Vikram Mehraj

CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV-positive patients

Absolute CD4 T cell count and plasma viral load have been established as predictors of HIV disease progression, and CD4 T cell count is used as an indicator for initiation of antiretroviral therapy. Following long‐term therapy, patients generally present with significant CD4 T cell recovery contrasting with persistently elevated CD8 T cell counts, which leads to a partial restoration of CD4:CD8 ratio. This review focuses on the relevance of the CD4:CD8 ratio on clinical outcomes, immune dysfunction and HIV reservoir size in long‐term treated patients.

HIV and the Gut Microbiota, Partners in Crime: Breaking the Vicious Cycle to Unearth New Therapeutic Targets

The gut microbiota plays a key role in health and immune system education and surveillance. The delicate balance between microbial growth and containment is controlled by the immune system. However, this balance is disrupted in cases of chronic viral infections such as HIV. This virus is capable of drastically altering the immune system and gastrointestinal environment leading to significant changes to the gut microbiota and mucosal permeability resulting in microbial translocation from the gut into the peripheral blood. The changes made locally in the gut have far-reaching consequences on the other organs of the body starting in the liver, where microbes and their products are normally filtered out, and extending to the blood and even brain. Microbial translocation and their downstream effects such as increased indolamine 2,3-dioxygenase (IDO) enzyme expression and activity create a self-sustaining feedback loop which enhances HIV disease progression and constitute a vicious cycle of inflammation and immune activation combining viral and bacterial factors. Understanding this self-perpetuating cycle could be a key element in developing new therapies aimed at the gut microbiota and its fallout after infection.

Elevation and persistence of CD8 T-cells in HIV infection: the Achilles heel in the ART era

HIV infection leads to a disturbed T‐cell homeostasis, featured by a depletion of CD4 T‐cells and a persistent elevation of CD8 T‐cells over disease progression. Most effort of managing HIV infection has been focused on CD4 T‐cell recovery, while changes in the CD8 compartment were relatively underappreciated in the past.

The Kynurenine Pathway Is a Double-Edged Sword in Immune-Privileged Sites and in Cancer: Implications for Immunotherapy

The term “immune privilege” was originally coined to describe the suppression of inflammatory responses within organs protected by anatomic barriers, ie, the eyes, brain, placenta, and testes. However, cellular and metabolic processes, which orchestrate immune responses, also control inflammation within these sites. Our current understanding of tolerogenic mechanisms has extended the definition of immune privilege to include hair follicles, the colon, and cancer. By catabolizing tryptophan, cells expressing the enzyme indoleamine-2,3-dioxygenase produce kynurenine metabolites, which orchestrate local and systemic responses to control inflammation, thus maintaining immune privilege. This review highlights the double-edged role played by the kynurenine pathway (KP), which establishes and maintains immune-privileged sites while contributing to cancer immune escape. The identification of the underlying molecular drivers of the KP in immune-privileged sites and in cancer is essential for the development of novel therapies to treat autoimmunity and cancer and to improve transplantation outcomes.

Tryptophan Catabolism in Chronic Viral Infections: Handling Uninvited Guests

L-Tryptophan (L-Trp) is an essential amino acid that possesses diverse metabolic, neurological, and immunological roles spanning from the synthesis of proteins, neurotransmitter serotonin, and neurohormone melatonin, to its degradation into immunosuppressive catabolites by indoleamine-2, 3-dioxygenase (IDO) in the kynurenine pathway (KP). Trp catabolites, by activating aryl hydrocarbon receptor (AhR), play an important role in antimicrobial defense and immune regulation. IDO/AhR acts as a double-edged sword by both depleting L-Trp to starve the invaders and by contributing to the state of immunosuppression with microorganisms that were not cleared during acute infection. Pathogens experiencing Trp deprivation by IDO-mediated degradation include certain bacteria, parasites, and less likely viruses. However, chronic viral infections highjack the host immune response to create a state of disease tolerance via kynurenine catabolites. This review covers the latest data involving chronic viral infections such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes, and cytomegalovirus (CMV) and their cellular interplay with Trp catabolites. Strategies developed by viruses to escape immune control also represent new avenues for therapeutic interventions based on Trp metabolism.

Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts

BACKGROUND CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time. METHODS Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years. RESULTS At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group. CONCLUSIONS ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation.

The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation

ABSTRACT The intestinal microbiota plays a key role in the pathogenesis of acute graft-versus-host disease (aGVHD). High-dose conditioning regimens given prior to allogeneic hematopoietic stem cell transplantation (aHSCT) modulate the composition of gut microbiota and damage the gut epithelial barrier, resulting in increased systemic inflammation. We assessed whether gut decontamination with antibiotics (ATB) prior to aHSCT influenced the frequency of aGVHD and mortality in 500 patients from two Canadian centers between 2005 and 2012. The rate of grade II–IV aGVHD was higher in the ATB arm compared with the arm without ATB (42% vs 28%; p < 0.001). This difference was mainly driven by a 2-fold higher rate of grade II–IV gastrointestinal aGVHD (GI-GVHD) in the ATB arm compared with the arm without ATB (20.7% vs 10.8%; p = 0.003). Multivariate analyses adjusted for known aGVHD risk factors revealed that more patients in the ATB group developed clinically significant GI-GVHD and liver aGVHD; adjusted odds ratio (aOR) = 1.83; p = 0.023 and aOR = 3.56; p = 0.047, respectively. Importantly, median overall survival (OS) was significantly lower in the group receiving ATB and the OS at 10 y remained decreased in the ATB group; adjusted hazard ratio (aHR) = 1.61 (p < 0.001). Without undermining the role of ATB prophylaxis to prevent infection in aHSCT, we have shown that the use of ATB that targets intestinal bacteria is associated with a more severe aGVHD that involves the GI organs and impacts OS. Prospective studies that evaluate the contribution of bacterial decontamination to aGVHD are warranted.

HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy

Objectives: The objective of this article is to investigate the contribution of colon and blood CD4+ T-cell subsets expressing the chemokine receptor CCR6 to HIV persistence during antiretroviral therapy. Design: Matched sigmoid biopsies and blood samples (n = 13) as well as leukapheresis (n = 20) were collected from chronically HIV-infected individuals receiving antiretroviral therapy. Subsets of CD4+ T cells with distinct differentiation/polarization profiles were identified using surface markers as follows: memory (TM, CD45RA−), central memory (TCM; CD45RA−CCR7+), effector (TEM/TM; CD45RA−CCR7−), Th17 (CCR6+CCR4+), Th1Th17 (CCR6+CXCR3+), Th1 (CCR6−CXCR3+), and Th2 (CCR6−CCR4+). Methods: We used polychromatic flow cytometry for cell sorting, nested real-time PCR for HIV DNA quantification, ELISA and flow cytometry for HIV p24 quantification. HIV reactivation was induced by TCR triggering in the presence/absence of all-trans retinoic acid. Results: Compared with blood, the frequency of CCR6+ TM was higher in the colon. In both colon and blood compartments, CCR6+ TM were significantly enriched in HIV DNA when compared with their CCR6− counterparts (n = 13). In blood, integrated HIV DNA levels were significantly enriched in CCR6+ versus CCR6− TCM of four of five individuals and CCR6+ versus CCR6− TEM of three of five individuals. Among blood TCM, Th17 and Th1Th17 contributed the most to the pool of cells harboring integrated HIV DNA despite their reduced frequency compared with Th2, which were infected the least. HIV reactivation was induced by TCR triggering and/or retinoic acid exposure at higher levels in CCR6+ versus CCR6− TM, TCM, and TEM. Conclusion: CCR6 is a marker for colon and blood CD4+ T cells enriched for replication-competent HIV DNA. Novel eradication strategies should target HIV persistence in CCR6+CD4+ T cells from various anatomic sites.

Current topics in HIV pathogenesis, part 2: Inflammation drives a Warburg-like effect on the metabolism of HIV-infected subjects

HIV-1 infection leads to a depletion of CD4 T-cells associated with a persistent immune inflammation and changes in cellular metabolism. Most effort of managing HIV infection with combination of antiretroviral therapies (ART) has been focused on CD4 T-cell recovery, while control of persistent immune inflammation and metabolism were relatively underappreciated in the past. Recent discoveries on the interplay between innate immunity, inflammation (especially the inflammasome) and metabolic changes in the context of cancer and autoimmunity provide an emerging field for chronic viral infections including HIV-1. In a previous review, we described the deregulated metabolism contributing to immune dysfunctions such as alteration of memory T-cell responses, mucosal protection, and dendritic cell-related antigen presentation. Here, we summarize the latest knowledge on the detrimental influence of long-lasting inflammation and inflammasome activation induced by HIV-1, gut dysbiosis, and bacterial translocation, on metabolism during the course of viral infection. We also report on the inability of ART to fully counteract inflammation, resulting in partial metabolic improvement and leading to an insufficient decrease in the risk of non-AIDS events. Further advances in our understanding of the relationship between inflammation, altered metabolism, and long-term ART is warranted. Additionally, there is a critical need for developing new strategies to regulate the pro-inflammatory signals to enhance cellular metabolism and immune functions in order to improve the quality of life of individuals living with HIV-1.

Immune tolerance properties of the testicular tissue as a viral sanctuary site in ART-treated HIV-infected adults.

Objective:HIV persistence in long-lived infected cells and in anatomical sanctuary sites are major hurdles to HIV eradication. Testicular tissue may represent a significant viral sanctuary site as it constitutes an immunologically privileged compartment. We assessed immunotolerance properties of the testicular tissue in individuals receiving suppressive antiretroviral therapy (ART). Design and methods:Testicular tissue and matched blood samples were collected from six virally suppressed adults and 10 HIV-uninfected controls prior to sex reassignment surgery. T cells were purified from freshly isolated testicular interstitial cell suspensions. T-cell subsets, expression of immune activation markers and HIV DNA were assessed in matched testicular cells and peripheral blood mononuclear cells (PBMCs). Results:When compared with PBMCs, testes were characterized by a lower CD4+ T-cell proportion among total T cells, a decrease in the frequency of naive cells, an increase in the frequency of effector-memory T cells and an increase in CCR5 expression in both the HIV+ and HIV− groups. In HIV-infected individuals on ART, testes displayed higher T-cell immune activation (Coexpression of CD38 and Human Leukocyte Antigen - antigen D Related) than PBMCs. In both groups, testes were characterized by higher frequencies of immunosuppressive CD39+ regulatory T cells and a massive increase in CD73 expression on CD8+ T cells. In addition, a remarkable increase in indoleamine-pyrrole 2,3-dioxygenase immunosuppressive enzyme involved in tryptophan/kynurenine catabolism was observed in testes versus blood. Rare cells harboring HIV DNA were detected in testes from five out six participants. Conclusion:These findings suggest that the adenosine and tryptophan/kynurenine immune-metabolic pathways contribute to immune tolerance in testicular tissue. Our results suggest that testes may represent a distinctive HIV sanctuary site during ART.