Search PubMed⌕ Search

Biomedical subjects

S Pahwa

Publications and source records attributed to S Pahwa.

At least 55 records · Page 3Linked to original sources
PubMed1997

Signals transduced through the CD4 molecule interfere with TCR/CD3-mediated ras activation leading to T cell anergy/apoptosis.

It has been previously demonstrated that the occupancy of CD4 molecules by the HIV-1 envelope glycoprotein gp120 results in marked inhibition of T cell receptor-CD3 complex (TCR/CD3) activation-induced IL-2 secretion. To elucidate the mechanism of inhibitory effects of gp160 on T cell signaling, we have investigated the intracellular biochemical events and biological output in response to anti-CD3 mAb activation of purified peripheral blood CD4+ T cells from healthy donors with and without prior exposure to HIV-1 gp160. Pretreatment with gp160 resulted in marked inhibition of tyrosine phosphorylation of p59(fyn), PLC-gamma1, ras activation, and TNF-alpha secretion in anti-CD3 mAb activated CD4+ T cells, and a subset of CD4+ cells underwent activation-induced cell death. The data presented here provide insight into the mechanism by which the interaction of HIV-1 envelope glycoproteins with CD4 molecules may alter TCR/CD3-activation-induced signal transduction resulting in anergy and apoptosis with consequent functional deficiency of CD4+ T cells.

Apoptosis↗
PubMed1997

The relationship between serum human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 lymphocyte percent, and long-term mortality risk in HIV-1-infected children. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group.

Association of human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 cell percent, and mortality was examined in stored sera from 254 infected children in an intravenous immunoglobulin infection prophylaxis trial. Ninety-two children (36.2%) died (41 during the study, 51 during long-term follow-up). The geometric mean baseline HIV-1 RNA level was 104,626 copies/mL, and the mean CD4 cell percent was 25%. Relative risk of death (RR) was 2.1 if the baseline RNA level was >100,000 copies/mL (95% confidence interval [CI], 1.4-3.0) and was 3.0 if the baseline CD4 cell percent was <15% (95% CI, 2.2-4.0). If RNA levels increased after baseline, the RR was 1.8 (95% CI, 1.3-2.6), and if the CD4 cell percent dropped to <15%, the RR was 2.8 (95% CI, 1.6-4.9). In a multivariate model, both baseline RNA level and CD4 cell percent were independently associated with mortality risk. In a time-dependent model, the RR per log10 increase in HIV-1 RNA copy numbers was 2.8 (95% CI, 2.1-3.6) and per 5 percentage point decrement in CD4 cell percent was 1.3 (95% CI, 1.2-1.5). Both variables should be considered for in decision-making regarding therapy and evaluation of antiretroviral response.

AIDS-Related Opportunistic Infections↗
PubMed1997

Cytokine pattern in relation to disease progression in human immunodeficiency virus-infected children.

Cytokine mRNA expression and stimulus-induced cytokines were examined in peripheral blood mononuclear cells in 62 human immunodeficiency virus (HIV)-infected children and uninfected controls. Compared with that in controls, constitutive mRNA expression in patients was increased for tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-10 and decreased for IL-12; it was undetectable for IL-2 and IL-4 in both patients and controls. Stimulus-induced secretion of TNF-alpha, IFN-gamma, IL-12, and IL-4 was less than that in controls; IL-10 secretion was similar. There was no increase in stimulus-induced or constitutive IL-4 or IL-10 in children with severe immunologic deficit compared with controls. A higher stimulus-induced IL-10 secretion and a lower constitutive TNF-alpha mRNA were associated with a slower rate of disease progression, and TNF-alpha mRNA expression correlated with lower plasma HIV RNA. Thus, constitutive cytokine mRNA expression differs from stimulus-induced cytokine responses. The dominant defect in HIV-infected children appears to be one of reduced type 1 cytokines, predominantly IL-2.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Diagnosis of human immunodeficiency virus type 1 infection in infants by immune complex dissociation p24 assay.

