Relationship between T Cell Activation and CD4<sup>+</sup>T Cell Count in HIV‐Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy

Hunt, Peter W.; Brenchley, Jason M.; Sinclair, Elizabeth; McCune, Joseph M.; Roland, Michelle E.; Page, Kimberly; Hsue, Priscilla Y.; Emu, Brinda; Krone, Melissa; Lampiris, Harry; Douek, Daniel C.; Martin, Jeffrey N.; Deeks, Steven G.

doi:10.1086/524143

Cited by 583 publications

(605 citation statements)

References 48 publications

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“…HIV virions have multiple means to promote immune activation, among which are double-stranded RNA binding to Toll-like receptors (15), binding of gp120 to cell surface receptors (11), Tat internalization by uninfected cells (12), and antigenic stimulation (17). Current studies also show that microbial translocation can be associated with immune activation in HIV-1-infected individuals independently of the viral load (13), which may also be the case in HIV-2-infected individuals. Thus, in HIV-2-infected individuals, the association of immune activation and downregulation of the TCR by Nef is present and visible at low activation levels but is likely masked by the activation induced by viral replication in Ps.…”

Section: Vol 83 2009 Hiv-2 Nef Does Not Protect Against Disease Promentioning

confidence: 94%

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

Feldmann

Leligdowicz

Jaye

et al. 2009

J Virol

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Chronic immune activation is thought to play a major role in human immunodeficiency virus (HIV) pathogenesis, but the relative contributions of multiple factors to immune activation are not known. One proposed mechanism to protect against immune activation is the ability of Nef proteins from some HIV and simian immunodeficiency virus strains to downregulate the T-cell receptor (TCR)-CD3 complex of the infected cell, thereby reducing the potential for deleterious activation. HIV type 1 (HIV-1) Nef has lost this property. In contrast to HIV-1, HIV-2 infection is characterized by a marked disparity in the disease course, with most individuals maintaining a normal life span. In this study, we examined the relationship between the ability of HIV-2 Nef proteins to downregulate the TCR and immune activation, comparing progressors and nonprogressors. Representative Nef variants were isolated from 28 HIV-2-infected individuals. We assessed their abilities to downregulate the TCR from the surfaces of CD4 T cells. In the same individuals, the activation of peripheral lymphocytes was evaluated by measurement of the expression levels of HLA-DR and CD38. We observed a striking correlation of the TCR downregulation efficiency of HIV-2 Nef variants with immune activation in individuals with a low viral load. This strongly suggests that Nef expression can influence the activation state of the immune systems of infected individuals. However, the efficiency of TCR downregulation by Nef was not reduced in progressing individuals, showing that TCR downregulation does not protect against progression in HIV-2 infection.

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Section: Vol 83 2009 Hiv-2 Nef Does Not Protect Against Disease Promentioning

confidence: 94%

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

Feldmann

Leligdowicz

Jaye

et al. 2009

J Virol

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“…In addition, newly generated activated T cells are themselves targets of HIV infection, in turn sustaining viral replication (10) and therefore creating a self-perpetuating vicious circle between HIV replication and immune activation. For these reasons, it is not surprising that the magnitude of this chronic immune activation has been long identified as a major determinant of disease progression independent of the level of virus replication (5,11,12). Of note, antiretroviral therapy (ART), which results in the complete suppression of HIV replication, is not sufficient to fully turn off immune activation, and indeed, HIV-infected individuals with poor CD4 ϩ recovery on virologically suppressive ART often exhibit higher levels of immune activation (13,14).…”

Section: Introductionmentioning

confidence: 99%

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

2013

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SUMMARYIn pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections, the translocation of microbial products from the gastrointestinal (GI) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. Consistently, microbial translocation is not present in nonpathogenic SIV infections of natural host species.In vivostudies demonstrated that HIV/SIV-associated microbial translocation results from a series of immunopathological events occurring at the GI mucosa: (i) early and severe mucosal CD4+depletion, (ii) mucosal immune hyperactivation/persistent inflammation; (iii) damage to the integrity of the intestinal epithelium with enterocyte apoptosis and tight junction disruption; and (iv) subverted the gut microbiome, with a predominance of opportunistic bacteria. Directin situevidence of microbial translocation has been provided for SIV-infected rhesus macaques showing translocated microbial products in the intestinal lamina propria and distant sites. While the mechanisms by which microbial translocation causes immune activation remain controversial, a key pathogenic event appears to be innate immunity activation via Toll-like receptors and other pathogen recognition receptors. Accumulating clinical observations suggest that microbial translocation might affect HIV disease progression, response to therapy, and non-AIDS comorbidities. Given its detrimental effect on overall immunity, several interventions to prevent/block microbial translocation are currently under investigation as novel therapeutic agents for HIV/AIDS.

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“…14,15 Various clinical factors have been associated with impaired CD4 T-cell reconstitution following cART, including lower CD4 T-cell counts at initiation of cART, [16][17][18][19] being older at cART initiation 1,17,19,20 and higher levels of immune activation both before and while on cART as measured by T-cell activation markers (such as human leukocyte antigen (HLA)-DR þ CD38 þ expression). [21][22][23][24] Multiple host genetic factors have also been found to influence CD4 T-cell recovery. [25][26][27][28][29][30][31] We recently demonstrated by using a multivariable model that IL-7Ra haplotype-2 was a significant predictor of more rapid CD4 T-cell recovery following suppressive cART in an Australian-based largely Caucasian HIVinfected cohort.…”

Section: Introductionmentioning

confidence: 99%

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

et al. 2011

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We previously found an association between faster CD4 þ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-a (IL-7Ra) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n ¼ 352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Ra single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n ¼ 57). Soluble (s)IL-7Ra levels were measured by ELISA. In UARTO, IL-7Ra haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P ¼ 0.020) and no association was found with LMM (P ¼ 0.958). The tagging-SNP for IL-7Ra haplotype-2 (rs6897932) was associated with decreased sIL-7Ra (Po0.001). The haplotypes for the IL-7Ra were significantly different in Africans and Caucasians. Using IL-7Ra genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P ¼ 0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P ¼ 0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Ra haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Ra SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

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Relationship between T Cell Activation and CD4⁺T Cell Count in HIV‐Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy

Abstract: HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.

Cited by 583 publications

References 48 publications

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

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Relationship between T Cell Activation and CD4+T Cell Count in HIV‐Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy

Abstract: HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.

Cited by 583 publications

References 48 publications

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

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Product

Resources

About

Relationship between T Cell Activation and CD4⁺T Cell Count in HIV‐Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy