Loss Of CD4 Research Articles

The role of IL-21 in rescuing CD8 T Cell responses in chronically infected HIV patients (105.38)

Abstract CD4 T cells are vital in regulating CD8 T cell responses during chronic viral infections. Notably, the hallmark of HIV infection is the severe loss of CD4 T cells resulting in defective CD8 T cell responses. One consequence of CD4 depletion following HIV infection is the loss of interleukin-21 (IL-21) production by the CD4 T cells, which has been demonstrated to be a critical factor in promoting viral control in murine studies. However, it is unknown whether IL-21 can rescue the exhausted CD8 T cells in chronically infected HIV+ patients. In this study we build upon novel murine studies to demonstrate a key role for IL-21 in improving CD8 T cell responses in PBMC from chronically infected HIV patients. To determine whether IL-21 can rescue exhausted CD8 T cells, PBMCs from HIV patients with viral loads > 10,000 RNA copies/mL were incubated with IL-21. Following re-stimulation with overlapping Gag-peptide, IL-21 enhanced the production of IFN-γ by CD8 T cells although no effect was observed on IL-2 or TNF-α production. In addition, an increase in the central memory (CD45RO+CD27+) population was observed with IL-21 culture along with higher MFI of Bcl-6 levels. Interestingly, IL-21 cultured CD8 T cells expressed higher MFI of PD-1 even though CD8 T cell function was enhanced. Significantly, these results provide an approach in which IL-21 can be potentially used to enhance CD8 T cell responses in chronically infected HIV patients, whose CD4 counts are low or defective.

Phagocytosis, Interferon-γ, IL-21, and CD4+ MHC class II-restricted T cells in resistance to Babesia microti infection (43.14)

Abstract Babesiosis is an emerging infectious disease caused by the hematoprotozoan parasite Babesia microti. The mechanisms of resistance to B. microti are not fully understood. The laboratory has developed a murine model of babesiosis with many of the features of the human disease that is used to examine the genetic determinants of resistance. The goal of the present study was to identify cellular processes that convey resistance to this parasitic infection. We established that the depletion of macrophages by chronic administration of clodronate liposomes resulted in early (0 to 30 days post-infection) hyperacute phase parasitemia (quantified as percent parasitized erythrocytes) but did not affect late phase (days 35-50) clearance of B. microti. In contrast, the absence of MHC-ii or the αβ T cell receptor prevents both early and late resistance. We find that early resistance requires the production of the cytokine IL-21. We also observed that the dual loss of CD4 and IL-21 results in the complete loss of resistance. We therefore hypothesize that IL-21 activates CD4+ T lymphocytes to synthesize IFN- γ that, in turn, activates macrophages to phagocytose and destroy B. microti infected red blood cells or B. microti itself. A model of resistance that incorporates these observations will be presented.

Characterization of IL-10 producing CD8 T cells that limit immune surveillance during chronic virus infection. (105.34)

Abstract Gammaherpesvirus infection in AIDS patients is associated with severe disease. Progressive loss of CD4 T cells results in an erosion of immune surveillance, which may lead to gammaherpesvirus associated tumors. Studies by our group and others have used murine γHV-68 infection in combination with CD4 depletion to model this breakdown in immune surveillance. Mice initially control the infection, but virus reactivates after 6 weeks, indicating a lack of long-term immune surveillance. We previously showed mice had elevated IL-10 and therapeutic IL-10R blockade reduced reactivation of the virus, implicating IL-10 as a key factor suppressing immune surveillance. We identified a population of IL-10 producing CD8 T cells only in the infected mice lacking CD4 T cells but not in intact mice. Here we characterize IL-10+ CD8 T cells and elucidate how they arise in both the acute and chronic phase of the infection. In the acute phase of the infection less IL-10 producing CD8s arose in the absence of CD4 help or CD40-CD40L signaling, while in the chronic phase IL-10+ CD8s only arose in the absence of CD4 help. IL-10 producing CD8s in the chronic phase showed an anergic phenotype in terms of proliferation in vitro. In addition, they suppressed the proliferation of effector CD8 T cell in vitro. Dissection of the mechanisms involved in the generation and the function of these suppressive IL-10 producing CD8 T cells may expose new targets for therapeutic intervention for AIDS patients.

