John W Sleasman

Publications (38)186.86 Total impact

• Chapter: Protease Inhibitors and HIV-1 Genetic Variability in Infected Children

  Maureen M. Goodenow, Elena E. Perez, John W. Sleasman
  11/2006: pages 287-305;
• Source

  Available from: PubMed Central

  Article: LMP-420, a small-molecule inhibitor of TNF-alpha, reduces replication of HIV-1 and Mycobacterium tuberculosis in human cells.

  Soichi Haraguchi, Noorbibi K Day, Wasu Kamchaisatian, Macarena Beigier-Pompadre, Steffen Stenger, Nutthapong Tangsinmankong, John W Sleasman, Salvatore V Pizzo, George J Cianciolo
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  ABSTRACT: Co-infections of human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (M. Tb) are steadily increasing and represent a major health crisis in many developing countries. Both pathogens individually stimulate tumor necrosis factor-alpha (TNF) release from infected cells and TNF, in turn, enhances the replication of each. A recent report on a Phase I clinical trial suggested that etanercept (soluble TNF receptor) might be beneficial in treating HIV/M. Tb co-infected patients. We sought to determine if a small molecule inhibitor of TNF synthesis and activity could block replication of either organism and thus be a potential adjunct to existing drugs targeting these agents. LMP-420, a novel anti-inflammatory agent that inhibits TNF, was tested for HIV-1 inhibition both alone and in combination with AZT (3' -azido-3-deoxythymidine). LMP-420 alone was tested against M. Tb. HIV-1 infected human peripheral blood mononuclear cells (PBMC) or M. Tb-infected human alveolar macrophages (AM) were treated with a single dose of LMP-420 and viral or bacterial replication determined after 7 or 5 days respectively. Viral replication was determined from supernatant p24 levels measured by ELISA. M. Tb replication was determined by bacterial culture of macrophage lysates. LMP-420 alone inhibited HIV replication over 7 days with an IC50 of approximately 300 nM. Combination of LMP-420 with AZT doubled the level of HIV inhibition observed with AZT alone. LMP-420 alone inhibited the replication of virulent M. Tb by >80%, more than that observed with anti-TNF antibody alone. Inhibition of TNF with inexpensive, small-molecule, orally-active drugs may represent a useful strategy for enhancing the activity of currently-available antiviral and anti-M. Tb agents, particularly in those areas where co-infections with these pathogens act to synergistically enhance each other.
  AIDS Research and Therapy 02/2006; 3:8. · 2.54 Impact Factor
• Article: Complex determinants in human immunodeficiency virus type 1 envelope gp120 mediate CXCR4-dependent infection of macrophages.

  Guity Ghaffari, Daniel L Tuttle, Daniel Briggs, Brant R Burkhardt, Deepa Bhatt, Warren A Andiman, John W Sleasman, Maureen M Goodenow
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  ABSTRACT: Host cell range, or tropism, combined with coreceptor usage defines viral phenotypes as macrophage tropic using CCR5 (M-R5), T-cell-line tropic using CXCR4 (T-X4), or dually lymphocyte and macrophage tropic using CXCR4 alone or in combination with CCR5 (D-X4 or D-R5X4). Although envelope gp120 V3 is necessary and sufficient for M-R5 and T-X4 phenotypes, the clarity of V3 as a dominant phenotypic determinant diminishes in the case of dualtropic viruses. We evaluated D-X4 phenotype, pathogenesis, and emergence of D-X4 viruses in vivo and mapped genetic determinants in gp120 that mediate use of CXCR4 on macrophages ex vivo. Viral quasispecies with D-X4 phenotypes were associated significantly with advanced CD4+-T-cell attrition and commingled with M-R5 or T-X4 viruses in postmortem thymic tissue and peripheral blood. A D-X4 phenotype required complex discontinuous genetic determinants in gp120, including charged and uncharged amino acids in V3, the V5 hypervariable domain, and novel V1/V2 regions distinct from prototypic M-R5 or T-X4 viruses. The D-X4 phenotype was associated with efficient use of CXCR4 and CD4 for fusion and entry but unrelated to levels of virion-associated gp120, indicating that gp120 conformation contributes to cell-specific tropism. The D-X4 phenotype describes a complex and heterogeneous class of envelopes that accumulate multiple amino acid changes along an evolutionary continuum. Unique gp120 determinants required for the use of CXCR4 on macrophages, in contrast to cells of lymphocytic lineage, can provide targets for development of novel strategies to block emergence of X4 quasispecies of human immunodeficiency virus type 1.
  Journal of Virology 12/2005; 79(21):13250-61. · 5.40 Impact Factor
• Article: Acrodermatitis enteropathica-like eruption and food allergy.

