Disruption of Intestinal CD4+ T Cell Homeostasis Is a Key Marker of Systemic CD4+ T Cell Activation in HIV-Infected Individuals

Gordon, Shari N.; Cervasi, Barbara; Odorizzi, Pamela M.; Silverman, Randee; Aberra, Faten; Ginsberg, Gregory G.; Estes, Jacob D.; Paiardini, Mirko; Frank, Ian; Silvestri, Guido

doi:10.4049/jimmunol.1001801

Cited by 116 publications

(111 citation statements)

References 46 publications

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“…This conclusion is further supported by the fact that the increased turnover of T cells observed during chronic HIV-1 infection is driven by HIV-1-associated immune activation (41,44,45), and this increased T cell turnover is observed in blood and lymph nodes of HIV-1 patients (44,(46)(47)(48)(49). Furthermore, CD8 + T cells show evidence of increased proliferation during HIV-1 infection (50). Together these data indicate that HIV-1 represents a dominant source of cellular activation and proliferation for both CD4 + and CD8 + T cells.…”

Section: Discussionsupporting

confidence: 58%

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

Bastidas

Graw

Smith

et al. 2014

The Journal of Immunology

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Hyperactivation of T cells, particularly of CD8+ T cells, is a hallmark of chronic HIV 1 (HIV-1) infection. Little is known about the antigenic specificities and the mechanisms by which HIV-1 causes activation of CD8+ T cells during chronic infection. We report that CD8+ T cells were activated during in vivo HIV-1 replication irrespective of their Ag specificity. Cytokines present during untreated HIV-1 infection, most prominently IL-15, triggered proliferation and expression of activation markers in CD8+ T cells, but not CD4+ T cells, in the absence of TCR stimulation. Moreover, LPS or HIV-1–activated dendritic cells (DCs) stimulated CD8+ T cells in an IL-15–dependent but Ag-independent manner, and IL-15 expression was highly increased in DCs isolated from viremic HIV-1 patients, suggesting that CD8+ T cells are activated by inflammatory cytokines in untreated HIV-1 patients independent of Ag specificity. This finding contrasts with CD4+ T cells whose in vivo activation seems biased toward specificities for persistent Ags. These observations explain the higher abundance of activated CD8+ T cells compared with CD4+ T cells in untreated HIV-1 infection.

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Section: Discussionsupporting

confidence: 58%

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

Bastidas

Graw

Smith

et al. 2014

The Journal of Immunology

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“…Dr. Estes uses a classic marker of immune activation and proliferation, Ki67, which provides a generalized view of the activation state of lymphatic tissue in immunohistochemical studies. 56 The Estes group also uses the myxovirus-resistant protein A (MxA), which is tightly regulated and controlled by Type I interferons. They found a dramatic up-regulation of MxA in the lamina propria of the large bowel in both rhesus macaques and sooty mangabeys shortly after SIV infection.…”

Section: Markers In Hiv-infected Tissuesmentioning

confidence: 99%

Immune Activation in the Pathogenesis of Treated Chronic HIV Disease: A Workshop Summary

Plaeger

Collins

Musib

et al. 2012

AIDS Research and Human Retroviruses

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With the advent of highly effective antiretroviral therapy (ART), infection with human immunodeficiency virus (HIV) has become a chronic disease rather than a death sentence. Nevertheless, effectively treated individuals have a higher than normal risk for developing noninfectious comorbidities, including cardiovascular and renal disease. Although traditional risk factors of aging as well as treatment toxicity contribute to this risk, many investigators consider chronic HIV-associated inflammation a significant factor in such end-organ disease. Despite effective viral suppression, chronic inflammation persists at levels higher than in uninfected people, yet the stimuli for the inflammation and the mechanism by which inflammation persists and promotes disease pathology remain incompletely understood. This critical gap in scientific understanding complicates and hampers effective decision making about appropriate medical intervention. To better understand the mechanism(s) of chronic immune activation in treated HIV disease, three questions need answers: (1) what is the cause of persistent immune activation during treated HIV infection, (2) what are the best surrogate markers of chronic immune activation in this setting, and (3) what therapeutic intervention(s) could prevent or reverse this process? The NIH sponsored and convened a meeting to discuss the state of knowledge concerning these questions and the best course for developing effective therapeutic strategies. This report summarizes the findings of that NIH meeting.

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“…The disease progression of SIV/HIV is associated with depletion of Th17 cells from the GALT, a process that subsequently leads to impaired mucosal permeability and microbial translocation from the gut (33)(34)(35)(36)(37). Antiretroviral therapy (ART) is associated with a partial restoration of the CD4 + T cell and Th17 into the GALT (38)(39)(40). Thus, it appears that HIV causes dramatic alterations in mucosal immunity by efficiently infecting CD4 + T cells that are present at the portal sites of entry.…”

mentioning

confidence: 99%

Memory CCR6+CD4+ T Cells Are Preferential Targets for Productive HIV Type 1 Infection Regardless of Their Expression of Integrin β7

Monteiro

Gosselin

Wacleche

et al. 2011

The Journal of Immunology

129

162

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HIV type 1 infection is associated with a rapid depletion of Th17 cells from the GALT. The chemokine receptor CCR6 is a marker for Th17 lineage polarization and HIV permissiveness in memory CD4+ T cells. CCR6+ T cells have the potential to migrate into the GALT via the gut-homing integrin α4β7, a newly identified HIV-gp120 binding receptor. In this study, we investigated whether memory T cells coexpressing CCR6 and integrin β7 are selective HIV targets and whether retinoic acid (RA)-induced imprinting for gut-homing selectively increases CCR6+ T cell permissiveness to infection. We demonstrated that β7−R6+ and β7+R6+ compared with β7−R6− and β7+R6− T cells were highly permissive to HIV, produced Th17 cytokines, and their frequency was decreased in the peripheral blood of HIV-infected subjects. RA upregulated integrin α4 and β7 coexpression in both CCR6+ and CCR6− T cells, but increased HIV permissiveness selectively in CCR6+ T cells via entry (CCR5 upregulation) and postentry mechanisms. In conclusion, these results demonstrate that CCR6, but not the integrin β7, is a discriminative marker for memory T cells imprinted with a transcriptional program favorable to HIV replication. Nevertheless, given the ability of integrin β7 to regulate cell migration into the GALT and bind HIV-gp120, CCR6+ T cells coexpressing integrin β7 and CCR5 might have an extraordinary ability to disseminate HIV from the portal sites of entry. Understanding the molecular mechanisms of memory CCR6+ T cell differentiation is critical for the design of new therapeutic strategies that should interfere with viral permissiveness but not Th17 lineage commitment and gut-homing potential in CCR6+ T cells.

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Disruption of Intestinal CD4+ T Cell Homeostasis Is a Key Marker of Systemic CD4+ T Cell Activation in HIV-Infected Individuals

Cited by 116 publications

References 46 publications

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

Immune Activation in the Pathogenesis of Treated Chronic HIV Disease: A Workshop Summary

Memory CCR6+CD4+ T Cells Are Preferential Targets for Productive HIV Type 1 Infection Regardless of Their Expression of Integrin β7

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