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Biomedical subjects

D A Cooper

Publications and source records attributed to D A Cooper.

At least 19 recordsLinked to original sources

Long-term symptomless HIV-1 infection in recipients of blood products from a single donor.

There have been reported cases of long-term symptomless human immunodeficiency virus type 1 (HIV-1) infection, but it is not clear whether the benign course of infection was due to host, viral, or other unknown factors. During follow-up of subjects with transfusion-acquired HIV-1 infection in New South Wales, Australia, we identified a group of 6 subjects who had been infected through a single common donor. We were therefore able to study the contributions of various factors to the course of infection. Throughout follow-up (range 6.8-10.1 years after infection), 5 of the recipients and the donor (last follow-up 10.2 years after infection of the first recipient) remained clinically free of symptoms, with normal CD4 cell counts and no p24 antigenaemia. HIV-1 was isolated from only 1 recipient; the isolate did not induce syncytia in a SUPT1 co-culture assay and had a limited in-vitro host range. 1 infected recipient (who had received extensive immunosuppressive treatment for systemic lupus erythematosus) developed Pneumocystis carinii pneumonia and died 4.3 years after infection. The frequency of progression to AIDS or a CD4 cell count below 0.50 x 10(9)/l was significantly lower among the 6 subjects with a common donor (1/6) than among 101 other HIV-infected transfusion recipients for whom data from 7 years of follow-up were available (94/101; p less than 0.0001). These findings suggest that the subjects were infected by a less virulent strain of HIV-1. The identification of this group of subjects should stimulate a search for other similar groups, which will provide important information on the immunopathogenesis of HIV-1 disease.

Acquired Immunodeficiency Syndrome

Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS.

OBJECTIVE: To determine the efficacy of low-dose trimethoprim-sulfamethoxazole (trimethoprim, 160 mg plus sulfamethoxazole, 800 mg; one tablet twice daily, 2 days per week) as primary prophylaxis against toxoplasmic encephalitis in patients with human immunodeficiency virus (HIV) infection and previous Pneumocystis carinii pneumonia. DESIGN: A retrospective study. SETTING: Tertiary referral teaching hospital. PATIENTS: During a 3-year period after primary episodes of P. carinii pneumonia, 60 patients received trimethoprim-sulfamethoxazole, and 95 patients received pentamidine (aerosolized in 78 patients and intravenous in 17 patients) as secondary prophylaxis. RESULTS: No patient in the trimethoprim-sulfamethoxazole group and no patient seronegative for Toxoplasma gondii developed toxoplasmic encephalitis, compared with 12 of 36 (33%; 95% Cl, 19% to 51%) seropositive patients in the pentamidine group (trimethoprim-sulfamethoxazole compared with pentamidine, P = 0.008). A significant difference was seen in the time to development of toxoplasmic encephalitis between the trimethoprim-sulfamethoxazole group (no case at 1153 days) and the pentamidine group (median time, 460 days) (P = 0.004). Neither the CD4+ lymphocyte count at the start of prophylaxis nor zidovudine therapy during the period of prophylaxis influenced the rate of toxoplasmic encephalitis in any group. CONCLUSIONS: Low-dose trimethoprim-sulfamethoxazole (four tablets per week) appears to be effective prophylaxis against toxoplasmic encephalitis in HIV-infected patients with previous P. carinii pneumonia. A prospective, randomized, controlled study is needed to further evaluate these findings.

Acquired Immunodeficiency Syndrome

Chronic colitis associated with human immunodeficiency virus infection.

