease in general, the incidence is dramatically increased in regions of the world with high HIV prevalence. The molecular pathogenesis of this disease is poorly characterized. Here, we defined the genomic features of PBL in a cohort of 110 patients from South Africa (15 by whole-exome sequencing and 95 by deep targeted sequencing). We identified recurrent mutations in genes of the JAK–STAT signaling pathway, including STAT3 (42%), JAK1 (14%), and SOCS1 (10%), leading to its constitutive activation. Moreover, 24% of cases harbored gain-of-function mutations in RAS family members (NRAS and KRAS). Comparative analysis with other B-cell malignancies uncovered PBL-specific somatic mutations and transcriptional programs. We also found recurrent copy number gains encompassing the CD44 gene (37%), which encodes for a cell surface receptor involved in lymphocyte activation and homing, and was found expressed at high levels in all tested cases, independent of genetic alterations. These findings have implications for the understanding of the pathogenesis of this disease and the development of personalized medicine approaches. Significance: Plasmablastic lymphoma is a poorly studied and extremely aggressive tumor. Here we define the genomic landscape of this lymphoma in HIV-positive individuals from South Africa and identify pervasive mutations in JAK–STAT3 and RAS–MAPK signaling pathways. These data offer a genomic framework for the design of improved treatment strategies targeting these circuits. See related commentary by Küppers, p. 23. This article is highlighted in the In This Issue feature, p. 5

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Combination antiretroviral therapy (cART) restores HIV-1 infection-mediated impairment of JAK-STAT signaling pathway.

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Combination antiretroviral therapy (cART) restores HIV-1 infection-mediated impairment of JAK-STAT signaling pathway.

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