Foxp3-independent loss of regulatory CD4+T-cell suppressive capacities induced by self-deprivation

In the periphery, Foxp3 expression is considered sufficient to maintain natural regulatory CD4(+) T-cell suppressive function. In this study, we challenge this model. Indeed, in mouse chimeras in which major histocompatibility complex (MHC) class II expression is restricted to the thymus, peripheral regulatory CD4(+) T cells lack suppressive activity. In addition, regulatory CD4(+) T cells recovered 5 days after transfer into recipient mice lacking expression of MHC class II molecules (self-deprived) are unable to inhibit the proliferative response of conventional CD4(+) T cells both in vitro and in vivo. Disruption of TCR/MHC class II interactions rapidly leads to alterations in the regulatory CD4(+) T-cell phenotype, the ability to respond to stimulation and to produce interleukin-10, and the transcriptional signature. Interestingly, self-deprivation does not affect Foxp3 expression indicating that in regulatory CD4(+) T cells, self-recognition induces unique transcriptional and functional features that do not rely on Foxp3 expression.

NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells

NLRs (nucleotide-binding domain leucine-rich repeat containing receptors; NOD-like receptors) are a class of pattern recognition receptor (PRR) that respond to host perturbation from either infectious agents or cellular stress1,2. The function of most NLR family members has not been characterized and their role in instructing adaptive immune responses remains unclear 2,3. NLRP10 (also known as PYNOD, NALP10, PAN5 and NOD8) is the only NLR lacking the putative ligand binding leucine rich repeat domain, and has been postulated to be a negative regulator of other NLR members including NLRP34–6. We did not find evidence that NLRP10 functions through an inflammasome to regulate caspase-1 activity nor that it regulates other inflammasomes. Instead, Nlrp10−/− mice had a profound defect in helper T cell-driven immune responses to a diverse array of adjuvants including lipopolysaccharide (LPS), aluminium hydroxide (alum) and complete Freund’s adjuvant (CFA). Adaptive immunity was impaired in the absence of NLRP10 due to a dendritic cell (DC) intrinsic defect in emigration from inflamed tissues while upregulation of DC costimulatory molecules and chemotaxis to CCR7-dependent and independent ligands remained intact. The loss of antigen transport to the draining LN by this migratory DC subset resulted in an almost absolute loss in naïve CD4+ T cell priming, highlighting the critical link between diverse innate immune stimulation, NLRP10 activity and the immune function of mature DCs.

Influence of MHC class I and II haplotypes on the experimental infection of Mauritian cynomolgus macaques with SHIVSF162P4cy

Mauritian cynomolgus macaques (MCM) are widely used in human immunodeficiency virus research because of their restricted major histocompatibility complex (MHC) diversity which provides the opportunity to address the influence of host factors on vaccine studies. We herein report the impact of MHC haplotype on the outcome of 21 MCM infections with the CCR5-tropic simian/human immunodeficiency virus (SHIV)(SF162P4cy). MCM were susceptible to SHIV(SF162P4cy) infection as shown by viremia and loss of CD4+ T cells. A significant association between haplotype M7 (class IA, IB, II) and persistent viremia was observed in chronic phase, whereas recombinant class IA haplotype was associated with a reduction of viral RNA during acute infection. Class IB M4 haplotype displayed significantly lower acute phase provirus copy numbers. In addition, statistical analysis indicated a detrimental effect of haplotype M4 (class IA, IB) on the course of infection as indicated by lower CD4+ T-cell levels during chronic infection. A decrease in post-acute phase CD4+ T-cell numbers was also observed in haplotype M2 animals. This is the first report that documents the effects of host MHC class I and II molecules on the SHIV(SF162P4cy) infection in MCM, particularly with regard to the association between recombinant class IA, M4, and M7 haplotypes and the dynamic of viral replication and level of CD4+ T cells.

Exhaustion of Cytotoxic Effector Systems May Limit Monoclonal Antibody-Based Immunotherapy in Cancer Patients

The CD20 mAb ofatumumab (OFA) induces complement-mediated lysis of B cells. In an investigator-initiated phase II trial of OFA plus chemotherapy for chronic lymphocytic leukemia (CLL), OFA treatment promoted partial CLL B cell depletion that coincided with reduced complement titers. Remaining CLL B cells circulated with bound OFA and covalently bound complement breakdown product C3d, indicative of ongoing complement activation. Presumably, neither complement- nor effector cell-based mechanisms were sufficiently robust to clear these remaining B cells. Instead, almost all of the bound OFA and CD20 was removed from the cells, in accordance with previous clinical studies that demonstrated comparable loss of CD20 from B cells after treatment of CLL patients with rituximab. In vitro experiments with OFA and rituximab addressing these observations suggest that host effector mechanisms that support mAb-mediated lysis and tumor cell clearance are finite, and they can be saturated or exhausted at high B cell burdens, particularly at high mAb concentrations. Interestingly, only a fraction of available complement was required to kill cells with CD20 mAbs, and killing could be tuned by titrating the mAb concentration. Consequently, maximal B cell killing of an initial and secondary B cell challenge was achieved with intermediate mAb concentrations, whereas high concentrations promoted lower overall killing. Therefore, mAb therapies that rely substantially on effector mechanisms subject to exhaustion, including complement, may benefit from lower, more frequent dosing schemes optimized to sustain and maximize killing by cytotoxic immune effector systems.

Regulatory T Cells in HIV-1 Infection: The Good, the Bad, and the Ugly

The notion of a “suppressive” process that is active during inflammation was first introduced in the late 1960s [1, 2]. Research in this field faced a major setback in the early 1980s when DNAbased studies revealed that the genetic locus that was thought to control suppressor T-cell activity in mice (the I-J gene within the major histocompatibility complex region) did not exist [3]. Research in the field was revitalized by Sakaguchi et al [4] in 1995, when it was demonstrated that the adoptive transfer of CD4 T cells depleted of interleukin 2 (IL-2) receptor α-chain–positive (CD25) cells led to a spectrum of autoimmune diseases in immunocompromised mice and that cotransfer of the CD25 cells prevented these diseases. In 2003, the forkhead box protein P3 (FoxP3) was identified as a master control gene for the development and in vivo suppressor activity of these CD4CD25 T cells that have become commonly referred to as regulatory T cells or “Tregs” [5, 6]. A substantial number of reports have been generated in both human and murine systems on the characterization of Tregs and their role in the regulation of the immune response in health and disease. Today, Tregs are widely recognized as a subset of CD4CD25FoxP3 T cells capable of suppressing the activation, proliferation, and function of a wide variety of immune effector cells, including CD4 and CD8 T cells, natural killer (NK) and NKT cells, B cells, and antigen-presenting cells, such as dendritic cells and macrophages [7, 8]. There are at least 2 different types of Tregs present in humans: natural Tregs and induced (or adaptive) Tregs. Both Treg populations are characterized by high levels of expression of CD25 on the cell surface and intracellular expression of FoxP3 [6]. Although natural Tregs arise during the normal process of T-cell development in the thymus and survive in the periphery [9], induced or adaptive Tregs can be converted from extrathymic naive CD4 T cells in vivo by antigen stimulation in mice [10] or in vitro in mouse or human cells by culturing CD4FoxP3 T cells with different cytokines, including transforming growth factor β, IL-2, or interleukin 15 [11–13]. Intermittent in vivo administration of IL2 can lead to an expansion of Treg-like cells (CD4CD45ROCD25 T cells) in patients with human immunodeficiency virus type 1 (HIV-1) infection [14] or hepatitis C virus infection [15]. Although no clinical benefit was seen in a phase III study of IL-2 in patients with HIV-1 infection [16], patients with hepatitis C virus–induced vasculitis had remission of their disease. The immune systems of patients with HIV-1 infection are characterized by inadequate control of HIV-1 replication, progressive loss of CD4 T cells, and chronic generalized immune activation [17–19]. There is increasing evidence that clinical progression of HIV-1 infection is critically linked to the negative consequences of immune activation and that the level of immune activation is directly correlated to the plasma levels of HIV-1. [20]. The importance of immune activation in HIV-1 infection has been reinforced by the strong associations between baseline levels of CD4 and CD8 T cells that express CD38 and HLA-DR [21–23], plasma levels of interleukin 6, D-dimer or soluble CD14, and all-cause mortality [24, 25]. Given their potent suppressive capability, the role of Tregs in HIV-1 infection and, in particular, their impact on the host response to HIV-1 and immune activation have received much attention in recent years. In the context of HIV-1 infection, Tregs can be postulated to be beneficial by dampening excessive immune activation (the good) (Figure 1) or to be harmful by suppressing HIV-1–specific immune responses Received and accepted 7 February 2012; electronically published 28 March 2012. Correspondence: H. Clifford Lane, MD, Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (clane@niaid.nih.gov). The Journal of Infectious Diseases 2012;205:1479–82 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2012. DOI: 10.1093/infdis/jis238