OBJECTIVE: A clinical and pathological description of chronic colitis associated with human immunodeficiency virus (HIV) infection. DESIGN: A retrospective case review. SETTING: Tertiary referral institution and specialist gastroenterology practice. PATIENTS: A series of six patients with human immunodeficiency virus infection and chronic colitis observed for up to four years. RESULTS: The six patients had chronic diarrhoea for longer than six months, rectal bleeding, abdominal pain and stool leukocytosis. The mucosal pattern on colonoscopy showed diffuse proctocolitis, consisting of contact bleeding, superficial ulcerations, exudates, and/or loss of vascular pattern. Colonic biopsies showed a persisting diffuse colitis characterised principally by a mixed inflammatory cell infiltrate (mononuclear cells and neutrophils) and essentially preserved crypt architecture after six to 39 months of histological follow-up. The histopathology over this time frame was not typical of ulcerative colitis or Crohn's disease, nor of the conventionally described forms of infective colitis. HIV nucleic acid was identified by insitu hybridisation in colonic biopsies from four patients. In two of three patients tested, the presence of HIV DNA was confirmed by Southern blot analysis. No other microbial agent could be demonstrated as the cause of diarrhoea. At presentation all patients had CD4+ lymphocyte counts greater than 265 x 10(6)/L and none had the acquired immunodeficiency syndrome. Four patients have gone into remission, the other two patients were not in remission at four and a half to five years after onset. CONCLUSION: We suggest that chronic colitis may represent a new entity related to infection of the colon with human immunodeficiency virus.

Acquired Immunodeficiency Syndrome

The structure and complete nucleotide sequence of the avian lipoprotein lipase gene.

The entire gene for chicken lipoprotein lipase (LPL) has been isolated and characterized by primer extension and sequence analysis. The gene is 17 kilobase pairs long and comprises 10 exons and 9 introns. As determined by primer extension analysis the start sites of transcription map 176, 204 and 218 nucleotides upstream of the initiator methionine codon. The 1947 base pairs of 5' flanking sequence contains several putative regulatory elements including two adjacent Oct I binding elements, four glucocorticoid regulatory elements and a sequence very homologous to the previously described fat specific element at--1402 nt. The first intron is very large (6433 bp) and contains four consensus SpI binding-site sequences. Five polyadenylation signals are found in the 3' untranslated region, the last three of which give predicted mRNA species identical in size to those determined by Northern blot. The 5' flanking sequences of the LPL, pancreatic lipase and hepatic lipase genes do not show homology, however. This may account for the homologous amino acid sequences but dissimilar gene expression of these enzymes.

Amino Acid Sequence

CD8+ T-cells from HIV-infected patients can either augment or abrogate HIV-specific lymphoproliferation.

Despite the presence of activated CD8+ T-cells that have been identified in infected individuals, these cells do not overcome natural HIV infection. To understand this better, we analyzed the CD8+ cell-dependent HIV-specific lymphoproliferation that occurs after HIV infection. Our study group of 36 individuals included 11 asymptomatic and 16 symptomatic patients (12 ARC and 4 AIDS), as well as HIV-seronegative controls. After CD8+ cell depletion of PBMC cultures, the remaining cells were tested for proliferation during culture with a well-defined and immunodominant gp41-derived HIV analog, gp41(8). After CD8+ cell depletion, three functional outcomes, which differed in accordance with the disease status of the individual, were consistently recorded, namely (i) an "abrogation effect," (ii) an "augmentation effect," or (iii) "no effect." First, removal of CD8+ cells from PBMC cultures abrogated gp41(8)-specific lymphoproliferation in gp41(8)-specific responders. Paradoxically, in other patients, including 5 symptomatics, the same inhibition of CD8+ cell function caused significant augmentation of gp41(8)-specific lymphoproliferation. These results suggest that the subpopulations of CD8+ T-cells that predominate at different stages of HIV-induced disease have different functional properties, including the ability to modulate HIV-specific cell-mediated immunity.

CD8 Antigens

Expression of B-type Epstein-Barr virus in HIV-infected patients and cardiac transplant recipients.

In the present study, peripheral blood mononuclear cells (PBMCs) were obtained from HIV+ subjects as well as cardiac transplant recipients, and the presence of A- and B-type Epstein-Barr virus (EBV) was determined using the polymerase chain reaction (PCR). Of the HIV+ patients studied, 24% were found to be infected with A-type EBV, 27% with B-type EBV, and 39% with both A and B virus types. Analysis of PBMCs from cardiac transplant recipients revealed that 39% were infected with A-type EBV, 33% with B-type EBV, and 28% with both EBV types. These results demonstrate a higher prevalence of infection with B-type EBV in HIV+ patients, than had been found previously by an analysis of spontaneously generated lymphoblastoid cell lines. The data indicated that it is not HIV per se which is responsible for the high incidence of B-type EBV in HIV+ individuals.