Using immune complex dissociation (ICD), we retrospectively examined serum and plasma of 206 infants aged 0 to 4 months who were perinatally exposed to human immunodeficiency virus (HIV). All samples were analyzed in a blinded manner. Infection status was determined based on the results of HIV culture and Centers for Disease Control and Prevention classification. The overall diagnostic sensitivity of the assay was 59% (93 samples, 73 infants), and specificity was 100% (160 samples, 133 infants). When the samples were analyzed according to age, sensitivity was highest at age 1 to 2 months (17 of 21 infants, 81%). Sensitivities at other ages were 53% at < 1 month, 55% at 2 to 3 months, and 48% at 3 to 4 months (9 of 17, 11 of 20, and 12 of 25 cases, respectively). In 11 evaluable cases there was a possible correlation of p24 antigen quantitation (in picograms per milliliter) with disease progression. We conclude that, as determined in this study, the ICD p24 is a rapid diagnostic assay for HIV infection with a sensitivity of >80% at 1 to 2 months of age and 100% specificity, as evaluated, up to 4 months of age.

Antigen-Antibody Complex↗
PubMed1997

Upregulation of human immunodeficiency virus (HIV) replication by CD4 cross-linking in peripheral blood mononuclear cells of HIV-infected adults.

This study was conducted with peripheral blood mononuclear cells from 67 human immunodeficiency virus (HIV)-infected adults. It supports the hypothesis that cross-linking of CD4 molecules by HIV gp120 can result in HIV upregulation and spread of infection. Underlying mechanisms include activation of latent infection by factors in addition to, or other than, tumor necrosis factor alpha.

Adult↗
PubMed1996

IL-2 rescues in vitro lymphocyte apoptosis in patients with HIV infection: correlation with its ability to block culture-induced down-modulation of Bcl-2.

IL-2 administration in vivo has been shown to increase CD4+ T cell counts in HIV+ patients. We have previously reported that PBMC from HIV-infected patients undergo marked spontaneous apoptosis in vitro. In this study, we examined the effect of IL-2 added in vitro upon culture-induced apoptosis in PBMC from 80 HIV-infected patients by flow cytometry. IL-2 at concentrations of > or = 10 U/ml significantly reduced spontaneous apoptosis in CD3+ T lymphocytes in patients but not in healthy volunteers. Interestingly, we observed that Bcl-2 expression in patient lymphocytes decreased rapidly upon in vitro culture while that in cells of healthy volunteers was relatively unaffected. The most significant decrease in Bcl-2 expression was noted in the apoptotic cell population. The IL-2-mediated reduction in lymphocyte apoptosis was found to be associated with the blocking of this culture-induced down-modulation of Bcl-2 expression. IL-2 did not induce significant expansion of lymphocytes during the culture period nor did it affect Fas Ag expression in patient cells, which were already expressing Fas maximally. These findings strongly suggest that IL-2 mediates its apoptosis-blocking effects via suppressing down-modulation of Bcl-2. Our findings also provide an experimental basis for the ongoing therapies utilizing this cytokine for slowing HIV disease progression.

Adult↗
PubMed1996

Virus load as a marker of disease progression in HIV-infected children.

The relationship of virus load to clinical disease progression in HIV-infected children remains to be elucidated. In this study, HIV-1 proviral DNA load was determined in peripheral blood mononuclear cells (PBMCs) by the quantitative competitive DNA polymerase chain reaction assay (QC-PCR) in 47 HIV-infected children subdivided by age (group I, < or = 2 years; group II, > or = 5 years), who were further categorized to include 12 rapid progressors (RP, age < or = 2 years, Centers for Disease Control [CDC] defined clinical category C and/or immune category 3, or death before age 2 years) and slow progressors (SP, age > or = 5 years, excluding CDC categories C and/or immune category 3). Significantly higher mean proviral copies/10(3) PBMCs were detected in group I versus group II (75.4 +/- 104.3 and 13.0 +/- 17.8 respectively, p < 0.0001) and in RP (158.0 +/- 118.2) as compared to either SP (11.8 +/- 18.8, p < 0.0001) or other age-matched infected children (20.3 +/- 38.8, p < 0.0001). Thus HIV-infected children appear to have a higher cell-associated virus load early in life, especially in association with rapid disease progression.

