HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells

Catálfamo, Marta; Mascio, Michele Di; Hu, Zonghui; Srinivasula, Sharat; Thaker, Vishakha; Adelsberger, Joseph W.; Rupert, Adam; Baseler, Michael; Tagaya, Yutaka; Roby, Gregg; Rehm, Catherine; Follmann, Dean; Lane, H. Clifford

doi:10.1073/pnas.0810032105

Cited by 116 publications

(110 citation statements)

References 41 publications

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“…Proliferation of CD4 T cells is driven by a combination of the homeostatic response to CD4 T cell depletion (CD4 T cell counts) and viral load (HIV RNA levels). In contrast, CD8 T cell proliferation is driven mainly by HIV RNA levels (6).…”

Section: H Uman Immunodeficiency Virus Infection Is Characterizedmentioning

confidence: 99%

“…Complete CD4 T cell reconstitution after antiretroviral therapy (ART) is a slow process that typically requires many years and depends on the CD4 T cell number prior to therapy (9)(10)(11). In contrast, CD8 T cell numbers are already expanded, and the CD8 T cell pool does not seem to be influenced by the homeostatic forces associated with CD4 T cell depletion (6).…”

Section: H Uman Immunodeficiency Virus Infection Is Characterizedmentioning

confidence: 99%

“…During untreated HIV infection, the homeostatic response to CD4 T cell depletion occurs in an Ag-rich inflammatory environment. Together these forces contribute to increased proliferation in both CD4 and CD8 T cells (6). Complete CD4 T cell reconstitution after antiretroviral therapy (ART) is a slow process that typically requires many years and depends on the CD4 T cell number prior to therapy (9)(10)(11).…”

Section: H Uman Immunodeficiency Virus Infection Is Characterizedmentioning

confidence: 99%

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CD4 and CD8 T Cell Immune Activation during Chronic HIV Infection: Roles of Homeostasis, HIV, Type I IFN, and IL-7

Catálfamo

Wilhelm

Tcheung

et al. 2011

The Journal of Immunology

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112

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Immune activation plays an important role in the pathogenesis of HIV disease. Although the causes are not fully understood, the forces that lead to immune dysfunction differ for CD4 and CD8 T cells. In this study, we report that the molecular pathways that drive immune activation during chronic HIV infection are influenced by differences in the homeostatic regulation of the CD4 and CD8 T cell pools. Proliferation of CD4 T cells is controlled more tightly by CD4 T cell numbers than is CD8 T cell proliferation. This difference reflects the importance of maintaining a polyclonal CD4 T cell pool in host surveillance. Both pools of T cells were found to be driven by viral load and its associated state of inflammation. In the setting of HIV-induced lymphopenia, naive CD4 T cells were recruited mainly into the proliferating pool in response to CD4 T cell depletion, whereas naive CD8 T cell proliferation was driven mainly by levels of HIV RNA. RNA analysis revealed increased expression of genes associated with type I IFN and common γ chain cytokine signaling in CD4 T cell subsets and only type I IFN-associated genes in CD8 T cell subsets. In vitro studies demonstrated enhanced STAT1 phosphorylation in response to IFN-α and increased expression of the IFNAR1 transcripts in naive and memory CD4 T cells compared with that observed in CD8 T cells. CD4 T cell subsets also showed enhanced STAT1 phosphorylation in response to exogenous IL-7.

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Section: H Uman Immunodeficiency Virus Infection Is Characterizedmentioning

confidence: 99%

Section: H Uman Immunodeficiency Virus Infection Is Characterizedmentioning

confidence: 99%

Section: H Uman Immunodeficiency Virus Infection Is Characterizedmentioning

confidence: 99%

See 1 more Smart Citation

CD4 and CD8 T Cell Immune Activation during Chronic HIV Infection: Roles of Homeostasis, HIV, Type I IFN, and IL-7

Catálfamo

Wilhelm

Tcheung

et al. 2011

The Journal of Immunology

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112

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“…With the use of combination antiretroviral therapy (cART), prolonged viral suppression of plasma HIV-RNA levels (pVL) < 40 copies per milliliter is achievable in the majority of patients with HIV-1 infection (1). One paradoxical observation is that, despite prolonged viral suppression with no evidence of active viral replication, the majority of HIV-infected patients exhibit persistent presence of HIV-1 proviruses (2-4), persistent seropositivity to HIV-1 (5), and evidence of immune activation (6)(7)(8)(9)(10). The only setting in which this has not been the case has been following bone marrow transplantation in which seronegativity has been reported in association with a loss of peripheral blood proviral DNA (11,12).…”

mentioning

confidence: 99%

Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy

Imamichi

Dewar

Adelsberger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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298