Australia

Trimethoprim-sulphamethoxazole appears more effective than aerosolized pentamidine as secondary prophylaxis against Pneumocystis carinii pneumonia in patients with AIDS.

OBJECTIVE: We compared the efficacies of low-dose trimethoprim-sulphamethoxazole (TMP-SMX; one tablet: TMP, 160 mg, SMX, 800 mg, twice daily, twice a week) and aerosolized pentamidine (300 mg every 4 weeks) as secondary prophylaxis against Pneumocystis carinii pneumonia (PCP) in patients with HIV infection. DESIGN: A retrospective controlled study. SETTING: The study was performed at St Vincent's Hospital, Sydney, Australia, which is a tertiary referral university hospital. PATIENTS, PARTICIPANTS: Over a 4-year period, following primary episodes of PCP, 60 patients received TMP-SMX and 73 aerosolized pentamidine. Thirty-eight patients who received no secondary prophylaxis served as historical controls. MAIN OUTCOME MEASURES: The rate of and time to PCP relapse was recorded for patients receiving low-dose TMP-SMX, aerosolized pentamidine, or no prophylaxis. RESULTS: Only one (1.7%) patient in the TMP-SMX-treated group relapsed, compared with 31 (42.5%) of those in the aerosolized pentamidine group and 21 (55.1%) of those in the control group (P less than 0.0001). Median PCP-free survival times were greater than 1153 days in the TMP-SMX group, 496 days in the pentamidine group, and 265 days in the control group (P less than 0.0001 between all groups). The rate of or time to relapse was not influenced by CD4+ lymphocyte count at the start of prophylaxis, primary therapy of PCP, history of allergy to TMP-SMX, or zidovudine therapy during the period of secondary prophylaxis in any patient group. Both therapies were well tolerated, with three (5%) of those receiving TMP-SMX and four (5%) of those receiving pentamidine discontinuing therapy as a result of side-effects. CONCLUSIONS: Low-dose TMP-SMX appears to be more effective compared with aerosolized pentamidine as secondary prophylaxis against PCP in HIV-infected patients. Zidovudine was well tolerated by both groups, but did not influence the rate of or time to relapse.

Acquired Immunodeficiency Syndrome

Changes in neuropsychological performance of AIDS-related complex patients who progress to AIDS.

OBJECTIVE: To investigate the changes in neuropsychological performance associated with progression from AIDS-related complex (ARC) to AIDS. DESIGN: A repeated measures design was used to compare three groups: ARC patients who progressed to AIDS (n = 15), those who did not (n = 19) and seronegative controls (n = 16). METHODS: The three groups were compared on tests of memory, information processing, motor performance, attention and conceptual flexibility. Clinical and immunological characteristics were recorded. Rates of neuropsychological impairment among the three groups were calculated and compared. RESULTS: The only significant difference between the groups at baseline was for one measure of motor performance. Repeated measures analysis indicated that there was a differential rate of change for the three subject groups for tasks of motor performance and attention. ARC patients who progressed to AIDS did not differ significantly from the non-progressors, although both groups showed significant deterioration over time compared with seronegative controls. Although there was a tendency for the progressors to have a higher rate of impairment, there were no consistent significant differences between visits. CONCLUSION: There were no significant changes in performance exclusively associated with progression to AIDS.

AIDS-Related Complex

The effect of treatment with zidovudine with or without acyclovir on HIV p24 antigenaemia in patients with AIDS or AIDS-related complex.