Case study interpretation-Portland: Case 2

Case study interpretation-Portland: Case 2

Acute Hepatitis and Esophageal Candidiasis During Primary Human Immunodeficiency Virus Infection

Primary human immunodeficiency virus infection (PHI) may take place without symptoms or may be associated with mononucleosislike illness. Sometimes, the clinical presentation includes aseptic meningitis, mucocutaneous ulcers, oropharyngeal candidiasis and elevated aminotransferases. We describe the case of a 25-year-old male, who had sex with other men, and presented to the emergency department with elevated aminotransferases levels and esophageal candidiasis. Acute hepatitis markers (hepatitis A, B, C, Epstein-Barr virus and cytomegalovirus) were performed and all were negative. Repeated testes revealed 3 consecutive negative HIV antibody tests with a strongly high HIV-1 RNA plasma concentration (g 500,000 copies /mL) and a loss of CD4+ T cells (347 cells/µL), characterizing an acute hepatitis occurring during a course of an acute retroviral syndrome. Antiretroviral therapy was started while waiting a genotyping test performed to assess the presence of potential drug resistance mutations, and the patient recovered uneventfully, with normalization of aminotransferases, CD4 restoration and viral load become undetectable. Genotyping test indicated primary antiretroviral mutations, and appropriate changes in antiretroviral therapy were performed. Our case like other reports suggested that a diagnosis of PHI needs to be considered in patients who presented with acute hepatitis. J Med Cases. 2012;3(2):116-118 doi: https://doi.org/10.4021/jmc489w

Enzyme replacement therapy partially prevents invariant Natural Killer T cell deficiency in the Fabry disease mouse model

Fabry disease is a lysosomal storage disease caused by deficient activity of the α-Galactosidase A (α-Gal A) enzyme, which leads to abnormal accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in the lysosome. Glycosphingolipids are known to be invariant Natural Killer T (iNKT) cell antigens. Several animal models of lysosomal storage diseases, including Fabry disease, present a defect in iNKT cell selection by the thymus. We have studied the effect of age and the impact of enzyme replacement therapy on Gb3 accumulation and iNKT cells of Fabry knockout mice. At 4weeks of age, Fabry knockout mice already showed Gb3 accumulation and a reduction in the percentage of iNKT cells. In older mice (12-week old), we observed an accentuated peripheral iNKT deficiency. 12-week old animals also showed a reduced splenic CD4+/CD4− iNKT cell ratio due to greater loss in the iNKT CD4+ subset. Treatment of Fabry knockout mice with α-Gal A replacement therapy efficiently reduced Gb3 deposition in the liver and spleen. Moreover, enzyme replacement therapy had a positive effect on the number of iNKT cells in an organ-dependent fashion. Indeed, treatment of Fabry knockout mice with α-Gal A did not alter iNKT cell percentage in the thymus and liver but increased splenic iNKT cell percentage when compared to untreated mice. Study of animals prior to treatment indicates that enzyme replacement therapy stabilized iNKT cell percentage in the spleen. This stabilization is due to a specific effect on the iNKT CD4+ subset, preventing the decrease on the number of these cells that occurs with age in Fabry knockout mice. This study reveals that enzyme replacement therapy has a positive organ and subset-dependent effect in iNKT cells of Fabry knockout mice.

