HIV-Specific IL-21 Producing CD4+ T Cells Are Induced in Acute and Chronic Progressive HIV Infection and Are Associated with Relative Viral Control

Yue, Feng Yun; Lo, Chris; Sakhdari, Ali; Lee, Erika Yue; Kovacs, Colin; Benko, Erika; Li, Jun; Song, Haihan; Jones, R. Brad; Sheth, Prameet M.; Chege, Duncan; Kaul, Rupert; Ostrowski, Mario

doi:10.4049/jimmunol.0903915

Cited by 93 publications

(107 citation statements)

References 25 publications

(30 reference statements)

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“…In prior work we found that CXCL10 correlated with HIV load, while IL-17, CCL22, CXCL9, and fractalkine (CX3CL1) all showed inverse correlations with viral load (10). IL-21 has also been shown to inversely correlate with viral load (40). IL-10, IL-18, and soluble CD30 (sCD30) correlated positively with viral load in a cohort of subjects with low viral load (Ͻ1,000 RNA copies/ml) and noncontrollers (41).…”

Section: Discussionmentioning

confidence: 81%

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Jacobs

Keating

Abdel‐Mohsen

et al. 2017

J Virol

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A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4 ϩ T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4 ϩ T cells, and individually SDF-1␤, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1␤, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4 ϩ T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies.IMPORTANCE Approximately 1% of people infected with HIV control virus replication without taking antiviral medications. These subjects, termed elite controllers (ECs), are known to have stronger immune responses targeting HIV than the typical HIV-infected subject, but the exact mechanisms of how their immune responses control infection are not known. In this study, we identified five soluble immune signaling molecules (cytokines) in the blood that were higher in ECs than in subjects with typical chronic HIV infection. We demonstrated that these cytokines can activate CD4 ϩ T cells, the target cells for HIV infection. Furthermore, these five EC-

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Section: Discussionmentioning

confidence: 81%

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Jacobs

Keating

Abdel‐Mohsen

et al. 2017

J Virol

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“…Although we cannot fully exclude that the addition of exogenous recombinant IL-21 might skew the responses seen in vitro, these findings confirm via a separate approach the results of our multiplex bead based capture assay described above. Moreover, a recent publication ϩ T cells in long-term nonprogressors (Ͻ200 RNA copies/ml) (24). While the explanation for this discrepancy is not immediately apparent, it is interesting to note that Yue et al observed the highest level of HIV-specific IL-21-secreting CD4 ϩ T cells in individuals with "relative control" (defined as having viral loads between Ͼ200 and 20,000 RNA copies/ml).…”

Section: Fig 2 Il-21mentioning

confidence: 98%

HIV-1-Specific Interleukin-21 ⁺ CD4 ⁺ T Cell Responses Contribute to Durable Viral Control through the Modulation of HIV-Specific CD8 ⁺ T Cell Function

