Differential Dynamics of Regulatory T-Cell and Th17 Cell Balance in Mesenteric Lymph Nodes and Blood following Early Antiretroviral Initiation during Acute Simian Immunodeficiency Virus Infection

Yero, Alexis; Farnós, Omar; Rabezanahary, Henintsoa; Racine, Gina; Estaquier, Jérǒme; Jenabian, Mohammad-Ali

doi:10.1128/jvi.00371-19

Cited by 28 publications

(40 citation statements)

References 63 publications

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“…Also, we compared SR to SE to reveal the host-virus interaction in the context of virus-detectable host immunity status. In each single stage, our findings were highly consistent with previous studies (Hunt et al, 2008;Molina-Pinelo et al, 2009;Robbins et al, 2009;Hunt, 2012;Vandergeeten et al, 2012;Wittkop et al, 2013;Osuji et al, 2018;Yero et al, 2019;Antar et al, 2020;Bordoni et al, 2020).…”

Section: Discussionsupporting

confidence: 93%

Stage-Dependent Within-Individual Comparison Reveals SIV-Specific Activation/Exhaustion Shift in Rhesus Macaques

et al. 2021

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It is challenging to trace the complicated individual-based variations of HIV-specific immunocompetence shift during the successful antiretroviral therapy (ART) era. Using eight rhesus monkeys simulating a longitudinal stage-dependent cohort (baseline-SIV acute infection-SIV suppression by ART-ART withdrawal), baseline immunocompetence monitoring for 28 days (SIV-negative stage, SN) was compared with host immunocompetence undergoing 90-day ART treatment (SIV-suppressed stage, SS) to reveal the SIV-specific immunity shift aroused by undetectable individual viral replication. During acute SIV infection for 98 days (SIV-emerged stage, SE), immune activation was compared with re-immune activation post ART for 49-day follow-up (SIV-rebounded stage, SR) to reveal the SIV-specific immune activation variation aroused by detectable individual viral replication. Individual immunocompetence was measured by co-expression of CD4, CD8, CD38, HLA-DR, CCR7, CD45RA, and PD-1 on T cells and a cytokine panel. Compared with SN, mild immune activation/exhaustion was characterized by increased CD38+ HLA-DR– CD4+/CD8+ T-cell subsets and PD-1+ memory CD4+/CD8+ T-cell subsets with three elevated cytokines (MIP-1β, IL-8, and IL-10) significantly emerged in SS. Compared with SE, SR produced more exhaustion characterized by increased PD-1+ CD4+ TCM cells and decreased PD-1+ CD4+ TEM cells with four elevated pro-inflammatory cytokines (IFN-γ, IL-1β, IL-6, and TNF-α). By such individualized stage-dependent comparison, the sustainable immune activation was found from activation/exhaustion shifted into exhaustion during the longitudinal viral persistence. Further, validated SIV accelerates host immunosenescence continuously independent of viral replication.

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Section: Discussionsupporting

confidence: 93%

Stage-Dependent Within-Individual Comparison Reveals SIV-Specific Activation/Exhaustion Shift in Rhesus Macaques

et al. 2021

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“…Using eight SIV mac239infected rhesus macaques, we longitudinally tracked host immunosenescence and immunoactivation by comparing SS to SN and SR to SE. Our ndings were consistent with previous studies [21][22][23][24][25][26][27][28] , and comparing SS to SN, we showed accelerated host immunosenescence and elevated low-level in ammation at the same time as SIV expression was undetectable. In comparing SR to SE, we showed accelerated host immunoactivation with elevated in ammation that correlated with increased SIV replication during rebound 29,30 .…”

Section: Discussionsupporting

confidence: 93%

Longitudinal study of sustainable acceleration of immunosenescence and immunoactivation dependent on SIV replication stress in SIVmac239-infected rhesus macaques

Xue¹,

Tong²,

Cong³

et al. 2021

Preprint

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It is challenging to trace the variations of host immune features covering the whole process of ‘baseline-infection-treatment-withdrawal’ from HIV-negative to HIV-rebound in HIV-infected patients after discontinuing antiretroviral therapy (ART). Herein, eight monkeys were monitored for 28 days to acquire baseline immune function; infected with 100 TCID50 of SIVmac239 intravenously for 98 days; treated with standard ART for 90 days; followed up for 49 days post withdrawal of ART. Within the 266 days’ longitudinal study, four SIV-dependent stages, SIV-negative (SN, ‘baseline’), SIV-emerged (SE, ‘infection’), SIV-suppressed (SS, ‘treatment’), and SIV-rebounded (SR, ‘withdrawal’), were stratified according to plasma viral RNA quantification. Parallel comparisons of host immune function, including counts of CD4+ T cells, ratios of T-cell subsets and measurement of a panel of cytokines, were performed between SS and SN, and between SR and SE. Compared to the SN stage, an accelerated immunosenescence was found in the SS stage characterized with increased CD38+ HLA-DR− CD4+/CD8+ T-cell subsets, PD-1+ memory CD4+/CD8+ T-cell subsets and elevated cytokines including MIP-1β, IL-8 and IL-10. Compared to the SE stage, the SR phase exhibited an accelerated immune activation against SIV characterized with increased PD-1+ CD4+ TCM cells, decreased PD-1+ CD4+ TEM cells and enhanced pro-inflammatory cytokine levels including TNF-α, IL-6, IL-1β and IFN-γ. This longitudinal study of rhesus macaques demonstrated a sustainable acceleration of immunosenescence/immunoactivation dependent on the stress of SIV replication which may provide insights for future HIV therapies.