Adolescent↗
PubMed1996

Inhibition of CD4 cross-linking-induced lymphocytes apoptosis by vesnarinone as a novel immunomodulating agent: vesnarinone inhibits Fas expression and apoptosis by blocking cytokine secretion.

Evidence is accumulating that T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals show accelerated cell death through apoptosis. We have recently demonstrated that the cross-linking of CD4 molecules (CD4XL) results in death of normal peripheral T cells through apoptosis and imbalanced cytokine secretion (ie, induction of tumor necrosis factor-alpha [TNF-alpha] and interferon-gamma [IFN-gamma] in the absence of interleukin-2 [IL-2] or IL-4 secretion). These upregulated cytokines (TNF-alpha/IFN-gamma) largely contributed to upregulation of the apoptosis-inducing cell surface molecule, Fas (APO-1/CD95) and apoptosis induction. The present study investigated the effect of vesnarinone as a novel immunomodulating agent on CD4XL-induced T-cell apoptosis. The addition of vesnarinone to peripheral blood mononuclear cells (PBMC) significantly inhibited CD4XL-induced lymphocyte apoptosis. This apoptosis-inhibitory effect of vesnarinone was associated with the blocking of CD4XL-induced TNF-alpha IFN-gamma secretion and of Fas antigen upregulation. However, vesnarinone did not block effects of exogenously supplemented TNF-alpha/IFN-gamma on Fas induction. These data suggest that vesnarinone inhibits CD4XL-induced TNF-alpha/IFN-gamma secretion, thereby blocking subsequent Fas upregulation and apoptosis induction. Given the potent pathogenic role of imbalanced cytokine secretion observed in HIV-infection, an agent such as vesnarinone may be of therapeutic value in slowing disease progression.

Adjuvants, Immunologic↗
PubMed1996

HIV-1 gp160 induces transforming growth factor-beta production in human PBMC.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine secreted by many mononuclear cells in peripheral blood (PBMC) and has diverse effects on cellular and humoral immunity. Increased TGF-beta mRNA expression has been reported in PBMC of HIV-infected patients, but the mechanism by which HIV induces TGF-beta secretion is unknown. In this study, we observed that HIV gp160 could induce significant TGF-beta secretion and TGF-beta mRNA expression in PBMC from HIV-seronegative healthy donors. The cellular source of TGF-beta was attributed to non-T cells, presumably monocytes. Specificity of secreted TGF-beta was confirmed by the addition of anti-TGF-beta mAb which abrogated the proliferative response of CCL-64 cells by gp160-treated culture supernatants. Soluble CD4 blocked the gp160-induced TGF-beta production, suggesting that CD4-gp160 interaction is required to induce TGF-beta production. Our results suggest that HIV-1 gp160 may contribute to the immune defects in HIV infection by inducing TGF-beta secretion.

Antibodies↗
PubMed1996

HIV-1 gp 120 blocks jacalin-induced proliferative response in CD4+ T cells: jacalin as a useful surrogate marker for qualitative and quantitative deficiency of CD4+ T cells in HIV-1 infection.

Jacalin is a plant lectin that induces mitogenic responses selectively in CD4+ T lymphocytes and has been shown to block infection by the human immunodeficiency virus type 1 (HIV-1) in a T lymphoid cell line, but the relationship of jacalin to the HIV envelope glycoprotein gp 120 in its interaction with the CD4 molecule is unclear. Here we demonstrate that pretreatment of normal T cells with native HIV-1 gp 120 impairs their ability to proliferate and secrete IL-2 in response to jacalin. This effect was not observed with deglycosylated gp 120, which fails to bind to CD4 molecule, or with gp 120 that has been premixed with soluble CD4. Flow cytometric studies and Western blotting analysis indicated that gp 120 and jacalin compete with each other in binding to CD4 molecules. In HIV-infected patients, proliferative responses of PBMC in response to jacalin were found to correlate quantitatively with percentages of CD4+ T cells but also showed a qualitative defect in comparison to healthy volunteers based on responses that were correlated for CD4+ T cell numbers. These findings suggest that (i) gp 120 and jacalin compete with each other for CD4 binding and (ii) jacalin might be a useful surrogate marker for quantitative as well as qualitative deficiency of CD4+ T cells in HIV-1 infection.