  Diana P Martin, Nutthapong Tangsinmankong, John W Sleasman, Noorbibi K Day-Good, Danita R Wongchantara
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  ABSTRACT: Acrodermatitis enteropathica-like eruption (AE) is a distinct rash associated with profound zinc deficiency. It is seen in a variety of conditions but has not been reported as a presentation of food allergy. To report AE as an unusual presentation of food allergy in infants. Acrodermatitis enteropathica-like eruption was diagnosed by a characteristic rash and a low serum zinc level. The diagnosis of food allergy was made by history, serum total IgE and food specific IgE levels, or oral challenge with suspected foods. Two infants with AE, diarrhea, and low serum zinc levels were evaluated. Food allergy was found in both infants. The first infant had a serum IgE level of 4642 IU/mL. Specific IgE levels to milk, soybean, wheat, and peanut were 39.04, 10.14, 5.65, and 102.61 kU/L, respectively. Oral challenges to milk and peanut were positive and to soybean were negative. The second infant had a serum IgE level of 991 IU/mL; specific IgE levels to soybean and milk were 36.9 and 0.53 kU/L, respectively. Evaluation for other possible causes of diarrhea revealed homozygous delta F508 in the first infant, confirming the coexistence of cystic fibrosis; findings in the second infant were negative. Undiagnosed food allergy can lead to profound zinc deficiency. Food allergy should be suspected in a child with acquired AE.
  Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 04/2005; 94(3):398-401. · 2.83 Impact Factor
• Source

  Available from: Maureen M Goodenow

  Article: Impact on genetic networks in human macrophages by a CCR5 strain of human immunodeficiency virus type 1.

  Carter R Coberley, James J Kohler, Joseph N Brown, Joseph T Oshier, Henry V Baker, Michael P Popp, John W Sleasman, Maureen M Goodenow
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  ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) impacts multiple lineages of hematopoietic cells, including lymphocytes and macrophages, either by direct infection or indirectly by perturbations of cell networks, leading to generalized immune deficiency. We designed a study to discover, in primary human macrophages, sentinel genetic targets that are impacted during replication over the course of 7 days by a CCR5-using virus. Expression of mRNA and proteins in virus- or mock-treated macrophages from multiple donors was evaluated. Hierarchical agglomerative cluster analysis grouped into distinct temporal expression patterns >900 known human genes that were induced or repressed at least fourfold by virus. Expression of more than one-third of the genes was induced rapidly by day 2 of infection, while other genes were induced at intermediate (day 4) or late (day 7) time points. More than 200 genes were expressed exclusively in either virus- or mock-treated macrophage cultures, independent of the donor, providing an unequivocal basis to distinguish an effect by virus. HIV-1 altered levels of mRNA and/or protein for diverse cellular programs in macrophages, including multiple genes that can contribute to a transition in the cell cycle from G(1) to G(2)/M, in contrast to expression in mock-treated macrophages of genes that maintain G(0)/G(1). Virus treatment activated mediators of cell cycling, including PP2A, which is impacted by Vpr, as well as GADD45 and BRCA1, potentially novel targets for HIV-1. The results identify interrelated programs conducive to optimal HIV-1 replication and expression of genes that can contribute to macrophage dysfunction.
  Journal of Virology 12/2004; 78(21):11477-86. · 5.40 Impact Factor
• Article: Two-year clinical and immune outcomes in human immunodeficiency virus-infected children who reconstitute CD4 T cells without control of viral replication after combination antiretroviral therapy.

