Role of the Fas/FasL pathway in HIV or SIV disease

Human immunodeficiency virus disease involves progressive destruction of host immunity leading to opportunistic infections and increased rates for malignancies. Both depletion in immune cell numbers as well as defects in their effector functions are responsible for this immunodeficiency The broad impact of HIV reflects a similarly broad pattern of cell depletion including subsets that do not express viral receptors or support viral replication. Indirect cell killing, the destruction of uninfected cells, is due partly to activation of the Fas/FasL system for cell death. This death-signaling pathway is induced during HIV disease and contributes significantly to viral pathogenesis and disease

CD38: an ecto-enzyme with functional diversity in T cells

CD38, a nicotinamide adenine dinucleotide (NAD)+ glycohydrolase, is considered an activation marker of T lymphocytes in humans that is highly expressed during certain chronic viral infections. T cells constitute a heterogeneous population; however, the expression and function of CD38 has been poorly defined in distinct T cell compartments. We investigated the expression and function of CD38 in naïve and effector T cell subsets in the peripheral blood mononuclear cells (PBMCs) from healthy donors and people with HIV (PWH) using flow cytometry. Further, we examined the impact of CD38 expression on intracellular NAD+ levels, mitochondrial function, and intracellular cytokine production in response to virus-specific peptide stimulation (HIV Group specific antigen; Gag). Naïve T cells from healthy donors showed remarkably higher levels of CD38 expression than those of effector cells with concomitant reduced intracellular NAD+ levels, decreased mitochondrial membrane potential and lower metabolic activity. Blockade of CD38 by a small molecule inhibitor, 78c, increased metabolic function, mitochondrial mass and mitochondrial membrane potential in the naïve T lymphocytes. PWH exhibited similar frequencies of CD38+ cells in the T cell subsets. However, CD38 expression increased on Gag-specific IFN-γ and TNF-α producing cell compartments among effector T cells. 78c treatment resulted in reduced cytokine production, indicating its distinct expression and functional profile in different T cell subsets. In summary, in naïve cells high CD38 expression reflects lower metabolic activity, while in effector cells it preferentially contributes to immunopathogenesis by increasing inflammatory cytokine production. Thus, CD38 may be considered as a therapeutic target in chronic viral infections to reduce ongoing immune activation

Early and transient induction of nitric oxide (NO) in infectious bursal disease virus infection is T-cell dependent: A study in cyclosporin-A treated chicken-model

192-196The level of nitric oxide (NO) in the supernatants of mitogen (PHA) stimulated lymphocyte cultures from infectious bursal disease (IBD) virus infected T-cell suppressed and immune competent chickens was monitored. The immune competent chickens when infected with IBD virus showed 4-6 folds increased levels of NO as compared to uninfected chickens. The levels of NO in T-cell suppressed chickens were comparable to uninfected control chickens, in spite of markedly increased hemorrhage suggesting that the muscular hemorrhage observed in IBD in not solely and directly related with NO production. The immune suppressed chickens that did not induce NO production after IBD virus infection showed more severe lesions and supported enhanced virus replication. Taken together it may be suggested that NO production after IBD virus infection, may exert antiviral effect since the immune-suppressed chickens that failed to induce NO showed more severe disease and higher magnitude of virus replication, but does not seem to correlate with the hemorrhagic lesions which in fact may be as a result of the net outcome of various host-factors and the determinants responsible for virus virulence and virus clearance

Levels of CD56+TIM-3- effector CD8 T cells distinguish HIV natural virus suppressors from patients receiving antiretroviral therapy.

