Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CTLs can acquire MHC class I-peptide complexes from their target cells, whereas CD4(+) T cells obtain MHC class II-peptide complexes from APCs in a TCR-specific manner. As a consequence, Ag-specific CTL can kill each other (fratricide) or CD4(+) T cells become APCs themselves. The purpose of the acquisition is not fully understood and may be either inhibition or prolongation of an immunological response. In this study, we demonstrate that human CD4(+) Th cells are able to capture membrane fragments from APC during the process of immunological synapse formation. The fragments contain not only MHC class II-peptide complexes but also MHC class I-peptide complexes, rendering these cells susceptible to CTL killing in an Ag-specific manner. The control of CD4(+) Th cells by Ag-specific CTL, therefore, maybe another mechanism to regulate CD4(+) T cell expansion in normal immune responses or cause immunopathology during the course of viral infections such as HIV.
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PMID:CTLs target Th cells that acquire bystander MHC class I-peptide complex from APCs. 1761 73

Clinical observation shows pregnant women under antiretroviral therapy present bleeding episodes at delivery, although this therapy promotes a decrease in fibrinolysis in nonpregnant patients, suggesting a prothrombotic state in the former. Since these drugs provoke hepatic disorders, they can cause bleeding disturbances. We investigated effects of antiretroviral therapy on hemostasis in pregnant women. Two groups were studied: pregnant women with HIV (n = 11), and (control) pregnant women without HIV (n = 7). Four blood samples were collected from each individual in both groups: one at the beginning of pregnancy before treatment, two during pregnancy and therapy, and one 6 weeks after delivery. Treatment was performed according to recommendations of the Brazilian Health Department for the evaluation of the prothrombin time, activated partial thromboplastin time, factors VII, X, and XII, fibrinogen concentration, protein C, protein S, tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1, and fibrin degradation products (FbDPs). Statistical analysis demonstrated pregnancy caused increased factor VII (P = 0.0313), factor X (P = 0.0156) and factor XII (P = 0.0156) activity, fibrinogen concentration (P = 0.0156), t-PA (P = 0.0313), plasminogen activator inhibitor-1 (P = 0.0156) and FbDP levels (P = 0.0313). HIV infection caused increased factor XII (P = 0.0114), t-PA (P = 0.0346) and FbDPs (P = 0.0003), and decreased protein S levels (P = 0.0441). Antiretroviral therapy reduced the activated partial thromboplastin time (P = 0.0114) and protein S (P = 0.0012), and increased t-PA (P = 0. 0204) and FbDP levels (P = 0.0154). The results suggest a prothrombic state developing during pregnancy, maintenance of hemostatic equilibrium in HIV infection and occurrence of hyperfibrinolysis, not due to hepatotoxicity, during antiretroviral therapy, causing the clinically observed bleeding episodes.
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PMID:Effect of antiretroviral therapy on hemostasis in Brazilian pregnant women with HIV infection. 1798 18

CD8(+) cytotoxic T lymphocytes (CTL) play an important role in controlling virus replication in HIV- and SIV-infected humans and monkeys, respectively. Three well-studied SIV CTL determinants are the two Mamu A()01-restricted epitopes Gag CM9 and Tat SL8, and the Mamu B()17-restricted epitope Nef IW9. Point mutations leading to amino acid replacements in these epitopes have been reported to mediate SIV escape from CTL control. We found that synthetic peptides containing mutations in SIV Gag CM9 and Tat SL8 were no longer recognized by the respective CTL. On the other hand, the described I-to-T replacement at the N-terminal amino acid residue of the SIV Nef IW9 epitope only moderately affected CTL recognition of the variant peptide, TW9. In an attempt to dissect the mechanism of escape of the Nef TW9 mutation, we investigated the effect of this mutation on CTL recognition of CD4(+)T cells infected with an engineered SIV(mac)239 that contained the TW9 mutation in Nef. Although, the wild type and mutant virus both infected and efficiently replicated in rhesus macaque CD4(+)T cells, the TW9 mutant virus failed to induce IFN-gamma expression in an SIV Nef IW9-specific CTL clone. Thus, unlike escape from Gag CM9- or Tat SL8-specfic CTL control presumably by loss of epitope binding, these results point to a defect at the level of processing and/or presentation of the variant TW9 epitope with resultant loss of triggering of the cognate TCR on CTL generated against the wild type peptide. Our data highlight the value of functional assays using virus-infected target cells as opposed to peptide-pulsed APC when assessing relevant escape mutations in CTL epitopes.
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PMID:The Mamu B 17-restricted SIV Nef IW9 to TW9 mutation abrogates correct epitope processing and presentation without loss of replicative fitness. 1832 25

