Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

Petrovas, Constantinos; Mueller, Yvonne M.; Katsikis, Peter D.

doi:10.1038/sj.cdd.4401595

Cited by 24 publications

(30 citation statements)

References 192 publications

(218 reference statements)

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“…Elite controllers maintaining a viral load of < 50 copies/ml represent less than 1% of all untreated HIV-infected patients. 80 HIV-specific cytotoxic T lymphocytes (CTL) are preferentially primed for apoptosis and this represents a viral escape mechanism 81 ; however, HIV-specific CD8 + T cells from elite controllers are primed for survival. 82 The majority of elite controllers have very low rates of CD4 + T cell decline and progression of disease.…”

Section: Discussionmentioning

confidence: 99%

Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers

Tandon

Chew²,

Byron³

et al. 2014

AIDS Research and Human Retroviruses

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Galectin-9 (Gal-9) is a b-galactosidase-binding lectin that promotes apoptosis, tissue inflammation, and T cell immune exhaustion, and alters HIV infection in part through engagement with the T cell immunoglobulin mucin domain-3 (Tim-3) receptor and protein disulfide isomerases (PDI). Gal-9 was initially thought to be an eosinophil attractant, but is now known to mediate multiple complex signaling events that affect T cells in both an immunosuppressive and inflammatory manner. To understand the kinetics of circulating Gal-9 levels during HIV infection we measured Gal-9 in plasma during HIV acquisition, in subjects with chronic HIV infection with differing virus control, and in uninfected individuals. During acute HIV infection, circulating Gal-9 was detected as early as 5 days after quantifiable HIV RNA and tracked plasma levels of interleukin (IL)-10, tumor necrosis factor (TNF)-a, and IL-1b. In chronic HIV infection, Gal-9 levels positively correlated with plasma HIV RNA levels (r = 0.29; p = 0.023), and remained significantly elevated during suppressive antiretroviral therapy (median: 225.3 pg/ml) and in elite controllers (263.3 pg/ml) compared to age-matched HIV-uninfected controls (54 pg/ml). Our findings identify Gal-9 as a novel component of the first wave of the cytokine storm in acute HIV infection that is sustained at elevated levels in virally suppressed subjects and suggest that Gal-9:Tim-3 crosstalk remains active in elite controllers and antiretroviral (ARV)-suppressed subjects, potentially contributing to ongoing inflammation and persistent T cell dysfunction.

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Section: Discussionmentioning

confidence: 99%

Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers

Tandon

Chew²,

Byron³

et al. 2014

AIDS Research and Human Retroviruses

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Section: Introductionmentioning

confidence: 99%

“…[3][4][5] Among others, apoptosis of HIV-specific CD8 ϩ T cells has been suggested as a strategy employed by HIV to evade the immune system. 6,7 What governs this apoptosis sensitivity, however, remains to be elucidated.CD8 ϩ T cells from HIV-infected patients are susceptible to spontaneous and CD95/Fas-induced apoptosis. [8][9][10] We recently found HIVspecific CD8 ϩ T cells to be highly sensitive to apoptosis 11 whereas this is not the case for CMV-specific CD8 ϩ T cells from HIV ϩ individuals.…”