Prolonged antiretroviral therapy (ART) with effective HIV suppression and reconstitution of CD4 T cells, fails to restore CD8 T cell lytic effector function that is needed to eradicate the viral reservoir. Better understanding of the phenotype and function of circulating CD8 cells in HIV patients will contribute to new targeted therapies directed at increasing CD8 T cell lytic effector function and destruction of the viral reservoir. We show that CD8 T cells from ART treated patients had sharply reduced expression of CD56 (neural cell adhesion molecule-1), a marker associated with cytolytic function whereas elite patients who control HIV in the absence of ART had CD56+ CD8 T cell levels similar to uninfected controls. The CD56+ CD8 T cells had higher perforin upregulation as well as degranulation following stimulation with HIV gag peptides compared with CD56 negative CD8 T cells. Elite patients had the highest frequencies of perforin producing CD56+ CD8 T cells among all HIV+ groups. In patients receiving ART we noted high levels of the exhaustion marker TIM-3 on CD56+ CD8 T cells, implying that defective effector function was related to immune exhaustion. CD56+ CD8 T cells from elite or treated HIV patients responded to PMA plus ionomycin stimulation, and expressed transcription factors T-bet and EOMES at levels similar to uninfected controls. Consequently, the lytic effector defect in chronic HIV disease is due to immune exhaustion and quantitative loss of CD56+ CD8 T cells and this defect is not repaired in patients where viremia is suppressed and CD4 T cells are recovered after ART. Reconstituting the cytotoxic CD56+ subset of CD8+ T cells through new interventions might improve the lytic effector capacity and contribute to reducing the viral reservoir. Our initial studies indicate that IL-15 treatment partly reverses the CD56 defect, implying that myeloid cell defects could be targeted for immune therapy during chronic HIV disease

Transcription factors and MAPK signaling in CD56 subset.

<p>EOMES and T-bet control cytotoxic function of effector T cells. (A) Majority of CD56+ CD8 T cells expressed T-bet and/or EOMES and were double positive for these transcription factors, whereas a significant proportion of CD56- CD8 T cells were double negative for EOMES and T-bet. The representative plots show the trends presend in CD56+ or CD56- subsets from all patient groups irrespective of disease status (B) NVS group had highest frequency of T-bet expressing CD8 T cells whereas there was no significant difference in EOMES positive CD8 T cells among different cohorts of HIV infected patients. (C) Overall, the CD56+ fraction of CD8 T lymphocytes had higher levels of Erk phosphoryation upon PMA+inomycin stimulation compared with the CD56- CD8 T lymphocytes when samples from all groups were combined for analysis. CD56+ or CD56- CD8 T lymphocytes showed similar levels of Erk phosphorylation in all infected and control groups.</p

IL-15 restores CD56 on CD8 T cells from HIV infected patients.

<p>(A) Most CD8 T cells and almost all CD56 + CD8 T cells express the common gamma chain (γ_c) (or CD132). Representative plots (from left ND, PD, NVS, VIR) show there was no significant downregulation of this receptor on CD8 T lymphocytes from any infected group (B) Culture of PMBC in IL-15 resulted in a significant upregulation of CD56 on CD8 T lymphocytes at day 12 relative to start of culture in infected and uninfected samples.</p

High Affinity Allele for the Gene of FCGR3A Is Risk Factor for HIV Infection and Progression

Background: We investigated the genetics of Fc receptors, which function as activating receptors on immune cells and help to control HIV through antibody-mediated cellular cytotoxicity. Thus, Fc receptors may be important for virus immunity but might also promote immune hyperactivation that would enhance infection. Methodology/Principal Findings: We measured abundance of low and high activity alleles in two Fc receptor genes, FCGR2A and FCGR3A, for persons with HIV disease, natural virus suppressors (HIV+, without disease) and healthy controls to show whether genotypes were associated with infection and disease. Individuals homozygous for the high activity allele of FCGR3A (158VV) were predominantly found among HIV progressors and this group was also skewed toward higher allele frequencies for the V158 variant. Both of the HIV positive groups (progressors and natural virus suppressors) had significantly higher frequencies of the V158 allele compared with uninfected controls. There were no apparent associations among FCGR2A alleles and HIV status. Conclusions/Significance: Our results indicate that high activity alleles of FCGR3A may be risk factors for HIV infection or progression and we need to understand how allelic variants affect the balance between virus control and immune activation