Antiviral Agents↗
PubMed1996

Central brain atrophy in childhood AIDS encephalopathy.

OBJECTIVE: To determine differential patterns of brain atrophy in pediatric AIDS encephalopathy. DESIGN: We measured the bicaudate, bifrontal, and ventricle-brain ratio in brain magnetic resonance imaging scans of 42 control children, nine children with progressive AIDS encephalopathy, 25 AIDS children without progressive encephalopathy, and 23 children with cerebral atrophy of other causes. RESULTS: When compared with controls, encephalopathy patients showed significantly increased bicaudate and ventricle-brain ratios, but no significant increase in bifrontal ratio, whereas children with brain atrophy from causes other than AIDS showed increases in all three ratios. CONCLUSION: Children with AIDS encephalopathy demonstrate a specific pattern of brain atrophy distinct from other etiologies: a central atrophy, primarily affecting the subcortical white matter or the basal ganglia regions.

AIDS Dementia Complex↗
PubMed1996

Envelope glycoproteins of human immunodeficiency virus type 1: profound influences on immune functions.

Infection by human immunodeficiency virus type 1 (HIV-1) leads to progressive destruction of the CD4+ T-cell subset, resulting in immune deficiency and AIDS. The specific binding of the viral external envelope glycoprotein of HIV-1, gp120, to the CD4 molecules initiates viral entry. In the past few years, several studies have indicated that the interaction of HIV-1 envelope glycoprotein with cells and molecules of the immune system leads to pleiotropic biological effects on immune functions, which include effects on differentiation of CD34+ lymphoid progenitor cells and thymocytes, aberrant activation and cytokine secretion patterns of mature T cells, induction of apoptosis, B-cell hyperactivity, inhibition of T-cell dependent B-cell differentiation, modulation of macrophage functions, interactions with components of complement, and effects on neuronal cells. The amino acid sequence homologies of the envelope glycoproteins with several cellular proteins have suggested that molecular mimicry may play a role in the pathogenesis of the disease. This review summarizes work done by several investigators demonstrating the profound biological effects of envelope glycoproteins of HIV-1 on immune system cells. Extensive studies have also been done on interactions of the viral envelope proteins with components of the immune system which may be important for eliciting a "protective immune response." Understanding the influences of HIV-1 envelope glycoproteins on the immune system may provide valuable insights into HIV-1 disease pathogenesis and carries implications for the trials of HIV-1 envelope protein vaccines and immunotherapeutics.

AIDS Vaccines↗
PubMed1996

Proton MR spectroscopy of the basal ganglia in healthy children and children with AIDS.

PURPOSE: To evaluate proton magnetic resonance (MR) spectroscopy in children with the acquired immunodeficiency syndrome (AIDS) and to establish an age-dependent spectroscopic database of the normal basal ganglia in children. MATERIALS AND METHODS: Eighteen healthy children and 45 children with AIDS underwent both brain MR imaging and single-voxel MR spectroscopy with a long-echo-time point-resolved technique. A large part of the region of interest studied at MR spectroscopy included the basal ganglia. RESULTS: Seven patients with progressive encephalopathy and eight with static encephalopathy had significantly lower mean N-acetyl aspartate (NAA)/creatine (Cr) ratios than age-matched control subjects (P<.02). In determining the presence of progressive encephalopathy in children with AIDS, MR spectroscopy appears to be more sensitive and specific than MR imaging and immunologic testing. Thirty patients without encephalopathy had normal NAA/Cr ratios but significantly lower choline/Cr ratios than age-matched control subjects (P<.02). CONCLUSION: Proton MR spectroscopy may be a more sensitive diagnostic technique than MR imaging in childhood AIDS encephalopathy.

AIDS Dementia Complex↗
PubMed1995

Requirement of p56lck in T-cell receptor/CD3-mediated apoptosis and Fas-ligand induction in Jurkat cells.

