CD4+ recent thymic emigrants are infected by HIV in vivo, implication for pathogenesis

Fabre-Mersseman, Véronique; Dutrieux, Jacques; Louise, Anne; Rozlan, Sandra; Lamine, Aurélia; Parker, Raphaëlle; Rancez, Magali; Nunes‐Cabaço, Helena; Sousa, Ana E.; Lambotte, Olivier; Cheynier, Rémi

doi:10.1097/qad.0b013e3283471e89

Cited by 25 publications

(13 citation statements)

References 57 publications

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“…This finding indicates that quantification of viral DNA alone is not necessarily predictive of the size of the inducible latent reservoir and suggests caution in labeling a cellular reservoir of latent HIV-1 as "major" based solely on the frequency of infection. In addition to the memory CD4 ϩ T cell subsets, HIV-1 DNA is almost always detected in T N cells in both viremic and suppressed individuals, although with a much lower frequency than in the T CM and T TM compartments (6,7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Interestingly, in 2013 Saez-Cirion et al reported that in some HIV-1-infected individuals who received ART within 10 weeks of primary infection, viremia could be controlled for at least 24 months posttreatment interruption (8).…”

Section: A Latent Hiv-1 Reservoir Is Established In Resting Cd4mentioning

confidence: 99%

Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4⁺T CellsIn Vitro

Zerbato

Serrao

Lenzi

et al. 2016

J Virol

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The latent HIV-1 reservoir primarily resides in resting CD4؉ T cells which are a heterogeneous population composed of both naive (T N ) and memory cells. In HIV-1-infected individuals, viral DNA has been detected in both naive and memory CD4 ؉ T cell subsets although the frequency of HIV-1 DNA is typically higher in memory cells, particularly in the central memory (T CM ) cell subset. T N and T CM cells are distinct cell populations distinguished by many phenotypic and physiological differences. In this study, we used a primary cell model of HIV-1 latency that utilizes direct infection of highly purified T N and T CM cells to address differences in the establishment and reversal of HIV-1 latency. Consistent with what is seen in vivo, we found that HIV-1 infected T N cells less efficiently than T CM cells. However, when the infected T N cells were treated with latency-reversing agents, including anti-CD3/CD28 antibodies, phorbol myristate acetate/phytohemagglutinin, and prostratin, as much (if not more) extracellular virion-associated HIV-1 RNA was produced per infected T N cell as per infected T CM cell. There were no major differences in the genomic distribution of HIV-1 integration sites between T N and T CM cells that accounted for these observed differences. We observed decay of the latent HIV-1 cells in both T cell subsets after exposure to each of the latency-reversing agents. Collectively, these data highlight significant differences in the establishment and reversal of HIV-1 latency in T N and T CM CD4؉ T cells and suggest that each subset should be independently studied in preclinical and clinical studies. IMPORTANCE The latent HIV-1 reservoir is frequently described as residing within resting memory CD4؉ T cells. This is largely due to the consistent finding that memory CD4 ؉ T cells, specifically the central (T CM )

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Section: A Latent Hiv-1 Reservoir Is Established In Resting Cd4mentioning

confidence: 99%

Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4⁺T CellsIn Vitro

Zerbato

Serrao

Lenzi

et al. 2016

J Virol

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“…However, CDR3 diversity in T SCM is reduced during aging and, in the absence of cognate epitopes, T SCM persistence depends heavily on homeostatic proliferation (mediated through IL-7, IL-15, or IL-21) and the differentiation of scarce T RTE 11 . An increase in IL-7 levels was further correlated to the loss of naive 64 and CD4 T RTE cells 65 , which are both predictive of poor HIV prognosis [64][65][66] . Furthermore, co-infection with HCV presents an additional burden that contributes to the loss of T RTE 67 .…”

Section: Discussionmentioning

confidence: 92%

Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway

et al. 2020

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The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (T SCM ) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that T SCM heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/β-catenin signature in CD4 T SCM and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/β-catenin pathway. Functional assays support recent thymic emigrants as the precursors of CD4 T SCM . Our data thus hint that reversing T SCM defects by metabolic targeting of the Wnt/β-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history.

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“…As most naïve Tregs are generated in the thymus, they express high levels of CD31, which is a marker for recent thymic emigrants [ 30 , 37 ]. To understand whether the impairment on the recovery of the CD45RA + Tregs population was associated with lower thymic output, we quantified CD45RA + Tregs expressing high levels of CD31 (CD45RA + CD31 hi Tregs), which should reflect blood's Tregs most recently exported from the thymus [ 38 , 39 ]. We observed that the CD45RA + CD31 hi Tregs counts were consistently lower in HIV-infected patients with CD4 + T-cell counts less than 350 cells/μl, irrespective of their time on ART, in comparison to uninfected individuals (Fig.…”

Section: Resultsmentioning

confidence: 99%

Longitudinal evaluation of regulatory T-cell dynamics on HIV-infected individuals during the first 2 years of therapy

Nóbrega

Horta

Coutinho-Teixeira

et al. 2016

Aids

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Objectives:A sizeable percentage of individuals infected by HIV and on antiretroviral therapy (ART) fail to increase their CD4+ T-cells to satisfactory levels. The percentage of regulatory T-cells (Tregs) has been suggested to contribute to this impairment. This study aimed to address this question and to expand the analysis of Tregs subpopulations during ART.Design:Longitudinal follow-up of 81 HIV-infected individuals during the first 24 months on ART.Methods:CD4+ T-cell counts, Tregs percentages, and specific Tregs subpopulations were evaluated at ART onset, 2, 6, 9, 12, 16, 20, and 24 months of ART (five individuals had no Tregs information at baseline).Results:The slope of CD4+ T-cell recovery was similar for individuals with moderate and with severe lymphopenia at ART onset. No evidence was found for a contribution of the baseline Tregs percentages on the CD4+ T-cell counts recovery throughout ART. In comparison to uninfected individuals, Tregs percentages were higher at ART onset only for patients with less than 200 cells/μl at baseline and decreased afterwards reaching normal values. Within Tregs, the percentage of naive cells remained low in these patients. Reduced thymic export and increased proliferation of Tregs vs. conventional CD4+ T cells might explain these persistent alterations.Conclusion:No effect of Tregs percentages at baseline was detected on CD4+ T-cell recovery. However, profound alterations on Tregs subpopulations were consistently observed throughout ART for patients with severe lymphopenia at ART onset.

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CD4+ recent thymic emigrants are infected by HIV in vivo, implication for pathogenesis

Cited by 25 publications

References 57 publications

Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4⁺T CellsIn Vitro

Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4⁺T CellsIn Vitro

Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway

Longitudinal evaluation of regulatory T-cell dynamics on HIV-infected individuals during the first 2 years of therapy

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CD4+ recent thymic emigrants are infected by HIV in vivo, implication for pathogenesis

Cited by 25 publications

References 57 publications

Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4+T CellsIn Vitro

Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4+T CellsIn Vitro

Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway

Longitudinal evaluation of regulatory T-cell dynamics on HIV-infected individuals during the first 2 years of therapy

Contact Info

Product

Resources

About

Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4⁺T CellsIn Vitro

Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4⁺T CellsIn Vitro