Immune signatures for HIV-1 and HIV-2 induced CD4+T cell dysregulation in an Indian cohort

Salwe, Sukeshani; Singh, Amit Kumar; Padwal, Varsha; Velhal, Shilpa; Nagar, Vidya; Patil, Prashant; Deshpande, Alaka; Patel, Vainav

doi:10.1186/s12879-019-3743-7

Cited by 17 publications

(11 citation statements)

References 47 publications

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“…We observed anapparent increase in the frequency of Tregs (CD4+ CD25 high CD127 low ) in both PA and LTNP groups compared to SN controls (Figure 8A). This is in concurrence with our earlier reported data for both HIV-1 and HIV-2 infected individuals (16, 26). Expansion of Tregs exhibited a highly significant association with decline in the frequency of classical monocytes ( r = −0.7727, P < 0.01) and corresponding rise in the frequency of intermediate monocytes ( r = 0.8, P < 0.01) in PAs (Figure 8B).…”

Section: Resultssupporting

confidence: 94%

“…Chronic activation of the immune system is a hallmark of progressive HIV infection and frequency of activated T lymphocytes better predicts disease outcome than plasma viral load and CD4 counts alone (20, 26, 36). In our study, viral load showed a more significant association with frequency of activated CD8+ T lymphocytes (HLA-DR+CD38+) ( r = 0.6909, P < 0.05) in the PA group (Figure 7B) and frequency of activated CD4+ T lymphocytes (HLA-DR+CD38+) ( r = 0.7119, P < 0.001) in the LTNP group (Figure 7B).…”

Section: Resultsmentioning

confidence: 99%

“…T cell activation was estimated using anti-CD3 (Clone: SK7), anti-CD8 (Clone: SK1), anti-CD38 (Clone: HIT2), and anti-HLADR (Clone: L243) and examining the frequency of HLADR/CD38 dual-positive cells within CD4+ and CD8+ T lymphocyte gates as described previously (24–26). The frequency of regulatory T cells was estimated using anti-CD3 (Clone: SK7), anti-CD4 (Clone: RPA-T4), anti-CD25 (Clone: M-A251), and anti-CD127 (Clone: HIL-7R-M21) as described previously (26).…”

Section: Methodsmentioning

confidence: 99%

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Monocyte Based Correlates of Immune Activation and Viremia in HIV-Infected Long-Term Non-Progressors

et al. 2019

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Background: Disease progression monitoring through CD4 counts alone can be inadequate in HIV infection as ongoing immune activation may result in Serious non-AIDS events (SNAEs). SNAEs involve monocyte activation driven chronic inflammation with significant sequelae observed even during HAART. Here, we attempted to delineate functional monocyte based signatures across stages of HIV disease progression.Methods: Participants spanning four cohorts were recruited—pre-ART (PA; <7 years of infection; n = 20), long-term non-progressors (LTNP; >7 years of infection, CD4 > 350 cells/μL, n = 20), individuals on therapy (ART; n = 18) and seronegative controls (SN; n = 15). Immunophenotyping of monocyte subsets and evaluation of expression of HIV-binding receptors—CD4 and CCR5, marker of immune activation- HLA-DR and M2 phenotype—mannose receptor (CD206) was followed by association of monocyte-specific parameters with conventional markers of disease progression such as absolute CD4 count, CD4/CD8 ratio, viral load, and T cell activation.Results: A significant expansion of intermediate monocytes (CD14++CD16+) with a concomitant decline in classical subset (CD14++CD16–) was observed in all infected cohorts compared to seronegative controls. In addition, an expansion of the non-classical subset (CD14+CD16++) was observed in long-term non-progressors. Dysregulation in monocyte subsets associated with CD4 count and CD4/CD8 ratio in PAs but not in LTNPs. We report for the first time that expression of CD206 is most prominent on intermediate monocytes which also have the highest expression of CD4, CCR5, and HLA-DR. Despite preserved CD4 counts, LTNPs had similar immune activation profiles to PAs, as evidenced by elevated HLA-DR expression across monocyte subsets. HLA-DR expression, similar to that in SNs, observed in the ART group indicated partial immune restoration within the monocyte compartment. Increased CD206 expression on monocytes together with frequency of activated CD4+ T lymphocytes (HLA-DR+CD38+) showed significant and positive association with viral load in LTNPs, but not PAs.Conclusion: Our results describe for the first time the presence of monocyte dysregulation involving increased activation in LTNPs, who, in spite of preserved CD4 counts, may remain susceptible to prolonged effects of systemic inflammation and highlight CD206, as a unique non-T correlate of viremia, in viremic non-progression.