Interactions of Fas (CD95) and its ligand (Fas-L) has been shown to play a pivotal role in T cells receptor (TCR)/CD3 activation-induced cell death via apoptosis. Although several lines of evidence suggest involvement of protein tyrosine kinase (PTK) activity in this process, the role of src family PTK p561ck (lck) is not known. We report here that, contrary to wild type Jurkat, the lck-deficient mutant JCaM is resistant to anti-CD3-induced apoptosis and fails to express Fas-L mRNA upon anti-CD3 treatment. However, both Jurkat and JCaM were found to constitutively express Fas and were equally sensitive to anti-Fas-mediated apoptosis. If stimulated with PMA plus ionomycin, JCaM expressed Fas-L mRNA and underwent apoptosis. These findings indicate that p56lck is required for TCR/CD3-mediated Fas-L induction but not for the transduction of Fas receptor-mediated death signal.

Antigens, Surface↗
PubMed1995

HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells.

Activation of CD4 positive T cells is a primary requirement for human immunodeficiency virus (HIV) entry, efficient HIV replication, and progression to AIDS, Utilizing CD4 positive T cell lines and purified T cells from normal individuals, we have demonstrated that native envelope glycoproteins of HIV, gp 160, can induce activation of transcription factor, activated protein-1 (AP-1). The stimulatory effects of gp160 are mediated through the CD4 molecule, since treatment of gp160 with soluble CD4-IgG abrogates its activity, and CD4 negative T cell lines fail to be stimulated with gp160. Immunoprecipitation of the gp 160-induced nuclear extracts with polyclonal antibodies to Fos and Jun proteins indicates that AP-1 complex is comprised of members of these family of proteins. The gp160-induced AP-1 complex is dependent upon protein tyrosine phosphorylation and is protein synthesis-independent. This stimulation can also be abolished by inhibitors of protein kinase C, but it is unaffected by calcium channel blocker or cyclosporine A. This gp160 treatment adversely affects the functional capabilities of T cells: pre-treatment of CD4+ T cells with gp160 for 4 h at 37 degrees C inhibited anti-CD3-induced interleukin-2 secretion. Effects similar to gp160 were seen with anti-CD4 mAb. The aberrant activation of AP-1 by gp160 in CD4 positive T cells could result in up-regulation of cytokines containing AP-1 sites, e.g. interleukin-3 and granulocyte macrophage colony-stimulating factor, and concurrently lead to T cell unresponsiveness by inhibiting interleukin-2 secretion.

Base Sequence↗
PubMed1995

HIV gp120 inhibits T cell activation by interfering with expression of costimulatory molecules CD40 ligand and CD80 (B71).

One mechanism of the immune suppression in HIV infection has been postulated as being caused by the interaction of HIV envelope glycoprotein gp120 with CD4 molecules. Thus, pretreatment of purified peripheral blood T cells or CD4+ T cell clones with gp120 (or an anti-CD4 mAb) results in inhibition of anti-CD3 mAb-induced proliferative responses. In this study, we have analyzed the role of the interacting pairs of costimulatory molecules, CD28-B71 (CD80) and CD40 ligand (CD40L)-CD40, to elucidate further the mechanism of HIV gp120-induced inhibitory effects on T cell functions. Interactions between CD28-B71 and CD40L-CD40 were found to be essential for the anti-CD3 mAb-induced T cell proliferation, as demonstrated by up-regulation of B71 and CD40L and the ability of anti-B71 and anti-CD40L mAbs to inhibit this response. Pretreatment of CD4+ T cells with gp120 before CD3 ligation with anti-CD3 mAb resulted in failure of up-regulation of CD40L on T cells and B71 on APC. Exogenous addition of anti-CD28 mAb overcame the inhibitory effect of gp120 on anti-CD3 mAb-induced T cell proliferation. We conclude that binding of gp120 to CD4 molecules on T cells may interrupt the sequential cascade of intercellular interaction involving 1) Ag/MHC class II-TCR/CD4, 2) CD40L-CD40, and 3) B71-CD28. These studies indicate that the CD4-gp120 interaction results in dysregulation of expression of costimulatory molecules, CD40L, and B71 expression on T cells and APC, respectively, thereby contributing to the T cell hyporesponsiveness in HIV infection.

Antibodies, Monoclonal↗