The HR2 polymorphism N140I in the HIV-1 gp41 combined with the HR1 V38A mutation is associated with a less cytopathic phenotype

BackgroundResistance to the fusion inhibitor enfuvirtide (ENF) is achieved by changes in the gp41 subunit of the HIV envelope glycoprotein (Env). Specific ENF-associated mutational pathways correlate with immunological recovery, even after virological failure, suggesting that the acquisition of ENF resistance alters gp41 pathogenicity. To test this hypothesis, we have characterized the expression, fusion capability, induction of CD4+ T cell loss and single CD4+ T cell death of 48 gp41 proteins derived from three patients displaying different amino acids (N, T or I) at position 140 that developed a V38A mutation after ENF-based treatment.ResultsIn all cases, intra-patient comparison of Env isolated pre- or post-treatment showed comparable values of expression and fusogenic capacity. Furthermore, Env with either N or T at position 140 induced comparable losses of CD4+ T-cells, irrespective of the residue present at position 38. Conversely, Env acquiring the V38A mutation in a 140I background induced a significantly reduced loss of CD4+ T cells and lower single-cell death than did their baseline controls. No altered ability to induce single-cell death was observed in the other clones.ConclusionsOverall, primary gp41 proteins with both V38A and N140I changes showed a reduced ability to induce single cell death and deplete CD4+ T cells, despite maintaining fusion activity. The specificity of this phenotype highlights the relevance of the genetic context to the cytopathic capacity of Env and the role of ENF-resistance mutations in modulating viral pathogenicity in vivo, further supporting the hypothesis that gp41 is a critical mediator of HIV pathogenesis.

Polymyalgia rheumatica is characterised by pro-inflammatory, late stage CD8+ T cells

Backgroundand objectivesPolymyalgia rheumatica (PMR) is a frequent, inflammatory rheumatic disease affecting older people. Previous studies suggest that T cell mediated immune responses contribute to PMR. However, little is known about...

Different Baseline Characteristics and Different Outcomes of HIV-Infected Patients Receiving HAART Through Clinical Trials Compared With Routine Care in Mexico

The efficacy of antiretroviral therapy (ART) has been established through clinical trials (CTs). However, selection bias and differences can limit their applicability to the general population. All treatment-naive HIV-infected patients who began ART in routine care (RC) between 2000 and 2008 were compared with all patients who initiated ART through a CT in terms of incidence of virological failure (VF), increase in CD4(+) count, mortality rate, and loss to follow-up (LTFU). At baseline, the RC group had less years of education, higher unemployment rate, higher proportion of females (14.2 vs. 5.7%; P < 0.01), lower median CD4(+) (97 vs. 158 cells/μL; P < 0.01), and lower proportion of patients with hemoglobin >12 g/dL (74 vs. 83%, P = 0.04). VF at week 48 was less frequent in the CT compared with the RC group (1.8% vs. 6.21%, P = 0.02). In multivariate analysis, participation in CT [odds ratio (OR): 0.20, 95% confidence interval (CI): 0.04 to 0.91, P = 0.03], hemoglobin >12 g/dL (OR: 0.29, 95% CI 0.09-0.89, P = 0.03), and receiving an optimal highly active antiretroviral therapy regimen (OR: 0.09, 95% CI: 0.01 to 0.52, P < 0.01) remained associated with lower risk of VF. All cause mortality was 0.017 (95% CI: 0.002 to 0.122) versus 0.094 (95% CI: 0.053 to 0.17) deaths per 1000 person-days in the CT group and in the RC group, respectively (P = 0.05). No differences were found in the proportion of patients LTFU. Receiving ART through CT was associated with lower probability of VF, lower mortality (probably related to less severe clinical characteristics at baseline), and similar rates of LTFU than RC.