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Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Monocyte Based Correlates of Immune Activation and Viremia in HIV-Infected Long-Term Non-Progressors

et al. 2019

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“…Also, the frequency of these CD4 + T cell subsets was found to be similar in ART-naive and -receiving groups. These data confirm our previous findings, and extend these to the HIV-D group [37]. Also, T reg (CD25 high CD127 low ) frequency was lower, although not significantly (P = 0·0599), in ART-receiving, compared to ART-naive, HIV-1-infected individuals (Fig.…”

Section: Dysregulation In the Frequencies Of Homeostatically Significsupporting

confidence: 91%

T cell functionality in HIV-1, HIV-2 and dually infected individuals: correlates of disease progression and immune restoration

Salwe

Padwal

Nagar

et al. 2019

Clinical and Experimental Immunology

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Summary The role of suppressive anti‐retroviral therapy (ART) in eliciting restoration of dysregulated immune function remains unclear in HIV‐1 infection. Also, due to tailoring of therapeutic regimens towards HIV‐1, this possible impairment of therapy may be even more pronounced in HIV‐2 and dual (HIV‐D) infection. Thus, we evaluated the impact of ART on immune restoration by assessing T cell functions, including HIV specific responses in HIV‐1‐, HIV‐2‐ and HIV‐D‐infected individuals. Both ART‐treated and naive infected subjects showed persistently altered frequency of CD4+ T cell subsets [regulatory T cells (Treg), naive/central memory, effector memory], increased immune activation, cytoxicity and decreased frequency of natural killer T (NKT)‐ like cells and T helper type 17 (Th17)/Treg ratio with elevated microbial translocation. Further, HIV‐specific responses were dominated by gag‐specific CD4+ T cells in virologically suppressed HIV‐D individuals, suggesting retention of T cell memory for both viruses. Increased antigen‐specific responses, including dual‐functional interleukin (IL)‐2/interferon (IFN)‐γ CD4+ T cells, were detected in therapy receiving HIV‐2‐infected individuals indicative of a greater and more functionally diverse T cell memory repertoire. We delineated immune signatures specific to therapy‐naive single HIV infection, as well as a unique signature associated with HIV‐2 disease progression and immune restoration. Circulating Treg frequency, T cell activation and microbial translocation levels correlated with disease progression and immune restoration among all types of HIV infection. Also, memory responses negatively correlated, irrespective of type of infection, in ART receiving infected individuals, with CD4 rebound and decreased pan T cell activation. Our data highlight the need for adjunct immunomodulatory therapeutic strategies to achieve optimal immune restoration in HIV infection.

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“…For phenotypic characterization, immunostaining of 200 µl of fresh peripheral whole blood with four-color combinations of the following fluorescently labeled monoclonal antibodies, anti-CD3 (Clone:SK7), anti-CD4 (Clone: RPA-T4), anti-CD8 (Clone: SK1), anti-CD25 (Clone: M-A251), anti-CD127 (Clone: HIL-7R-M21), anti-CCR7 (Clone: 150503), anti-CD45RA (Clone: HI100), anti-HLA-DR (Clone: L243), anti-CD38-PECY5 (Clone: HIT2), anti-PD-1 (Clone: EH12.1), anti-CD28 (Clone: 28.2), and anti-CD31 (Clone: WM59), was performed as reported previously (21). Briefly, 200 µl of fresh EDTA blood was incubated with fluorescently labeled monoclonal antibodies for 20 min at room temperature.…”

Section: Immunophenotypingmentioning

confidence: 99%

Delineation of Homeostatic Immune Signatures Defining Viremic Non-progression in HIV-1 Infection

et al. 2020

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Viremic non-progressors (VNPs), a distinct group of HIV-1-infected individuals, exhibit no signs of disease progression and maintain persistently elevated CD4+ T cell counts for several years despite high viral replication. Comprehensive characterization of homeostatic cellular immune signatures in VNPs can provide unique insights into mechanisms responsible for coping with viral pathogenesis as well as identifying strategies for immune restoration under clinically relevant settings such as antiretroviral therapy (ART) failure. We report a novel homeostatic signature in VNPs, the preservation of the central memory CD4+ T cell (CD4+ T CM) compartment. In addition, CD4+ T CM preservation was supported by ongoing interleukin-7 (IL-7)-mediated thymic repopulation of naive CD4+ T cells leading to intact CD4+ T cell homeostasis in VNPs. Regulatory T cell (Treg) expansion was found to be a function of preserved CD4+ T cell count and CD4+ T cell activation independent of disease status. However, in light of continual depletion of CD4+ T cell count in progressors but not in VNPs, Tregs appear to be involved in lack of disease progression despite high viremia. In addition to these homeostatic mechanisms resisting CD4+ T cell depletion in VNPs, a relative diminution of terminally differentiated effector subset was observed exclusively in these individuals that might ameliorate consequences of high viral replication. VNPs also shared signatures of impaired CD8+ T cell cytotoxic function with progressors evidenced by increased exhaustion (PD-1 upregulation) and CD127 (IL-7Rα) downregulation contributing to persistent viremia. Thus, the homeostatic immune signatures reported in our study suggest a complex multifactorial mechanism accounting for non-progression in VNPs.

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Immune signatures for HIV-1 and HIV-2 induced CD4+T cell dysregulation in an Indian cohort

Cited by 17 publications

References 47 publications

Monocyte Based Correlates of Immune Activation and Viremia in HIV-Infected Long-Term Non-Progressors

Monocyte Based Correlates of Immune Activation and Viremia in HIV-Infected Long-Term Non-Progressors

T cell functionality in HIV-1, HIV-2 and dually infected individuals: correlates of disease progression and immune restoration

Delineation of Homeostatic Immune Signatures Defining Viremic Non-progression in HIV-1 Infection

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