HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients

Joshi, Anjali; Sedano, Melina J.; Beauchamp, Bethany; Punke, Erin B.; Mulla, Zuber D.; Meza, Armando; Alozie, Ogechika; Mukherjee, Debabrata; Garg, Himanshu

doi:10.4049/jimmunol.1501588

Cited by 23 publications

(41 citation statements)

References 72 publications

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“…P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1)(2)(3)(4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5)(6)(7)(8).…”

Section: The Persistence Of Functional Memory Cd4 T Cells Represents mentioning

confidence: 99%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

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Section: The Persistence Of Functional Memory Cd4 T Cells Represents mentioning

confidence: 99%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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“…In the SIV/HIV chimeric SHIV virus infection in macaques, a correlation between apoptosis and CD4 loss is also evident [ 8 , 9 ]. Multiple studies have reported increased apoptosis in peripheral blood mononuclear cells (PBMCs) from HIV infected individuals that correlates with CD4 decline [ 10 , 11 , 12 ]. Although the involvement of apoptosis in CD4 decline in HIV infections is widely accepted, the mechanism of apoptosis induction remains debated.…”

Section: Introductionmentioning

confidence: 99%

Host and Viral Factors in HIV-Mediated Bystander Apoptosis

Garg

Joshi

2017

Viruses

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Human immunodeficiency virus (HIV) infections lead to a progressive loss of CD4 T cells primarily via the process of apoptosis. With a limited number of infected cells and vastly disproportionate apoptosis in HIV infected patients, it is believed that apoptosis of uninfected bystander cells plays a significant role in this process. Disease progression in HIV infected individuals is highly variable suggesting that both host and viral factors may influence HIV mediated apoptosis. Amongst the viral factors, the role of Envelope (Env) glycoprotein in bystander apoptosis is well documented. Recent evidence on the variability in apoptosis induction by primary patient derived Envs underscores the role of Env glycoprotein in HIV disease. Amongst the host factors, the role of C-C Chemokine Receptor type 5 (CCR5), a coreceptor for HIV Env, is also becoming increasingly evident. Polymorphisms in the CCR5 gene and promoter affect CCR5 cell surface expression and correlate with both apoptosis and CD4 loss. Finally, chronic immune activation in HIV infections induces multiple defects in the immune system and has recently been shown to accelerate HIV Env mediated CD4 apoptosis. Consequently, those factors that affect CCR5 expression and/or immune activation in turn indirectly regulate HIV mediated apoptosis making this phenomenon both complex and multifactorial. This review explores the complex role of various host and viral factors in determining HIV mediated bystander apoptosis.

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“…In a model presented in our previous study 24 we proposed a role for the Env glycoprotein phenotype, viremia and immune activation in collectively mediating CD4 bystander apoptosis. Based on the findings from this study, inclusion of CCR5 promoter polymorphisms in this model is justified (Fig.…”

Section: Discussionmentioning

confidence: 99%

CCR5 promoter activity correlates with HIV disease progression by regulating CCR5 cell surface expression and CD4 T cell apoptosis

Joshi

Punke

Sedano

et al. 2017

Sci Rep

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CCR5 is the major co-receptor for HIV and polymorphisms in the CCR5 gene as well as promoter region that alter cell surface expression have been associated with disease progression. We determined the relationship between CCR5 promoter polymorphisms and CD4 decline and other immunopathological features like immune activation and CD4+ T cell apoptosis in HIV patients. CCR5 promoter haplotype HHC was significantly associated with higher CD4 counts in patients. The relative promoter activity (RPA) of each haplotype was determined in vitro and combined promoter activity based on both alleles (CRPA) was assigned to each patients. Interestingly, CCR5 CRPA correlated inversely with CD4 counts and CD4:CD8 ratio specifically in viremic patients. In normal individuals, the CRPA correlated with the number of CCR5+ CD4+ T cells in the peripheral blood suggesting an effect on CCR5 expression. In a subset of high viremic patients harboring R5 tropic HIV, there was a strong correlation between CCR5 CRPA and both CD4 counts and CD4 T cell apoptosis. Our study demonstrates that, CCR5 promoter polymorphisms correlate with CD4 T cell loss possibly by regulating CD4 T cell apoptosis in HIV patients. Furthermore, assigning CRPAs to each patient is a new method of translating genotype to phenotype.

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HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients

Cited by 23 publications

References 72 publications

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Host and Viral Factors in HIV-Mediated Bystander Apoptosis

CCR5 promoter activity correlates with HIV disease progression by regulating CCR5 cell surface expression and CD4 T cell apoptosis

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