313

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Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. By combining 5′LTR-to-3′LTR single-genome amplification and direct amplicon sequencing, we have identified the presence of “defective” proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection. Although these novel usHIV-RNA transcripts had exon structures that were different from those of the known spliced HIV-RNA variants, they maintained translationally competent ORFs, involving elements of gag, pol, env, rev, and nef to encode a series of novel HIV-1 chimeric proteins. These novel usHIV-RNAs were detected in five of five patients, including four of four patients with prolonged viral suppression of HIV-RNA levels <40 copies per milliliter for more than 6 y. Our findings suggest that the persistent defective proviruses of HIV-1 are not “silent,” but rather may contribute to HIV-1 pathogenesis by stimulating host-defense pathways that target foreign nucleic acids and proteins.

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“…19 This was not the case ( Table 1). The negative correlations of total CD3, CD4, and CD8 T cells, plus other T cell subsets, may be due to perturbed trafficking in response to changes in antigen load as reflected in changes in pVL.…”

mentioning

confidence: 66%

Short Communication: HIV Blips While on Antiretroviral Therapy Can Indicate Consistently Detectable Viral Levels Due to Assay Underreporting

Murray

Zaunders²,

Koelsch³

et al. 2013

AIDS Research and Human Retroviruses

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Viral blips, where HIV RNA plasma viral load (pVL) intermittently increases above the lower limit of assay detection, are a cause for concern. We investigated a number of hypotheses for their cause. We assessed HIV RNA, and total and episomal HIV DNA from 16 individuals commencing antiretroviral therapy (ART) consisting of raltegravir and tenofovir/emtricitabine for 3 years, using two assays: a single-copy assay [SCA; lower limit of quantification (LLOQ), < 1 copy/ml] and the Amplicor assay (LLOQ of 50 copies/ml). Two individuals exhibited viral blips. From week 20 onward, the period where ART had achieved its final suppressive levels, pVL ranged from < 1 to 330 copies/ml, except for one individual at the final time. Both assays were 98% consistent (108/110) in assessing pVL < 50 copies/ml, but the Amplicor assay registered 56% of samples (19/34) as below the LLOQ that were in the 50 to 1000 copy/ml range as quantified by SCA. pVL changes between successive time points did not correlate with changes in cellular infection as measured through either total or episomal HIV DNA. Changes in pVL were correlated (negatively) with changes in total CD4+ T cell numbersPatients receiving stable, seemingly suppressive ART can have pVL near the 50 copy LLOQ at multiple time points. The high Amplicor assay error rate around this level implies that viral blips underrepresent pVL being more consistently above the LLOQ. Activation of latently infected cells is less likely to contribute to this phenomenon. S uppression of HIV plasma viral load (pVL) to as low levels as possible and for as long as possible is the primary goal of antiretroviral therapy (ART). Sudden rises of pVL in a patient after extended periods in the undetectable range ( < 50 copies/ml for many assays) can be a cause for concern for both physician and patient. A consistent increase in pVL is often a sign of ART failure, most likely due to noncompliance, low plasma drug levels, or the outgrowth of a drug-resistant viral quasispecies. The clinical implications of viral "blips," where seemingly random detectable pVL levels occur amongst undetectable ones, are less clear.A number of theories have been advanced to explain viral blips, but there are essentially two hypotheses: (1) differences in detection of pVL at or around the lower limits of assay quantification (LLOQ) occur through errors in the reproducibility of the assays and fluctuations of pVL around mean HIV RNA levels below the LLOQ 1-3 ; and (2) new rounds of viral replication arise through a variety of mechanisms resulting in rapid increases in pVL above the LLOQ from previously low levels. [4][5][6] An underlying assumption with the second hypothesis is that successful ART suppresses pVL much lower than 50 copies/ml and a blip represents a large change in pVL.We investigated these questions using data from 16 HIVinfected, therapy-naive patients [eight primary (PHI) and eight chronic (CHI)] commencing raltegravir and Truvada (tenofovir/emtricitabine) who were followed for 3 years (the PINT Study 7...

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HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells

Cited by 116 publications

References 41 publications

CD4 and CD8 T Cell Immune Activation during Chronic HIV Infection: Roles of Homeostasis, HIV, Type I IFN, and IL-7

CD4 and CD8 T Cell Immune Activation during Chronic HIV Infection: Roles of Homeostasis, HIV, Type I IFN, and IL-7

Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy

Short Communication: HIV Blips While on Antiretroviral Therapy Can Indicate Consistently Detectable Viral Levels Due to Assay Underreporting

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