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“…As a result, HIV and SIV infections are characterized by a switch from Th1 to Th2 phenotype (56), and a significant depletion of Th17 cells is observed among circulating lymphocytes throughout the infection (7). HIV-1 can also infect Tregs (57), and, although reduced (7,(58)(59)(60), stable, and increased (61,62) absolute circulating Treg counts have all been reported during chronic infections, a decreased Th17/ Treg ratio is commonly observed in pathogenic infections and was linked to immune activation and disease progression (7,62). Furthermore, a selective depletion of circulating CD4 + T cells with gut homing potential (i.e., expressing the a4b7 integrin) preferentially occurs in untreated PWH (63) and in SIV-infected RMs in which those cells are selectively infected in the first days of infection (8).…”

Section: Cd4 + T-cell Depletion In Pathogenic Hiv/siv Infections Circulation and Lymph Nodesmentioning

confidence: 99%

“…Furthermore, Th17 cells were also restored in patients receiving ART, especially in those in which therapy was initiated very early in infection (85). However, Th17/Treg ratio remained reduced, as Treg cell counts in lymph nodes and in GALT did not return to baseline levels in PWH receiving ART (60,61), which might be due to the residual viral replication and immune activation in the GALT of those patients (219).…”

Section: Restoration Of Cd4 + T Cells During Artmentioning

confidence: 99%

“…In rhesus macaques in which ART was initiated prior to the acute mucosal CD4 + T-cell depletion (i.e., 7 days post-SIVmac251 infection), ART failed to prevent CD4 + T-cell depletion in the GALT, but enabled a virtually complete CD4 + T-cell restoration by 6 months postinfection, particularly through a significant increase in the Tcm levels ( 88 ). Meanwhile, while early ART initiation at 3 to 4 days postinfection did not prevent the establishment of the SIV reservoir in lymph nodes ( 222 ), it prevented Th17 depletion in the lymphoid tissues ( 61 ). Similarly, early treatment of acutely HIV-infected individuals (Fiebig stage I or II) could not halt mucosal CD4 + T-cell depletion in the first weeks post-treatment but generated a strong restoration of CD4 + T cells in the lamina propria at 96 weeks post-treatment ( 99 ) ( Figure 3 ).…”

Section: Restoration Of Cd4 + T Cells During Artmentioning

confidence: 99%

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The Hitchhiker Guide to CD4+ T-Cell Depletion in Lentiviral Infection. A Critical Review of the Dynamics of the CD4+ T Cells in SIV and HIV Infection

et al. 2021

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CD4+ T-cell depletion is pathognomonic for AIDS in both HIV and simian immunodeficiency virus (SIV) infections. It occurs early, is massive at mucosal sites, and is not entirely reverted by antiretroviral therapy (ART), particularly if initiated when T-cell functions are compromised. HIV/SIV infect and kill activated CCR5-expressing memory and effector CD4+ T-cells from the intestinal lamina propria. Acute CD4+ T-cell depletion is substantial in progressive, nonprogressive and controlled infections. Clinical outcome is predicted by the mucosal CD4+ T-cell recovery during chronic infection, with no recovery occurring in rapid progressors, and partial, transient recovery, the degree of which depends on the virus control, in normal and long-term progressors. The nonprogressive infection of African nonhuman primate SIV hosts is characterized by partial mucosal CD4+ T-cell restoration, despite high viral replication. Complete, albeit very slow, recovery of mucosal CD4+ T-cells occurs in controllers. Early ART does not prevent acute mucosal CD4+ T-cell depletion, yet it greatly improves their restoration, sometimes to preinfection levels. Comparative studies of the different models of SIV infection support a critical role of immune activation/inflammation (IA/INFL), in addition to viral replication, in CD4+ T-cell depletion, with immune restoration occurring only when these parameters are kept at bay. CD4+ T-cell depletion is persistent, and the recovery is very slow, even when both the virus and IA/INFL are completely controlled. Nevertheless, partial mucosal CD4+ T-cell recovery is sufficient for a healthy life in natural hosts. Cell death and loss of CD4+ T-cell subsets critical for gut health contribute to mucosal inflammation and enteropathy, which weaken the mucosal barrier, leading to microbial translocation, a major driver of IA/INFL. In turn, IA/INFL trigger CD4+ T-cells to become either viral targets or apoptotic, fueling their loss. CD4+ T-cell depletion also drives opportunistic infections, cancers, and comorbidities. It is thus critical to preserve CD4+ T cells (through early ART) during HIV/SIV infection. Even in early-treated subjects, residual IA/INFL can persist, preventing/delaying CD4+ T-cell restoration. New therapeutic strategies limiting mucosal pathology, microbial translocation and IA/INFL, to improve CD4+ T-cell recovery and the overall HIV prognosis are needed, and SIV models are extensively used to this goal.

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Differential Dynamics of Regulatory T-Cell and Th17 Cell Balance in Mesenteric Lymph Nodes and Blood following Early Antiretroviral Initiation during Acute Simian Immunodeficiency Virus Infection

Cited by 28 publications

References 63 publications

Stage-Dependent Within-Individual Comparison Reveals SIV-Specific Activation/Exhaustion Shift in Rhesus Macaques

Stage-Dependent Within-Individual Comparison Reveals SIV-Specific Activation/Exhaustion Shift in Rhesus Macaques

Longitudinal study of sustainable acceleration of immunosenescence and immunoactivation dependent on SIV replication stress in SIVmac239-infected rhesus macaques

The Hitchhiker Guide to CD4+ T-Cell Depletion in Lentiviral Infection. A Critical Review of the Dynamics of the CD4+ T Cells in SIV and HIV Infection

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