HIV controllers: how do they tame the virus?

Sáez‐Cirión, Asier; Pancino, Gianfranco; Sinet, Martine; Venet, Alain; Lambotte, Olivier

doi:10.1016/j.it.2007.09.002

Cited by 84 publications

(71 citation statements)

References 84 publications

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“…Interestingly, our work showed that the proportions of HIV-1-specific CD8 T SCM cells did not differ substantially between patients with high-level viral replication and those with spontaneous viral control (40,41), despite the fact that total CD8 T SCM cells were negatively associated with viral loads both in our work and in a recent study (29). Moreover, the frequency of HIV-1-specific CD8 T SCM cells was not associated with CD4 T cell counts or viral loads during untreated infection, and there was no association between the proportions of HIV-1-specific CD8 T SCM cells and protective HLA class I alleles.…”

Section: Discussionmentioning

confidence: 70%

Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

Viganó

Negron

Ouyang

et al. 2015

J Virol

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HIV-1-specific CD8 T cells can influence HIV-1 disease progression during untreated HIV-1 infection, but the functional and phenotypic properties of HIV-1-specific CD8 T cells in individuals treated with suppressive antiretroviral therapy remain less well understood. Here we show that a subgroup of HIV-1-specific CD8 T cells with stem cell-like properties, termed T memory stem cells (T SCM cells), is enriched in patients receiving suppressive antiretroviral therapy compared with their levels in untreated progressors or controllers. In addition, a prolonged duration of antiretroviral therapy was associated with a progressive increase in the relative proportions of these stem cell-like HIV-1-specific CD8 T cells. Interestingly, the proportions of HIV-1-specific CD8 T SCM cells and total HIV-1-specific CD8 T SCM cells were associated with the CD4 T cell counts during treatment with antiretroviral therapy but not with CD4 T cell counts, viral loads, or immune activation parameters in untreated patients, including controllers. HIV-1-specific CD8 T SCM cells had increased abilities to secrete interleukin-2 in response to viral antigen, while secretion of gamma interferon (IFN-␥) was more limited in comparison to alternative HIV-1-specific CD8 T cell subsets; however, only proportions of IFN-␥-secreting HIV-1-specific CD8 T SCM cells were associated with CD4 T cell counts during antiretroviral therapy. Together, these data suggest that HIV-1-specific CD8 T SCM cells represent a long-lasting component of the cellular immune response to HIV-1 that persists in an antigen-independent fashion during antiretroviral therapy but seems unable to survive and expand under conditions of ongoing viral replication during untreated infection. IMPORTANCE Memory CD8 T cells that imitate the functional properties of stem cells to maintain lifelong cellular immunity have been hypothesized for many years, but only recently have such cells, termed T memory stem cells (T SCM cells), been physically identified Cytotoxic T cell responses against HIV-1 are mounted early in the disease process and can be readily detected in the vast majority of untreated HIV-1-infected patients (1, 2). Evidence from a number of investigations, including animal models (3), immunogenetic associations (4, 5), human cohort studies (6, 7), and phylogenetic explorations of viral sequence evolution (8, 9), suggests that these cells can importantly modulate clinical HIV-1 disease progression, particularly in rare groups of patients who spontaneously control HIV-1 infection in the absence of treatment. In these patients, HIV-1-specific CD8 T cells typically exhibit a polyfunctional profile characterized by strong abilities to proliferate, secrete antiviral cytokines, and execute major histocompatibility complex (MHC) class I-restricted cytolysis through perforin and granzyme B (6, 10, 11). In contrast, HIV-1-specific CD8 T cells in persons with progressive untreated disease seem to have markedly weaker cytotoxic activities, upregulate markers of immune senescen...

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Section: Discussionmentioning

confidence: 70%

Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

Viganó

Negron

Ouyang

et al. 2015

J Virol

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“…Understanding exactly how CD4 ϩ T helper cells coordinate the immune system and respond to immune challenges is crucial for the development of an effective HIV vaccine (15,20). Several previous studies have focused on a potential role of CD4 ϩ T cell help in HIV-specific CD8 ϩ T cell responses.…”

Section: Because Il-21mentioning

confidence: 99%

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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“…HIV-1 infection leads to progressively rising viremia, loss of CD4 + T cell counts, and clinical symptoms of immunodeficiency in the vast majority of untreated individuals; however, a small proportion of patients maintain undetectable levels of viral replication in the absence of antiretroviral therapy (1,2). These individuals, termed elite controllers, have moved into the center of current efforts to identify correlates of immune protection against HIV-1, but the mechanisms responsible for undetectable HIV-1 viremia in these patients remain unresolved.…”

Section: Introductionmentioning

confidence: 99%

CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21

et al. 2011

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HIV controllers: how do they tame the virus?

Cited by 84 publications

References 84 publications

Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

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

CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21

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HIV controllers: how do they tame the virus?

Cited by 84 publications

References 84 publications

Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

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

CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21

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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