Chevalier

Jülg

Pyo

et al. 2011

J Virol

178

161

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Functional defects in cytotoxic CD8؉ T cell responses arise in chronic human viral infections, but the mechanisms involved are not well understood. In mice, CD4 cell-mediated interleukin-21 (IL-21) production is necessary for the maintenance of CD8 ؉ T cell function and control of persistent viral infections. To investigate the potential role of IL-21 in a chronic human viral infection, we studied the rare subset of HIV-1 controllers, who are able to spontaneously control HIV-1 replication without treatment. HIV-specific triggering of IL-21 by CD4؉ T cells was significantly enriched in these persons (P ‫؍‬ 0.0007), while isolated loss of IL-21-secreting CD4 ؉ T cells was characteristic for subjects with persistent viremia and progressive disease. IL-21 responses were mediated by recognition of discrete epitopes largely in the Gag protein, and expansion of IL-21 cells in acute infection resulted in lower viral set points (P ‫؍‬ 0.002). Moreover, IL-21 production by CD4؉ T cells of HIV controllers enhanced perforin production by HIV-1-specific CD8 ؉ T cells from chronic progressors even in late stages of disease, and HIV-1-specific effector CD8؉ T cells showed an enhanced ability to efficiently inhibit viral replication in vitro after IL-21 binding. These data suggest that HIV-1-specific IL-21؉ CD4 ؉ T cell responses might contribute to the control of viral replication in humans and are likely to be of great importance for vaccine design. CD4ϩ T cell help is essential to generate long-lived antiviral CD8 ϩ T cell memory (17, 18). Although antigen-specific CD8 ϩ T cells can be primed in the absence of CD4 ϩ T cell help, secondary expansion upon antigen reencounter is inefficient under such circumstances (7,11,18,22). Progressive loss of CD4 ϩ T cells in human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections has been associated with dysfunction of virus-specific CD8 ϩ T cells and ineffective containment of these chronic viral infections. Moreover, under repetitive antigenic stimulation, virus-specific cytotoxic CD8 ϩ T cells (CTL) become increasingly impaired, exhibiting decreased effector functions and upregulation of negative immunoregulatory molecules (2, 19). This dysfunction is likewise more severe in the absence of CD4 ϩ T cell help (21). The nature of CD4 help required to control chronic human infections remains unclear. In mice, recent studies indicate that CD4 ϩ T cell production of interleukin-21 (IL-21), a common ␥-chain cytokine, is required for maintenance of CD8 ϩ T cell function in persistent but not resolving viral infections (3,4,23). During lymphocytic choriomeningitis virus (LCMV) infection, expansion of CD4 ϩ T helper cells producing IL-21 is required for sustained CD8 ϩ T cell proliferation and control of viremia. In contrast, mice lacking either IL-21 or the IL-21 receptor are more susceptible to uncontrolled chronic LCMV infection, providing evidence that this cytokine is a key regulator of viral control in a murine model of chronic viral infection.

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“…Recent studies have highlighted the possible contribution of this cytokine to HIV control, with the findings that IL-21 in plasma correlates positively with CD4 counts (33) and that IL-21 secreted by HIV-specific CD4 ϩ T cells could induce a cytotoxic differentiation program with perforin induction in cognate CD8 ϩ T cells (11). Whether the frequencies of IL-21-producing specific CD4 ϩ T cells differ in HIV controllers and other patient groups remains debated, with one study showing an increase in the controller group (11) and two studies showing equivalent or lower levels (77,83). However, in the population of patients with detectable viremia, the persistence of IL-21-producing CD4 ϩ T cells is clearly associated with a beneficial outcome, as indicated by an inverse correlation with viral load (11,83) and a positive correlation with the frequency of IL-2 ϩ -specific CD8 ϩ T cells (77).…”

Section: Controller Cd4mentioning

confidence: 99%

HIV Controllers Maintain a Population of Highly Efficient Th1 Effector Cells in Contrast to Patients Treated in the Long Term

Vingert

Benati

Lambotte

et al. 2012

J Virol

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HIV-Specific IL-21 Producing CD4+ T Cells Are Induced in Acute and Chronic Progressive HIV Infection and Are Associated with Relative Viral Control

Cited by 93 publications

References 25 publications

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

HIV-1-Specific Interleukin-21 ⁺ CD4 ⁺ T Cell Responses Contribute to Durable Viral Control through the Modulation of HIV-Specific CD8 ⁺ T Cell Function

HIV Controllers Maintain a Population of Highly Efficient Th1 Effector Cells in Contrast to Patients Treated in the Long Term

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HIV-Specific IL-21 Producing CD4+ T Cells Are Induced in Acute and Chronic Progressive HIV Infection and Are Associated with Relative Viral Control

Cited by 93 publications

References 25 publications

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

HIV-1-Specific Interleukin-21 + CD4 + T Cell Responses Contribute to Durable Viral Control through the Modulation of HIV-Specific CD8 + T Cell Function

HIV Controllers Maintain a Population of Highly Efficient Th1 Effector Cells in Contrast to Patients Treated in the Long Term

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HIV-1-Specific Interleukin-21 ⁺ CD4 ⁺ T Cell Responses Contribute to Durable Viral Control through the Modulation of HIV-Specific CD8 ⁺ T Cell Function