To study the prevalence of oral lesions in HIV infected patients and its relationship with CD4+ cell count in Georgia 732 HIV positive adult patients who were admitted to the Infectious Diseases, AIDS and Clinical Immunology Research Center (IDACIRC) since January, 2006 till October, 2008 were evaluated. Each patient underwent full clinical and standard laboratory examination. CD4+ cell count was determined by the Becton-Dickinson FACSCalibur flow cytometer (MultiTEST CD3 FITC/CD8 PE/CD45 PerCP/CD4 APC Reagent). Socio-demographic data was obtained using a standard questionnaire at the epidemiology department of IDACIRC. Oral manifestations were diagnosed according to EEC clearinghouse classification (1993). Oral lesions were revealed in 546 patients (75%). 186 patients (25%) did not exhibit any oral complications. The prevalence of two or more simultaneously exhibited types of lesions was as follows: three types of lesions were detected in 45 patients (6%) and two types of lesions were detected in 245 patients (33%). The investigation revealed oral candidiasis constituted the most common form of oral lesions, representing a 64% (467 patients), followed by HIV associated periodontal diseases in 216 patients (30%), recurrent aphthous like ulcerations in 118 patients (16%), oral hairy leukoplakia in 58 patients (8%), orolabial herpes simplex infection in 50 patients (7%), human papillomavirus (wart like lesions) in 37 patients (5%) and Kaposi's sarcoma in 3 patients (0.4%). Most of oral lesions cases were found in patients with low CD4+ cell count. Results of this study provide evidence that mucous membrane disorders with HIV infection might serve as an indicator for advanced HIV infection, immunosuppression and decreased CD4 cell counts. The physicians who are taking care of HIV patients have to be familiar with HIV-associated mucocutaneous diseases, their diagnoses, and management.
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PMID:Oral lesions in HIV-positive patients in Georgia. 1912 19

Immunity to the bovine apicomplexan parasite Theileria parva is associated with MHC-I restricted CD8+ T cell responses directed against the intralymphocytic schizont stage of the parasite. A number of schizont-stage antigens that are targets of CD8+ T cell responses from immune animals have been identified but an effective delivery strategy that consistently induces protective CD8+ T cell responses remains to be developed. This study aimed to determine whether fusing Tat, a cell penetrating peptide (CPP) from HIV-1 TAT, to a CD8+ T cell target antigen from T. parva (Tp2) enhances the cytosolic delivery and subsequent stimulation of bovine CD8+ T cell responses in vitro. Using IFN-gamma ELISpot and cytotoxicity assays, it was demonstrated that recombinant Tat-Tp2 fusion protein possessed a superior ability to access MHC-I processing and presentation pathway and to stimulate CD8+ T cell responses compared to recombinant Tp2 protein. Exposure of APC to Tat-Tp2 protein for only 30 min was sufficient for protein uptake and stimulation of CD8+ T cells. This work describes for the first time the utility of a CPP to enhance MHC-I presentation in a veterinary species and supports the evaluation of CPP fusion proteins in the induction of CD8+ T cell responses in vivo.
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PMID:Fusion of a cell penetrating peptide from HIV-1 TAT to the Theileria parva antigen Tp2 enhances the stimulation of bovine CD8+ T cell responses. 1924 7

Anti-Gal constitutes approximately 1% of circulating IgG in humans and interacts specifically with alpha-gal epitopes. We reported previously that expression of alpha-gal epitopes on HIV gp120 and influenza virus vaccines increases immunogenicity by approximately 100-fold. We hypothesize that immunogenicity of any microbial vaccine can be markedly increased by linked alpha-gal epitopes due to in vivo formation of immune complexes with anti-Gal and the effective internalization of such immune complexes by APC, via Fc/FcgammaR interaction. The increased transport to lymph nodes and processing of anti-Gal complexed vaccines internalized by APC, results in effective activation of vaccine specific CD4(+) and CD8(+) T cells, and high cellular and humoral immune response. This universal mechanism for anti-Gal mediated increased immunogenicity is demonstrated in alpha1,3galactosyltransferase knockout mice with ovalbumin as a model vaccine.
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PMID:Mechanism for increased immunogenicity of vaccines that form in vivo immune complexes with the natural anti-Gal antibody. 1942 21

Vaccinia virus (VV) has been used as a vaccine to eradicate smallpox and as a vaccine for HIV and tumors. However, the immunoevasive properties of VV have raised safety concerns. VV infection of APCs perturbs MHC class II-mediated Ag presentation. Exposure of human B cell lines to VV induced a substantial reduction in cellular expression of the class II chaperone, invariant chain (Ii), during the late stages (i.e., 8-10 h) of infection. Yet, cell viability and surface expression of MHC class II molecules were maintained up to 24 h after exposure to virus. Reductions in Ii and class II mRNA levels were detected as early as 6 h after VV infection of APCs. To examine whether VV was acting solely to disrupt host protein synthesis, B cells were treated with an inhibitor of translation, cycloheximide (CHX). Within 1 h of B cell CHX treatment, Ii protein expression decreased coupled with a loss of class II presentation. Analysis of Ii degradation in VV- or CHX-treated cells, revealed ongoing Ii proteolysis contributing to reduced steady-state Ii levels in these APC. Yet in contrast with CHX, VV infection of APCs altered lysosomal protease expression and Ii degradation. Virus infection induced cellular cathepsin L expression while reducing the levels of other lysosomal proteases. These results demonstrate that at late stages of VV infection, reductions in cellular Ii levels coupled with changes in lysosomal protease activity, contribute in part to defects in class II presentation.
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PMID:Diminished intracellular invariant chain expression after vaccinia virus infection. 1959 62