  Guity Ghaffari, Dominick J Passalacqua, Jennifer L Caicedo, Maureen M Goodenow, John W Sleasman
  [show abstract] [hide abstract]
  ABSTRACT: To evaluate 96-week clinical and immune outcomes to protease inhibitor-containing antiretroviral therapy. A prospective study was conducted of 40 human immunodeficiency virus (HIV)-infected children who displayed viral suppression (VS) with successful immune reconstitution (IS), failure to suppress virus (VF) or develop immune reconstitution (IF), or discordant immune and viral responses (VF/IS) at 24 weeks posttherapy. All children enrolled had viral RNA >4.0 log10 copies per mL and were Centers for Disease Control ad Prevention immune stage 2 or 3. Clinical, viral, and immune outcomes were assessed during the subsequent 72 weeks. VS/IS and VF/IS groups displayed similar sustained increases in CD4 T cells, although viral levels rebounded by 48 and 96 weeks posttherapy to pretherapy levels in the discordant group. The VF/IS outcome group had significant increases in height and weight z scores compared with entry and were similar to the VS/IS group. After treatment, antigen-specific responses after tetanus immunization were similar in the VF/IS and VS/IS groups. Prevalence of HIV-associated illnesses decreased in both VS/IS and VF/IS but not in VF/IF response groups. The findings indicate that viral replication under the selective pressure of protease inhibitors fails to exhibit the same deleterious impact on T-cell immunity as pretherapy viruses. CD4 T-cell counts may be a better predictor of disease progression and improvement in growth than viral burden in HIV-infected children who receive a protease inhibitor as part of a highly active antiretroviral therapy regimen.
  PEDIATRICS 12/2004; 114(5):e604-11. · 4.47 Impact Factor
• Article: Effect of influenza virus vaccine on the expression of human immunodeficiency virus co-receptor CCR5.

  Rajivi P Rucker, Noorbibi K Day, Robert A Good, Wasu Kamchaisatian, Patricia Emmanuel, John W Sleasman, Cathy Mayeski, Elmer Dinglasan, Soichi Haraguchi, Nutthapong Tangsinmankong
  [show abstract] [hide abstract]
  ABSTRACT: Administration of influenza vaccine to human immunodeficiency virus (HIV)-infected children can lead to increased viral load. CCR5 and CXCR4 are known to play an important role in HIV cell entry and viral replication. To determine the effects of influenza vaccine on chemokine receptors and on viral load in HIV-infected children. Eight HIV-infected children receiving stable therapy and 11 healthy adults were enrolled. Chemokine expression and immune activation were determined before and 48 hours after influenza vaccination. CCR5 and beta-chemokine gene expression were analyzed using real-time polymerase chain reaction. Viral load was measured at baseline, 48 hours, and 6 to 12 weeks. Forty-eight hours after influenza vaccination, mean CCR5 expression was significantly decreased on the CD3 (21.1% vs 11.3% in HIV-infected children; P = .02; and 18.3% vs 10.7% in controls; P = .008) and CD4 (13.0% vs 3.6% in the HIV group; P = .04; and 13.6% vs 6.5% in controls; P = .02) lymphocytes. This was observed in conjunction with an increase in HLA-DR expression on T lymphocytes in HIV-infected children (P = .046). No significant changes were observed in HIV viral load, CD3 and CD8 lymphocyte counts, expression of interleukin 2 receptor and CXCR4, or gene expression of CCR5 and beta-chemokines 48 hours after vaccination. Influenza virus vaccine markedly decreased chemokine receptor CCR5 expression on CD4 T lymphocytes. However, this immunomodulatory effect does not seem to affect overall viral replication in HIV-infected children who received highly active antiretroviral therapy.
  Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 10/2004; 93(3):272-6. · 2.83 Impact Factor
• Article: HIV and older adults: clinical outcomes in the era of HAART.

  Constance R Uphold, Javier Maruenda, Hossein N Yarandi, John W Sleasman, Bradley S Bender
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  ABSTRACT: As the human immunodeficiency virus (HIV) epidemic enters its third decade, nurses are caring for increasing numbers of older adults with HIV who are on complicated medication regimens or highly active antiretroviral therapy (HAART). Although HAART has revolutionized HIV and acquired immunodeficiency syndrome (AIDS) care, little is known about how older adults respond to the new therapies. A review of the medical records of 19 older (> or = 50 years) and 18 younger (< 40 years) adults initiated on their first HAART regimen revealed both older and younger adults had similar positive clinical outcomes. Nurses need to individualize their care to patients of all ages rather than develop specific clinical guidelines for older adults with HIV.
  Journal of Gerontological Nursing 08/2004; 30(7):16-24; quiz 55-6. · 0.78 Impact Factor
• Article: Varicella zoster as a manifestation of immune restoration disease in HIV-infected children.

  Nutthapong Tangsinmankong, Wasu Kamchaisatian, Jorge Lujan-Zilbermann, Cynthia L Brown, John W Sleasman, Patricia J Emmanuel
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  ABSTRACT: Exacerbation of opportunistic infections in HIV-infected patients shortly after initiation of highly active antiretroviral therapy (HAART) has been named immune restoration disease (IRD). Thus far, IRD has not been reported in children. We describe the clinical and immune characteristics of IRD in HIV-infected children treated with HAART. A historical cohort study was conducted in a tertiary HIV center in perinatally HIV-infected children who were started on a first stable HAART between January 1996 and July 2002. The incidence of opportunistic infections, newly AIDS-defining events or death after initiation of HAART, and virologic and immunologic information was evaluated at baseline and every 3 months post-HAART. Sixty-one perinatally HIV-infected children were started and maintained on HAART for >6 months. Seven episodes of IRD occurred. All were cutaneous herpes zoster (HZ). Children who developed HZ had significantly lower baseline CD4+ and CD8+ T-cell numbers compared with children who did not. HZ occurred only in children (7 of 34 subjects) with virological and immunological success to HAART. In children with a previous history of varicella infection, the risk of developing HZ after HAART was higher in those without a protective level of varicella-specific IgG (50%, or 5 of 10 subjects) compared with those with seroprotection (10%, or 2 of 20). Herpes zoster is a common manifestation of IRD in HIV-infected children after the initiation of HAART. Risks for developing HZ include no protective varicella-specific antibody despite previous varicella infection, severe immunodeficiency at baseline, and vigorous immunologic and virologic responses to HAART.
  Journal of Allergy and Clinical Immunology 05/2004; 113(4):742-6. · 11.00 Impact Factor
• Article: Immunogenicity of 23-valent pneumococcal polysaccharide vaccine in children with human immunodeficiency virus undergoing highly active antiretroviral therapy.

  Nutthapong Tangsinmankong, Wasu Kamchaisatian, Noorbibi K Day, John W Sleasman, Patricia J Emmanuel
  [show abstract] [hide abstract]
  ABSTRACT: The 23-valent pneumococcal polysaccharide vaccine (23PSV) has been recommended for children infected with human immunodeficiency virus (HIV); however, the efficacy of this vaccination in HIV-infected children undergoing highly active antiretroviral therapy (HAART) has not been studied. To study the immunogenicity and immunologic protection of 23PSV in HIV-infected children after stable HAART. Serotype-specific IgG antibodies to 12 pneumococcal capsular polysaccharides were analyzed before and after 23PSV vaccination in 41 HIV-infected children undergoing HAART and compared with 95 HIV-negative control children. Seropositivity, clinical protection, and additional clinical protection from 23PSV were calculated based on serotype specific IgG antibody levels and on the known incidence of these serotypes for causing invasive disease. Children with HIV infection undergoing HAART developed a significant increase in specific IgG levels to Streptococcus pneumoniae after 23PSV vaccination (0.95 vs 1.84 micro/gmL, P < .001). The HIV-infected children with CD4+ cell counts of 25% or higher at the time of vaccination developed a higher additional clinical protection gain from 23PSV vaccination than did children with a lower percentage of CD4+ cells. HIV-infected children undergoing stable HAART develop a significant immunologic response to 23PSV, especially those with higher T-cell counts and lower viral loads at the time of vaccination.
  Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 05/2004; 92(5):558-64. · 2.83 Impact Factor
• Article: Effects of human immunodeficiency virus type 1 infection on CCR5 and CXCR4 coreceptor expression on CD4 T lymphocyte subsets in infants and adolescents.

  Daniel L Tuttle, Carter R Coberley, Xiaoming Xie, Zhong C Kou, John W Sleasman, Maureen M Goodenow
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  ABSTRACT: HIV-1 infection alters expression of CCR5 and CXCR4 on CD4 T cells in adults, although an effect by virus on expression of coreceptor genes in pediatric subjects is unknown. We designed an exploratory study to evaluate surface expression of CXCR4 and CCR5 on CD45RA and CD45RO subsets of CD4 T lymphocytes from 17 HIV-1-infected infants and adolescents and 16 healthy age-matched individuals. While age in the absence of HIV-1 infection was unrelated to coreceptor expression, infection affected coreceptor expression differentially in infants and adolescents. Among infected adolescents, CCR5 and CXCR4 expression was significantly increased on CD4 CD45RO T cells, while CXCR4 was diminished in the CD4 CD45RA subset. Although HIV-1 infection in infants was also associated with increased CXCR4 expression on the CD4 CD45RO subset, in contrast to adolescents, infection in infants had no impact on coreceptor expression within the CD45RA CD4 subset. The proportion of CD4 T cells coexpressing CD45RA and CD45RO was increased by infection in both infants and adolescents. The CD45RA CD45RO subset in culture expressed high levels of CD4, CXCR4, and CD69, an early activation marker, and was highly susceptible to HIV-1 infection and replication. Infection of transitional CD4 T cells coexpressing CD45RA and CD45RO could contribute in part to provirus in either CD45RA or CD45RO subsets. Deleterious effects by HIV-1 infection on CD4 T cell homeostasis were greater in infants then adolescents, indicating that adolescence may be an optimal age group for assessing vaccines to prevent or treat HIV-1 infection.
  AIDS Research and Human Retroviruses 04/2004; 20(3):305-13. · 2.25 Impact Factor
• Article: HIV-1 fitness and macrophages.

  Maureen M Goodenow, Stephanie L Rose, Daniel L Tuttle, John W Sleasman
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  ABSTRACT: HIV-1 comprises a collection of closely related, but not identical, viruses or quasispecies. Fitness represents a selective advantage for propagation among populations of organisms competing in a particular environment and is an important characteristic of viruses because of a link between fitness and pathogenesis. Environmental differences based on the type of cell that is targeted for infection or the cell type that produces virus, impact fitness. CD4-expressing cells of lymphocyte or macrophage lineage are the principal host cells for HIV-1, although the milieu in lymphocytes is distinct from the macrophage environment from the perspective of cell half-life and activation, signal transduction and expression of coreceptors, and bioavailability of antiretroviral drugs. Multiple viral determinants, including entry via envelope glycoproteins, replication by reverse transcriptase, and virion maturation by protease activity, contribute to fitness in different cells and provide targets for current antiretroviral therapies. This review focuses on fitness of HIV-1 in macrophages and examines the impact of protease inhibitors on fitness of quasispecies and an unexplained discordance between fitness and pathogenesis.
  Journal of Leukocyte Biology 12/2003; 74(5):657-66. · 4.99 Impact Factor
• Article: Human immunodeficiency virus type 1 (HIV-1) induces activation of multiple STATs in CD4+ cells of lymphocyte or monocyte/macrophage lineages.

  James J Kohler, Daniel L Tuttle, Carter R Coberley, John W Sleasman, Maureen M Goodenow
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  ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) impacts the activation state of multiple lineages of hematopoietic cells. Chronic HIV-1 infection among individuals with progressive disease can be associated with increased levels of activated signal transducers and activators of transcription (STATs) in peripheral blood mononuclear cells. To investigate interactions between HIV-1 and CD4(+) cells, activated, phosphorylated STAT proteins in nuclear extracts from lymphocytic and promonocytic cell lines as well as primary monocyte-derived macrophages were measured. Levels of activated STATs increased six- to tenfold in HUT78 and U937 cells within 2 h following exposure to virions. The response to virus was dose-dependent, but kinetics of activation was delayed relative to interleukin-2 or interferon-gamma. Activation of STAT1, STAT3, and STAT5 occurred with diverse viral envelope proteins, independent of coreceptor use or viral replication. Envelope-deficient virions had no effect on STAT activation. Monoclonal antibody engagement of CD4 identified a novel role for CD4 as a mediator in the activation of multiple STATs. Results provide a model for HIV-1 pathogenesis in infected and noninfected hematopoietic cells.
  Journal of Leukocyte Biology 04/2003; 73(3):407-16. · 4.99 Impact Factor
• Article: 13. HIV-1 infection.

  John W Sleasman, Maureen M Goodenow
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  ABSTRACT: This review is intended to provide a fundamental perspective on the dynamic interplay between HIV-1 and the immune system, an essential aspect in defining the pathogenesis and treatment of AIDS. HIV-1 infection, the cause of AIDS, is a worldwide pandemic with enormous adverse heath and economic implications, particularly in the developing world. This bloodborne and sexually transmitted disease, which evolved from simian immunodeficiency virus, infects and replicates in helper T cells and macrophages and utilizes CD4 and a chemokine coreceptor for entry. Immune deficiency occurs as a result of virally induced attrition of CD4 T cells, resulting in the development of opportunistic infections and malignancy. Prophylaxis against opportunistic infections is required according to the extent of immune deficiency. HIV-specific immunity can control viral replication and delay disease progression but does not clear infection. Antiretroviral treatment consists of inhibitors that target for viral entry, reverse transcriptase, and viral protease. Therapy can control viral replication, restore immunity, and delay disease progression, but it cannot eliminate infection. Thus chronic infection persists even in treated patients. Antiretroviral drugs have been highly effective in preventing mother-to-child transmission and for postexposure prophylaxis. Several novel vaccines in development hold promise for either effective infection prevention or attenuation of disease progression.
  Journal of Allergy and Clinical Immunology 03/2003; 111(2 Suppl):S582-92. · 11.00 Impact Factor
• Article: Combination antiretroviral therapy results in a rapid increase in T cell receptor variable region beta repertoire diversity within CD45RA CD8 T cells in human immunodeficiency virus-infected children.

  Zhong Chen Kou, Joshua S Puhr, Samuel S Wu, Maureen M Goodenow, John W Sleasman
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  ABSTRACT: Human immunodeficiency virus (HIV) type 1 disrupts the T cell receptor (TCR) variable region (V) beta repertoire in CD8 T cells by impairing thymic capacity and skewing postthymic cellular maturation. The TCR repertoire was examined using spectratyping of CDR3 length diversity within CD45RA and CD45RO CD8 T cells in HIV-infected and healthy children. In healthy children, CDR3 lengths displayed Gaussian distribution in both CD45RA and CD45RO subsets. Vbeta families in HIV-infected children displayed a large proportion of perturbations in both subsets. High virus load and advanced immunosuppression correlated with increased perturbations within CD45RA but not CD45RO CD8 T cells. After therapy and virus suppression, there was rapid reestablishment of Gaussian distributions in CD45RA cells. HIV-1-induced disruption of TCR diversity within CD45RA CD8 T cells correlates with disease progression. Suppression of viral replication by treatment results in the rapid correction of TCR diversity in this CD8 subset because of emergence of new T cells from the thymus.
  The Journal of Infectious Diseases 03/2003; 187(3):385-97. · 6.41 Impact Factor
• Article: Anti-CD20 monoclonal antibody (rituximab) therapy for acute cardiac humoral rejection: a case report.

  Juan M Aranda, Juan C Scornik, Sigurd J Normann, Richard Lottenberg, Richard S Schofield, Daniel F Pauly, Maureen Miles, James A Hill, John W Sleasman, Suzanne Skoda-Smith
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  ABSTRACT: Humoral or antibody-mediated rejection in cardiac transplant recipients is mediated by donor-specific cytotoxic antibodies and is histologically defined by linear deposits of immunoglobulin and complement in the myocardial capillaries. Antibody-mediated rejection often is accompanied by hemodynamic compromise and is associated with reduced long-term graft survival. Standard immunosuppression, designed to target T cell immune function, is largely ineffective against this B cell-driven process. Current treatment options for humoral rejection are limited by a lack of specific anti-B cell therapies. We present the case of a 50-year-old woman with hemodynamically significant humoral rejection resistant to steroids, cyclophos-phamide, and plasmapheresis who responded to the addition of anti-CD20 monoclonal antibody therapy (rituximab). One year posttransplant, the patient is rejection-free, with normal left ventricular systolic function and coronary arteries.
  Transplantation 04/2002; 73(6):907-10. · 4.00 Impact Factor
• Article: Increased replication of non-syncytium-inducing HIV type 1 isolates in monocyte-derived macrophages is linked to advanced disease in infected children.

  Daniel L Tuttle, Cynthia B Anders, M Janette Aquino-De Jesus, Paul P Poole, Susanna L Lamers, Daniel R Briggs, Steven M Pomeroy, Louis Alexander, Keith W C Peden, Warren A Andiman, John W Sleasman, Maureen M Goodenow
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  ABSTRACT: Non-syncytium-inducing (NSI) strains of HIV-1 prevail among most infected children, including pediatric patients who develop advanced disease, severe immune suppression, and die. A study was designed to address the hypothesis that genotypic and/or phenotypic markers can distinguish NSI viruses isolated during early infection from NSI viruses found in advanced disease. Primary HIV-1 isolates, which were obtained from 43 children, adolescents, and adults who displayed a cross-section of clinical disease and immune suppression but were untreated by protease inhibitor antiretroviral therapy, were characterized for replication phenotype in different cell types. Most individuals (81%) harbored NSI viruses and almost half had progressed to advanced disease or severe immune deficiency. About 51% of NSI isolates produced low levels of p24 antigen (median, 142 pg/ml) in monocyte-derived macrophages (MDMs), 31% produced medium levels (median, 1584 pg/ml), and 17% produced high levels (median, 81,548 pg/ml) (p < 0.001). Seven of eight syncytium-inducing isolates also replicated in MDMs and displayed a dual-tropic phenotype that was associated with advanced disease. Replication of NSI viruses in MDMs varied as much as 100- to 1000-fold and was independent of replication in peripheral blood mononuclear cells. Replication in MDMs provided a clear biological feature to distinguish among viruses that were otherwise identical by NSI phenotype, V3 genotype, and CCR5 coreceptor usage. Low-level MDM replication was characteristic of viruses isolated from asymptomatic individuals, including long-term survivors. Enhanced MDM replication was related to morbidity and mortality among patients. Replication levels in MDMs provide a novel prognostic indicator of pathogenic potential by NSI viruses.
  AIDS Research and Human Retroviruses 03/2002; 18(5):353-62. · 2.25 Impact Factor
• Article: Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease.

  Maureen M Goodenow, Gregory Bloom, Stephanie L Rose, Steven M Pomeroy, Patricia O O'Brien, Elena E Perez, John W Sleasman, Ben M Dunn
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  ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) protease activity is targeted at nine cleavage sites comprising different amino acid sequences in the viral Gag-Pol polyprotein. Amino acid polymorphisms in protease and in regions of Gag, particularly p7(NC) and the C-cleavage site between p2 and p7(NC), occur in natural variants of HIV-1 within infected patients. Studies were designed to examine the role of natural polymorphisms in protease and to identify determinants in Gag that modulate protease processing activity. Closely related Gag-Pol regions from an HIV-1-infected mother and two children were evaluated for processing in an inducible expression system, for protease activity on cleavage-site analogues, and for impact on replication by recombinant viruses. Gag-Pol regions displayed one of three processing phenotypes based on the appearance of Gag intermediates and accumulation of mature p24(CA). Gag-Pol regions that were processed rapidly to produce p24(CA) resulted in high-level replication by recombinant viruses, while slow-processing Gag-Pol variants resulted in recombinant viruses that replicated with reduced kinetics in both T cell lines and peripheral blood mononuclear cells. Direct impact by Gag sequences on processing by protease was assessed by construction of chimeric Gag-Pol regions and by site-directed mutagenesis. Optimal protease activity occurred when Gag and Pol regions were derived from the same gag-pol allele. Heterologous Gag regions generally diminished rates and extent of protease processing. Natural polymorphisms in novel positions in p7(NC) and the C-cleavage site have a dominant effect on protease processing activity. Accumulation of Gag products after processing at the C site appears to delay subsequent cleavage and production of mature p24(CA).
  Virology 02/2002; 292(1):137-49. · 3.35 Impact Factor