mentioning

confidence: 99%

Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells

Petrovas¹,

Mueller²,

Dimitriou³

et al. 2006

Blood

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What governs the increased apoptosis sensitivity of HIV-specific CD8 ؉ T cells is poorly understood. Here, we examined the involvement of mitochondria in this apoptosis. Remarkably higher mitochondrial mass (MM) was found in HIV-specific compared with CMV-specific CD8 ؉ T cells from HIV ؉ patients and this could not be attributed to their different differentiation status. MM High phenotype characterized those CD8 ؉ T cells from HIV ؉ patients that are sensitive to spontaneous and CD95/Fas-induced apoptosis. CD38 expression did not correlate with high MM, whereas Bcl-2 levels were significantly reduced in both CD38 ؉ and CD38 ؊ HIVspecific CD8 ؉ T cells. Although CD38 ؉ HIV-specific CD8 ؉ T cells were more susceptible to apoptosis, CD38 expression does not explain on its own the selective apoptosis sensitivity of HIV-specific CD8 ؉ T cells, as CD38 ؊ HIV-specific CD8 ؉ T cells were more apoptotic than CD38 ؉ CMV-specific ones. Proapoptotic HIVspecific CD8 ؉ T cells were CD38 ؉ Bcl-2 Low MM High . Copolarization of mitochondria with CD95/Fas capping, very early in CD95/Fas-induced apoptosis of HIV-specific CD8 ؉ T cells, suggests that mitochondria act as an amplification step for this apoptosis. Thus, an extensive mitochondrial network contributes to apoptosis sensitivity of CD8 ؉ T cells and, when this occurs together with reduced levels of Bcl-2 and chronic activation, determines the proapoptotic state of HIV-specific CD8 ؉ T cells. IntroductionCD8 ϩ T-cell response is a critical player for controlling HIV infection and AIDS progression. 1,2 However, HIV-specific CD8 ϩ T cells ultimately fail to control the virus. Various mechanisms related either to HIV-infected cells or to intrinsic defects in CD8 ϩ T cells themselves have been proposed to explain this failure. [3][4][5] Among others, apoptosis of HIV-specific CD8 ϩ T cells has been suggested as a strategy employed by HIV to evade the immune system. 6,7 What governs this apoptosis sensitivity, however, remains to be elucidated.CD8 ϩ T cells from HIV-infected patients are susceptible to spontaneous and CD95/Fas-induced apoptosis. [8][9][10] We recently found HIVspecific CD8 ϩ T cells to be highly sensitive to apoptosis 11 whereas this is not the case for CMV-specific CD8 ϩ T cells from HIV ϩ individuals. 11 This sensitivity is associated with a remarkable down-regulation of Bcl-2 and Bcl-xL antiapoptotic molecules, 12 suggesting a role of mitochondria in this apoptotic process. Several studies have revealed a mitochondrial dysfunction in T cells during HIV infection. 13,14 CD95/ Fas cross-linking initiates a complex signaling process involving CD95/Fas capping and formation of death-inducing signaling complex (DISC), 15,16 ultimately leading to activation of the executor caspase-3 directly by caspase-8 or through mitochondrial-secreted proapoptotic factors. 17 The cross-talk of these 2 pathways in apoptosis of primary T cells, particularly in CD8 ϩ T cells from HIV ϩ patients, is currently unknown. Furthermore, no studies have addressed the role and impact of ...

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“…CD8 T cells in chronic HIV infection succumb to exhaustion and cell death in an environment of uncontrolled viremia and nonspecific immune activation (23)(24)(25). Surface markers, including PD-1, CD160, and 2B4, have provided insights into predicting exhaustion and correlate with clinical parameters of disease progression (26).…”

mentioning

confidence: 99%

HIV-Specific CD8⁺T Cells from Elite Controllers Are Primed for Survival

Yan

Sabbaj

Bansal

et al. 2013

J Virol

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HIV-specific cytotoxic T lymphocytes (CTL) are preferentially primed for apoptosis, and this may represent a viral escape mechanism. We hypothesized that HIV-infected individuals that control virus to undetectable levels without antiretroviral therapy (ART) (elite controllers [EC]) have the capacity to upregulate survival factors that allow them to resist apoptosis. To address this, we performed cross-sectional and longitudinal analysis of proapoptotic (cleaved caspase-3) and antiapoptotic (Bcl-2) markers of cytomegalovirus (CMV) and HIV-specific CD8 T cells in a cohort of HIV-infected subjects with various degrees of viral control on and off ART. We demonstrated that HIV-specific CTL from EC are more resistant to apoptosis than those with pharmacologic control (successfully treated patients [ST]), despite similar in vivo conditions. Longitudinal analysis of chronically infected persons starting ART revealed that the frequency of HIV-specific T cells prone to death decreased, suggesting that this phenotype is partially reversible even though it never achieves the levels present in EC. Elucidating the apoptotic factors contributing to the survival of CTL in EC is paramount to our development of effective HIV-1 vaccines. Furthermore, a better understanding of cellular markers that can be utilized to predict response durability in disease-or vaccine-elicited responses will advance the field.

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Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

Cited by 24 publications

References 192 publications

Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers

Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers

Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells

HIV-Specific CD8⁺T Cells from Elite Controllers Are Primed for Survival

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Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

Cited by 24 publications

References 192 publications

Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers

Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers

Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells

HIV-Specific CD8+T Cells from Elite Controllers Are Primed for Survival

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HIV-Specific CD8⁺T Cells from Elite Controllers Are Primed for Survival