Viruses that infect T cells, including those of the lentivirus genus, such as HIV-1, modulate the responsiveness of infected T cells to stimulation by interacting APCs in a manner that renders the T cells more permissive for viral replication. HIV-1 and other primate lentiviruses use their Nef proteins to manipulate the T cell/APC contact zone, the immunological synapse (IS). It is known that primate lentiviral Nef proteins differ substantially in their ability to modulate cell surface expression of the TCR-CD3 and CD28 receptors critical for the formation and function of the IS. However, the impact of these differences in Nef function on the interaction and communication between virally infected T cells and primary APCs has not been investigated. Here we have used primary human cells to show that Nef proteins encoded by HIV-2 and most SIVs, which downmodulate cell surface expression of TCR-CD3, disrupt formation of the IS between infected T cells and Ag-presenting macrophages or DCs. In contrast, nef alleles from HIV-1 and its simian precursor SIVcpz failed to suppress synapse formation and events downstream of TCR signaling. Our data suggest that most primate lentiviruses disrupt communication between virally infected CD4+ Th cells and APCs, whereas HIV-1 and its SIV precursor have largely lost this capability. The resulting differences in the levels of T cell activation and apoptosis may play a role in the pathogenesis of AIDS.
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PMID:The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses. 1975 18

The incidence of arterial and venous thrombosis in HIV-infected patients is increased compared to healthy controls. In this cross-sectional analysis we measured markers of endothelial cell activation, thrombin generation, fibrinolysis and anticoagulation combined with endogenous thrombin potential (ETP) and activated protein C sensitivity ratio (APCsr) as more global markers. We included 160 consecutive HIV-infected patients with a median age of 46 years (range, 27-77), of whom 92% were male, 74% Caucasian, 11% African American, 9% Hispanic, and 6% Asian. Homosexual contact was the main transmission mode. Seventy percent of patients were using combined antiretroviral therapy (cART). In 83% of patients laboratory markers outside the normal range for a non-HIV-infected population were observed. Significant lower levels of von Willebrand factor (vWF; p = 0.03), factor VIII (p < 0.0001), D-dimer (p = 0.01), and ETP (p = 0.01) were observed in HIV-infected patients on cART compared to patients not on cART. Significant lower levels of protein C (p = 0.05) and free protein S (p < 0.0001), and increased APCsr (p < 0.0001) were found in the HIV-infected patients not on cART. A single association was observed between raised levels of fibrinogen and use of a protease inhibitor (p = 0.002). No significant difference was observed in the percentage of patients with laboratory markers outside the normal range between patients using cART-regimens containing abacavir, stavudine, or didanosine and those with other nucleoside reverse transcriptase inhibitors. Although the prevalence of coagulation abnormalities was lower in HIV-infected patients using cART, a considerable proportion of HIV-infected patients on cART show endothelial cell activation and increased APCsr, suggestive of a persistent procoagulant state.
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PMID:The hemostatic balance in HIV-infected patients with and without antiretroviral therapy: partial restoration with antiretroviral therapy. 1992 30

Developing an effective HIV-1 vaccine will require strategies to enhance antigen presentation to the immune system. In a previous study we demonstrated a marked increase in immunogenicity of the highly glycosylated HIV-1 gp120 protein following enzymatic addition of alpha-gal epitopes to the carbohydrate chains. In the present study we determined whether gp120(alphagal) can also serve as an effective platform for targeting other HIV-1 proteins to APC and thus increase immunogenicity of both proteins. For this purpose we produced a recombinant fusion protein between gp120 and the HIV-1 matrix p24 protein (gp120/p24). Multiple alpha-gal epitopes were synthesized enzymatically on the gp120 portion of the fusion protein to generate a gp120(alphagal)/p24 vaccine. Immune responses to gp120(alphagal)/p24 compared to gp120/p24 vaccine lacking alpha-gal epitopes were evaluated in alpha1,3galactosyltransferase knockout (KO) mice. These mice lack alpha-gal epitopes and, therefore, are capable of producing the anti-Gal antibody. T cell responses to p24, as assessed by ELISPOT and by CD8+ T cells intracellular staining assays for IFNgamma, was on average 12- and 10-fold higher, respectively, in gp120(alphagal)/p24 immunized mice than in mice immunized with gp120/p24. In addition, cellular and humoral immune responses against gp120 were higher by 10-30-fold in mice immunized with gp120(alphagal)/p24 than in gp120/p24 immunized mice. Our data suggest that the alpha-gal epitopes on the gp120 portion of the fusion protein can significantly augment the immunogenicity of gp120, as well as that of the fused viral protein which lacks alpha-gal epitopes. This strategy of anti-Gal mediated targeting to APC may be used for production of effective HIV-1 vaccines comprised of various viral proteins fused to gp120.
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PMID:Increased immunogenicity of HIV-1 p24 and gp120 following immunization with gp120/p24 fusion protein vaccine expressing alpha-gal epitopes. 2003 7


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