Tumor‐induced changes in the phenotype of blood‐derived and tumor‐associated T cells of early stage breast cancer patients

Tumor-induced immune suppression has mainly been studied in patients with advanced cancer. Despite the fact that they are most likely to benefit from immunotherapy, patients with early stage cancers were under-represented in these studies. We analyzed blood and tumor-derived T cells from patients with stage 1 (n = 20), stage 2 (n = 23) or stage 3 (n = 1) breast cancer and found that, even early stage tumors induced T cell differentiation. Breast cancer patients had significantly more circulating CD8+ memory and fewer CD8+ naïve T cells than healthy controls (n = 10). Up-regulation of CD69 and PD1 on cancer patient T cells suggests previous activation, and increased expression of the chemokine receptors CCR5 and CXCR3 on CD8+ T cells indicates that their homing capacity differs from that of healthy individuals. Comparison of blood-derived and tumor-associated T cells from patients with different metastatic status and tumor grades revealed that tumor progression and aggressiveness seem to favor the expansion of memory T cells over naive T cells. We have previously shown that immunosuppression in this patient population is stronger in the tumor than in the blood. Here, we report signs of exhaustion, such as loss of CD28, on tumor-associated as compared to blood-derived CD8+ T cells, despite the fact that tumor-associated T cells are predominantly effector memory cells and express high levels of CD69. The finding that the presence of a tumor potentially induces immunosenescence early during tumorigenesis indicates that efficient immunotherapy might be difficult even in patients with early stage cancer due to T cell exhaustion and tolerance.

Regulatory T cells in cattle and their potential role in bovine paratuberculosis

The intracellular bacterium Mycobacterium avium subspecies paratuberculosis (MAP) causes Johne's disease in wild and domestic ruminants. Johne's disease presents as a chronic enteritis with severe inflammation of intestinal tissues, characterized by widespread infiltration of macrophages, the target cell of MAP. Clinical signs of Johne's disease are typically accompanied by a loss of peripheral CD4+ T cell responses to MAP antigens and an increase in anti-MAP serum IgG levels. Recently, it was proposed that regulatory T cells might develop over the lengthy course of subclinical MAP infection. In the past five years, significant progress in defining bovine regulatory T cells has been made. These studies grew out of observations that IL-10 is produced by PBMCs in response to MAP antigen stimulation and that neutralization of this IL-10 could enhance IFN-γ production from MAP-antigen reactive effector T cells. Depletion studies revealed that MAP responsive cell populations producing IL-10 were largely CD4+ and CD25+, although monocytes have also been shown to produce IL-10 in response to MAP. In addition, evidence for a regulatory population of γδ T cells has also begun to accumulate. We summarize current thinking regarding regulatory T cells in MAP infection and provide data suggesting a potential link between regulatory T cells, bovine leukemia virus, and MAP.

Both activating and inhibitory Fc gamma receptors mediate rituximab-induced trogocytosis of CD20 in mice

Antigenic modulation by trogocytosis during anti-CD20 mAb treatment with rituximab (RTX) leads to loss of CD20 and therefore can compromise therapy. During trogocytosis, effector cells, such as macrophages, remove CD20 from the surface of antibody-coated cells in an Fc receptor-dependent manner. Importantly, Fcγ receptors (FcγRs) are also crucial in the anti-tumor effects of RTX by inducing antibody dependent cell-mediated cytotoxicity (ADCC). Here we studied the role of FcγR during RTX-induced trogocytosis of CD20 in an intraperitoneal tumor model with EL4-CD20 cells. We found marked RTX-induced trogocytosis of CD20 in FcγRI- or FcγRIII-deficient mice, similar to wild type mice, demonstrating a redundancy for activating FcγR in trogocytosis. Interestingly, in FcRγ-chain-deficient mice, trogocytosis was still apparent, indicating that the inhibitory receptor FcγRIIB alone can also mediate trogocytosis. These data were confirmed by in vitro analysis with blocking antibodies. Decreasing the amount of RTX in vivo resulted in less trogocytosis of CD20, supporting clinical studies with lower RTX dose. Importantly, we show that cells which undergo in vivo trogocytosis can still be killed ex vivo by ADCC but not by complement-mediated cytotoxicity (CDC), underscoring the clinical relevance of trogocytosis.Taken together, our study provides more insights into the mechanism and consequences of RTX-induced trogocytosis of CD20.

Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence

Vigorous proliferative CD4(+) T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4(+) T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers. Surprisingly, broadly directed HCV-specific CD4(+) T cell responses were universally detectable at early stages of infection, regardless of the clinical outcome. However, persistent viremia was associated with early proliferative defects of the HCV-specific CD4(+) T cells, followed by rapid deletion of the HCV-specific response. Only early initiation of antiviral therapy was able to preserve CD4(+) T cell responses in acute, chronically evolving infection. Our results challenge the paradigm that HCV persistence is the result of a failure to prime HCV-specific CD4(+) T cells. Instead, broadly directed HCV-specific CD4(+) T cell responses are usually generated, but rapid exhaustion and deletion of these cells occurs in the majority of patients. The data further suggest a short window of opportunity to prevent the loss of CD4(+) T cell responses through antiviral therapy.

Acute Hepatitis and Esophageal Candidiasis During Primary Human Immunodeficiency Virus Infection

Primary human immunodeficiency virus infection (PHI) may take place without symptoms or may be associated with mononucleosislike illness. Sometimes, the clinical presentation includes aseptic meningitis, mucocutaneous ulcers, oropharyngeal candidiasis and elevated aminotransferases. We describe the case of a 25-year-old male, who had sex with other men, and presented to the emergency department with elevated aminotransferases levels and esophageal candidiasis. Acute hepatitis markers (hepatitis A, B, C, Epstein-Barr virus and cytomegalovirus) were performed and all were negative. Repeated testes revealed 3 consecutive negative HIV antibody tests with a strongly high HIV-1 RNA plasma concentration (&amp;gt; 500,000 copies /mL) and a loss of CD4&lt;sup&gt;+&lt;/sup&gt; T cells (347 cells/µL), characterizing an acute hepatitis occurring during a course of an acute retroviral syndrome. Antiretroviral therapy was started while waiting a genotyping test performed to assess the presence of potential drug resistance mutations, and the patient recovered uneventfully, with normalization of aminotransferases, CD4 restoration and viral load become undetectable. Genotyping test indicated primary antiretroviral mutations, and appropriate changes in antiretroviral therapy were performed. Our case like other reports suggested that a diagnosis of PHI needs to be considered in patients who presented with acute hepatitis. J Med Cases. 2012;3(2):116-118 doi: https://doi.org/10.4021/jmc489w

Immune Modulators of HIV Infection: The Role of Reactive Oxygen Species

A continue loss of CD4+ T lymphocytes, immune response dysfunction and chronic immune activation (IA) are hallmarks of untreated chronic HIV-1 infection. ROS and the subsequent oxidative stress have been connected with chronic activation of the immune system, viral replication, immune dysfunction, programmed cell death, and neurological damage, all considered to be major contributing issues in HIV-1 diseases progression. It has been demonstrated that HAART partially restore the antioxidant capacity by suppressing HIV, and it has been suggested that antioxidant therapy in combination with HAART could protect the blood brain barrier from oxidative stressinduced damage. Several mechanisms have been proposed to explain how HIV could modulate ROS generation and several HIV proteins have been shown to modulate ROS production. This review is intended to highlight the role played by ROS as modulators of the immune system during the course of HIV infection, which could explain its contribution to disease progression, opening the scope to new strategies for drug design and future treatment.