T-Cell and Neuronal Apoptosis in Hiv Infection: Implications for Therapeutic Intervention

Régulier, Emmanuel G.; Reiss, Kryzsztof; Khalili, Kamel; Amini, Shohreh; Rappaport, Jay; Zagury, Jean‐François; Katsikis, Peter D.

doi:10.1080/08830180490265538

Cited by 32 publications

(21 citation statements)

References 245 publications

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“…Taken together, our investigation and previous reports suggest that therapeutic strategies to reduce the level of inflammation and increase mucosal growth and injury repair should be investigated to enhance the efficacy of anti-HIV or -SIV therapy in restoring mucosal immune system. Down regulation of lymphocyte activation during HIV infection has been proposed by several investigators as a potential method to improve the rate of disease progression (3,5,17,24). It is also noteworthy that inhibitors of tumor necrosis factor have been shown to markedly reduce mucosal inflammation caused by infection of intestinal xenografts, suggesting that tumor necrosis factor-associated pathways may play an important role in the manifestation of intestinal inflammation in HIV and SIV infections (43).…”

Section: Discussionmentioning

confidence: 99%

Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4⁺T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration

George

Reay

Sankaran

et al. 2005

J Virol

114

118

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Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections lead to rapid depletion of CD4؉ T cells from gut-associated lymphoid tissue (GALT). Although the administration of antiretroviral therapy (ART) has been shown to increase CD4 ؉ T-cell levels in the peripheral blood in both SIV and HIV infections, its efficacy in restoring intestinal mucosal CD4؉ T cells has not been well investigated. To gain insights into the molecular mechanisms of virally induced disruptions in the mucosal immune system, we have evaluated longitudinal changes in viral burden, T-cell subsets, and mucosal gene expression profiles in SIV-infected rhesus macaques in the absence or presence of ART. Our results demonstrate a dramatic suppression of mucosal viral loads and rapid reconstitution of CD4 ؉ T cells in GALT in animals receiving ART that were not observed in untreated SIV-infected animals. DNA microarray-based gene expression profiling indicated that CD4؉ T-cell restoration in GALT was associated with up regulation of growth factors and genes involved in repair and regeneration of the mucosal epithelium. In contrast, untreated SIV-infected animals increased expression of lymphocyte activation and inflammatory response-associated genes and did not up regulate mucosal growth and repair associated transcription. In conclusion, these data indicate that initiating ART in primary SIV infection may lead to the restoration of the mucosal immune system through reduction of inflammation and promotion of epithelial repair in the intestinal mucosa.

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Section: Discussionmentioning

confidence: 99%

Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4⁺T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration

George

Reay

Sankaran

et al. 2005

J Virol

114

118

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“…For example, Regulier et al 32 and Luker and Leib 33 demonstrated that Tat exerts a negative effect on cell growth in neural cells in CNS, while Bettaccini et al 34 has noted mitogenic effects on mammary and amniotic epithelial cells. We found out that HIV-1 Tat protein was able to speed up proliferation of HeLa cells through increase in cyclin A expression and downregulation of CKIs.…”

Section: Hiv-1 Tat Oncogenic Role In Cervical Carcinogenesismentioning

confidence: 99%

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis

Nyagol¹,

Leucci²,

Onnis³

et al. 2006

Cancer Biology & Therapy

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The role of HPV in the carcinogenesis of intraepithelial and invasive anogenital lesions is currently well established. E6 and E7 oncoproteins of high-risk HPV genotypes are known to inactivate p53 and pRb pathways. Several studies have described an increased prevalence and recurrence of both cervical HPV infection and invasive cervical cancer among HIV-1 positive women compared to HIV-1 negative cases. For these reasons, cervical cancer is considered an AIDS-defining neoplasm. Unlike other AIDS-associated neoplasms, the occurrence of cervical cancer is independent of immune suppression. HIV-1 infection in patients with high grade precancerous lesions and invasive cervical cancers results in a therapy refractory and more aggressive disease phenotype, which is not yet well understood at the molecular level. An upregulation of HPV E6 and E7 gene expressions by HIV-1 proteins such as Tat has been documented by some authors. However, the role of HIV-1 in cervical carcinomas is still unclear. It is already known that HIV-1 Tat protein is able to influence cell cycle progression. Altogether, these facts led us to investigate the effects of Tat on the expression of cell cycle regulator genes. After transfection of HeLa cells with Tat, we analyzed the expression of cell cycle regulators from these cells by IHC and Real-time PCR. A significant reduction in the expression of cell cycle inhibitors of transcription and an increase in the levels of proliferation markers were observed. These results suggest that HIV-1 may enhance cervical carcinogenesis by promoting cell cycle progression. We also found that this HIV-1 Tat-induced cell proliferation was not dependent on the E2F family of transcription factors, and therefore postulate that Sp factors may be involved.

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“…The mechanisms of apoptosis in T cells and neurons appear to be similar, involving death receptors (TNF receptors and Fas), some chemokines, calcium dysregulation, mitochondrial membrane permeabilization and caspase activation. 123 Both gp120 and Tat may be key triggers of apoptosis in different cell types that die in HIV-1 AIDS. HIV-1-infected monocytes produce a protein called FLJ21908 that is cytotoxic to CD4( þ ) and CD8( þ ) T and B cells, as well as in neuroblastoma cells.…”

Section: Apoptosismentioning

confidence: 99%

Cell death in HIV dementia

2005

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Many patients infected with human immunodeficiency virus type-1 (HIV-1) suffer cognitive impairment ranging from mild to severe (HIV dementia), which may result from neuronal death in the basal ganglia, cerebral cortex and hippocampus. HIV-1 does not kill neurons by infecting them. Instead, viral proteins released from infected glial cells, macrophages and/ or stem cells may directly kill neurons or may increase their vulnerability to other cell death stimuli. By binding to and/or indirectly activating cell surface receptors such as CXCR4 and the N-methyl-D-aspartate receptor, the HIV-1 proteins gp120 and Tat may trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations. Membrane lipid metabolism and inflammation may also play important roles in determining whether neurons live or die in HIV-1-infected patients. Drugs and diets that target oxidative stress, excitotoxicity, inflammation and lipid metabolism are in development for the treatment of HIV-1 patients.

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T-Cell and Neuronal Apoptosis in Hiv Infection: Implications for Therapeutic Intervention

Cited by 32 publications

References 245 publications

Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4⁺T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration

Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4⁺T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis

Cell death in HIV dementia

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T-Cell and Neuronal Apoptosis in Hiv Infection: Implications for Therapeutic Intervention

Cited by 32 publications

References 245 publications

Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4+T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration

Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4+T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis

Cell death in HIV dementia

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Product

Resources

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Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4⁺T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration

Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4⁺T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration