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Biomedical subjects

M R Wallace

Publications and source records attributed to M R Wallace.

At least 37 records · Page 2Linked to original sources
PubMed2001

The strategy of immunologic control of HIV-1 with structured treatment interruptions (STIs).

Structured treatment interruptions (STIs) have evolved as an experimental approach of interrupting highly active antiretroviral therapy (HAART) similar to cycles of cancer chemotherapy in order to develop immune control of HIV-1. There are multiple, ongoing clinical trials examining interruptions in antiviral therapy with and without immune-based therapies. If successful in developing immune control, STIs may be clinically useful but require large scale clinical trials to prove their utility and safety.

AIDS Vaccines↗
PubMed2000

Cell-mediated immune responses to autologous virus in HIV-1-seropositive individuals after treatment with an HIV-1 immunogen.

OBJECTIVE: We hypothesized that cell mediated immune responses to an HIV-1 immunogen (whole-killed, gp120-depleted HIV-1 in IFA, REMUNE) would include those to autologous virus. METHODS: Five chronically HIV-1 infected individuals were examined for HIV-specific immune responses to their own virus (autologous viral antigen) after treatment with an HIV-1 immunogen. RESULTS: Subjects had low proliferative responses to HIV and p24 antigens prior to immunization and mounted strong lymphocyte proliferative responses to the immunizing HIV-1 virus, native p24, and autologous viral antigen post immunization. Similarly, subjects produced low amounts of interferon-gamma in response to HIV and p24 antigens prior to immunization and increased their interferon-gamma production in response to HIV-1, native p24, and to autologous antigen post-immunization. Furthermore, beta-chemokine responses measured as migratory inhibitory protein-1beta production were low at baseline in response to HIV-1 and native p24 antigens and were enhanced post immunization to HIV-1, native p24, and autologous antigen. CONCLUSIONS: In this study HIV-specific immune responses to autologous virus were observed after treatment with an HIV-specific immunogen.

AIDS Vaccines↗
PubMed2000

HIV-1-Specific CD4 helper function in persons with chronic HIV-1 infection on antiviral drug therapy as measured by ELISPOT after treatment with an inactivated, gp120-depleted HIV-1 in incomplete Freund's adjuvant.

OBJECTIVE: We hypothesized that treatment of HIV-1-seropositive study subjects receiving potent antiviral therapy with an HIV-specific immune-based therapy would increase HIV-1-specific T-helper immune function. DESIGN: 10 HIV-1-seropositive study subjects receiving antiretroviral therapy were treated with an inactivated, gp120-depleted immunogen in IFA (HIV-1 immunogen, Remune) at baseline, week 12, and week 24. METHODS: The frequency of HIV-1 antigen-stimulated interferon-gamma (IFN-gamma)-producing cells was determined by the ELISPOT assay. RESULTS: Study subjects significantly increased their frequency of HIV-1-stimulated (p <. 001) or p24 antigen-stimulated (p <.01) IFN-gamma-producing cells after one, two, and three treatments of HIV-1 immunogen. Depletion of CD4 cells resulted in the strongest abrogation of the IFN-gamma response. The frequency of HIV-1 (r = 0.64; p =.0002) and p24 (r = 0. 72; p <.001) antigen-stimulated IFN-gamma-producing cells in the CD8-depleted population before and after treatment was associated with the lymphocyte-proliferative response. CONCLUSIONS: Treatment with HIV-1 immunogen significantly enhanced the frequency of HIV-1-specific IFN-gamma-producing cells. Studies are ongoing to determine the relationship between this reversal of HIV-specific anergy and virologic outcomes.

AIDS Vaccines↗
PubMed2000

Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis.

Few molecular events important to platelet biogenesis have been identified. Mice homozygous for the spontaneous, recessive mutation gunmetal (gm) have prolonged bleeding, thrombocytopenia, and reduced platelet alpha- and delta-granule contents. Here we show by positional cloning that gm results from a G-->A substitution mutation in a splice acceptor site within the alpha-subunit of Rab geranylgeranyl transferase (Rabggta), an enzyme that attaches geranylgeranyl groups to Rab proteins. Most Rabggta mRNAs from gm tissues skipped exon 1 and lacked a start codon. Rabggta protein and Rab geranylgeranyl transferase (GGTase) activity were reduced 4-fold in gm platelets. Geranylgeranylation and membrane association of Rab27, a Rab GGTase substrate, were significantly decreased in gm platelets. These findings indicate that geranylgeranylation of Rab GTPases is critical for hemostasis. Rab GGTase inhibition may represent a new treatment for thrombocytosis and clotting disorders.

Alkyl and Aryl Transferases↗
PubMed2000

Enhancement of HIV type 1 antigen-specific CD4+ T cell memory in subjects with chronic HIV type 1 infection receiving an HIV type 1 immunogen.

We examined HIV-1 specific memory helper T immune responses in chronically HIV-infected subjects who received an immune-based therapy (HIV-1 immunogen, Remune). Subjects in this study exhibited significant increases (p < 0.05) in the frequency of helper T memory cells expressing interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in response to HIV-1 antigens in vitro. The frequencies of HIV-specific memory T cells increased after successive immunizations and exhibited a correlation with the standard tritiated thymidine incorporation lymphocyte proliferation assay (r = 0.72, p < 0.0008). These results support the notion that HIV-specific memory immune responses can be stimulated in subjects with chronic HIV infection. Further investigations are warranted to determine whether the induction of such responses is associated with virologic control.

AIDS Vaccines↗
PubMed2000

Gastrointestinal manifestations of HIV infection.

Since the beginning of the AIDS pandemic, gastrointestinal (GI) problems have been among the most common features of the disease. Despite the introduction of highly active antiretroviral therapy (HAART) in 1995 and 1996, most HIV-infected patients continue to have GI complications. The clinician must be able to diagnose and treat the opportunistic gastrointestinal infections and neoplasms that occur in the advanced AIDS patient, as well as the treatment-induced symptoms and non-HIV-related GI disorders that predominate in early HIV disease. This review addresses the GI manifestations of HIV, with particular emphasis on new developments in the era of highly effective therapy.

AIDS-Related Opportunistic Infections↗
PubMed2000

Increase in community-acquired methicillin-resistant Staphylococcus aureus at a Naval Medical Center.

A retrospective review of methicillin-resistant Staphylococcus aureus isolates from the Naval Medical Center, San Diego, for the years 1994 through 1997, found that the annual number of community-acquired MRSA isolates increased during the period. These outpatient isolates were more likely than inpatient isolates to be sensitive to a greater number of antibiotics.

Hospital Bed Capacity, 300 to 499↗
PubMed2000

T-helper-cell proliferative responses to whole-killed human immunodeficiency virus type 1 (HIV-1) and p24 antigens of different clades in HIV-1-infected subjects vaccinated with HIV-1 immunogen (Remune).

The discovery of multiple subtypes of human immunodeficiency virus type 1 (HIV-1) worldwide has created new challenges for the development of both therapeutic and preventive AIDS vaccines. We examined T-helper proliferative responses to HIV-1 clade A, B, C, G, and E whole-killed virus and to HIV-1 clade G and B core (p24) antigens in HIV-1-infected subjects taking potent antiviral drugs who received HIV immunogen (Remune) therapeutic vaccination. Subjects who were immunized mounted strong proliferative responses to both whole virus and core antigens of the different clades. These results suggest that a whole-killed immunogen may have broad applications as a therapeutic as well as a preventive vaccine in the current multiclade HIV-1 pandemic.

AIDS Vaccines↗
PubMed2000

Culture of cytogenetically abnormal schwann cells from benign and malignant NF1 tumors.

Dermal and plexiform neurofibromas are benign peripheral nerve sheath tumors that arise in neurofibromatosis type 1 (NF1). NF1 patients also have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs), thought to arise in a subset of plexiform neurofibromas. Plexiform neurofibroma pathogenesis is poorly understood, despite the serious clinical problem posed by these tumors. The Schwann cell is hypothesized to be the cell type initially mutated and clonally expanded in plexiform neurofibromas. To test this hypothesis and search for genetic alterations involved in tumorigenesis, we established Schwann cell cultures from plexiform and dermal neurofibromas. Cytogenetic abnormalities were identified in 4/6 plexiform cultures (including one from a plexiform with a sarcomatous component) and 0/7 dermal neurofibroma Schwann cell cultures. There were no consistent chromosomal regions involved in the abnormal karyotypes, suggesting that plexiform tumors are heterogeneous and may bear a variety of primary and/or secondary genetic changes. This is the first study to show successful culturing of genetically abnormal Schwann cell lineages from plexiform neurofibromas. Thus, we present the strongest evidence yet to support the theory that the Schwann cell is the central component in the development of plexiform neurofibromas. This is a key finding for NF1 research, which will lead to further studies of the genetic and biochemical pathogenesis of these Schwann cell tumors. Genes Chromosomes Cancer 27:117-123, 2000.

Cell Division↗
PubMed2000

Chromosome 17 loss-of-heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition characterized by benign tumor (neurofibroma) growth and increased risk of malignancy. Dermal neurofibromas, arising from superficial nerves, are primarily of cosmetic significance, whereas plexiform neurofibromas, typically larger and associated with deeply placed nerves, extend into contiguous tissues and may cause serious functional impairment. Malignant peripheral nerve sheath tumors (MPNSTs) seem to arise from plexiform neurofibromas. The NF1 gene, on chromosome segment 17q11.2, encodes a protein that has tumor suppressor function. Loss of heterozygosity (LOH) for NF1 has been reported in some neurofibromas and NF1 malignancies, but plexiform tumors have been poorly represented. Also, the studies did not always employ the same markers, preventing simple comparison of the frequency and extent of LOH among different tumor types. Our chromosome 17 LOH analysis in a cohort of three tumor types was positive for NF1 allele loss in 2/15 (13%) dermal neurofibromas, 4/10 (40%) plexiform neurofibromas, and 3/5 (60%) MPNSTs. Although the region of loss varied, the p arm (including TP53) was lost only in malignant tumors. The losses in the plexiform tumors all included sequences distal to NF1. No subtle TP53 mutations were found in any tumors. This study also reports the identification of both NF1 "hits" in plexiform tumors, further supporting the tumor suppressor role of the NF1 gene in this tumor type.

Adolescent↗
PubMed1999

Efficacy of influenza vaccination in HIV-infected persons. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although influenza vaccination is recommended in persons infected with HIV-1, its efficacy is unknown. OBJECTIVE: To assess the immunogenicity, efficacy, and risks associated with influenza vaccination in persons infected with HIV-1. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Outpatient military clinic. PATIENTS: 102 patients with HIV-1 infection. INTERVENTION: Influenza vaccine (n = 55) or saline placebo (n = 47). MEASUREMENTS: Influenza antibody titers, CD4+ cell counts, and plasma HIV-1 RNA levels at baseline, 1 month after immunization, and 3 months after immunization; viral cultures from persons presenting with respiratory illness; and respiratory symptom interview. RESULTS: Twenty-three placebo recipients (49%) and 16 vaccine recipients (29%) reported respiratory symptoms (P = 0.04). Ten placebo recipients but no vaccine recipients had laboratory-confirmed symptomatic influenza (P < 0.001) (protective efficacy, 100% [95% CI, 73% to 100%]). No effect on plasma HIV-1 RNA levels or CD4+ cell counts was noted. CONCLUSION: Influenza vaccination is highly effective in HIV-1-infected persons and does not seem to be associated with substantial changes in viral load or CD4 cell count.

CD4 Lymphocyte Count↗
PubMed1999

Immune activation and virologic response to immunization in recent HIV type 1 seroconverters.

Antigenic stimulation from invasive bacterial infections, and the vaccines designed to prevent them, may promote T cell activation and enhancement of HIV-1 replication. Changes in viral load have been correlated with antigen-specific responses. We prospectively determined the impact of immunization with 23-valent pneumococcal vaccine (PVAX) and Haemophilus influenzae type b (Hib)-modified diphtheria toxoid CRM197 (DT) vaccine on HIV-1 replication in recent HIV-1 seroconverters (n = 14; median, 5.5 months from infection; median CD4+ T cells, 535 microl), and correlated results with vaccine-related immune activation. Specific antibody responses, markers of CD4+ T cell activation (transferrin and interleukin 2 receptors), and viral burden were measured at weeks -2 (pre), 0, 1, 2, 6, and 12 after immunization. By week 2, levels of IgG had increased significantly over baseline in both HIV-1-infected patients and HIV-1-seronegative control subjects (n = 9) for each antigen (geometric mean fold rise: PVAX, 10.1 versus 5.3; Hib, 16.0 versus 11.7; and DT, 26.2 versus 24.5, respectively). Despite these vigorous responses to both polysaccharide and protein antigens, HIV-1-infected patients showed limited evidence of CD4+ T cell activation at 1 week, no consistent rise in HIV-1 burden at any point, and no decline in CD4+ T cell number over time. We conclude that recent HIV-1 seroconverters show vigorous humoral responses to vaccine antigens and limited early evidence of T cell activation, but no substantial or sustained increase in viral replication or decline in CD4+ T cell number. Thus, respiratory bacterial vaccines appear immunogenic and safe early in HIV-1 infection.

Adult↗
PubMed1999

Phenotypic analysis of human immunodeficiency virus (HIV) type 1 cell-mediated immune responses after treatment with an HIV-1 immunogen.

It was hypothesized that immune recognition could be stimulated with combined immune-based and potent antiviral drug therapies. This study examined human immunodeficiency virus type 1 (HIV-1)-specific lymphocyte proliferation before and after treatment with an inactivated HIV-1 immunogen in 15 chronically infected HIV-1 seropositive subjects. Lymphocyte proliferation to the immunizing antigen (gp120-depleted HIV-1; P<.001), purified native p24 (P<.001), and recombinant p24 (P<.05) increased after treatment with the HIV-specific immune-based therapy. By HIV-1 antigen-specific flow cytometry, T helper CD4 lymphocytes, CD8 lymphocytes, and NK cells (all P<.001) were the predominant cell types proliferating in vitro after treatment. Additional phenotyping of proliferating cells revealed predominantly CD4 and CD8 memory (both P<.001) phenotypes. This study supports the concept that in vitro lymphocyte proliferation to HIV-1 antigens, augmented after treatment with an inactivated HIV-1 immunogen, involves primarily CD4 and CD8 cell memory immune responses.

AIDS Vaccines↗
PubMed1999

Elastin region deletions in Williams syndrome.

Williams syndrome (WS) is considered a contiguous gene syndrome, with most patients having a 1.5-Mb deletion of chromosome 7q11.23 containing the elastin gene and flanking genes. Studies of the frequency, extent, and origin of these deletions are ongoing in many labs to discover ultimately the molecular and pathogenetic basis for WS. An analysis of 9 sporadic WS families with typical phenotypes was performed by genotyping polymorphisms in the region. This study revealed deletions in all 9 patients, with one showing a novel deletion extending much further centromeric than any other WS deletions yet reported.

Elastin↗