OBJECTIVE: To evaluate changes in serum HIV p24-antigen levels in a subset of patients who participated in a European/Australian double-blind, placebo-controlled trial evaluating the efficacy of zidovudine (250 mg every 6 h) alone or in combination with acyclovir (800 mg every 6 h) in patients with AIDS, AIDS-related complex (ARC) or Kaposi's sarcoma (KS). DESIGN: Double-blind, placebo-controlled randomized clinical trial of less than or equal to 6 months' therapy. SETTING: Samples were obtained from patients attending teaching hospital outpatient clinics in seven European countries and Australia. SUBJECTS: One hundred and ninety-seven HIV-infected patients (60 with AIDS and 137 with ARC or KS). MAIN OUTCOME MEASURES: Serum HIV p24-antigen levels measured using the Abbott HIV solid-phase enzyme immunoassay. RESULTS: Of 76 ARC/KS patients who were initially HIV p24-antigen-positive, one out of 25 randomized to placebo, eight out of 23 to zidovudine and 11 out of 28 to the zidovudine/acyclovir combination became antigen-negative. The proportion of patients who became antigen-negative was significantly higher in both the zidovudine group (P = 0.016) and the zidovudine/acyclovir group (P = 0.004), compared with the placebo group. There were no statistical differences between the zidovudine and the zidovudine/acyclovir groups. During the trial p24-antigen levels in the zidovudine-treated patients reached their minimum after 4-8 weeks of therapy, and tended to increase gradually thereafter. Disease progression occurred irrespective of whether p24-antigen levels declined during therapy. No association between p24-antigen responses to therapy and baseline disease stage, Karnofsky score or baseline CD4 cell count was detectable. CONCLUSION: Acyclovir does not potentiate the effect of zidovudine on p24-antigen levels. Change in antigen level in response to antiviral therapy needs further investigation before it is used as a surrogate marker for clinical efficacy of antiviral therapy.

AIDS-Related Complex

Identification of HIV-1 in semen following primary HIV-1 infection.

OBJECTIVE: To determine whether HIV could be identified in semen samples during the first few weeks after infection. DESIGN: A series of three homosexual men with symptomatic primary HIV-1 infection. METHODS: Each subject provided a series of semen samples that was examined for HIV-1 by virus culture, polymerase chain reaction (PCR) and transmission electron micrography. RESULTS: The first samples obtained for each subject (17, 22 and 24 days following onset of primary HIV-1 infection) were all positive by PCR and negative by viral culture. Of 13 samples obtained during the first 80 days after onset of primary HIV-1 infection and analysed by PCR, 10 were positive. Only one of these samples was virus culture-positive. Four semen samples obtained from two subjects during treatment with zidovudine were PCR-positive. Eight samples were examined for presence of HIV-1 by electron microscopy and one was found to be positive. CONCLUSIONS: These results indicate that men with HIV-1 infection are potentially infectious through sexual transmission during the first few weeks after infection. The findings emphasize that individuals in all stages of HIV-1 infection should practise safer sex to reduce transmission of HIV-1.

Adult

Epstein-Barr virus and HIV play no direct role in persistent generalized lymphadenopathy syndrome.

Persistent generalized lymphadenopathy (PGL) and polyclonal B cell activation are features of infection with HIV. Epstein-Barr virus (EBV) and HIV are known to activate B cells in vitro, but whether they are important B cell activators in patients infected with HIV is less clear. In this study, lymph node tissue was obtained from 10 patients with PGL and assessed for evidence of EBV and HIV gene sequences. DNA was extracted and specific viral gene sequences identified using the polymerase chain reaction (PCR). EBV sequences were difficult to detect in the PGL tissue, with a signal intensity similar to that of other benign and malignant lymphoid conditions not associated with EBV. HIV sequences were also rare in the PGL tissue, consistent with HIV infection of the small number of peripheral blood cells and nodal T cells likely to be present in such a sample. These findings suggest that the polyclonal B cell activation typical of HIV is not driven by direct EBV or HIV infection of B cells.

AIDS-Related Complex

Heterogeneous effects of exogenous IL-2 on HIV-specific cell-mediated immunity (CMI).

A characteristic feature associated with HIV-1 infection of the human host is a chronic decline in circulating CD4+ T helper/inducer cell numbers. Impaired cell-mediated immune functions usually occur in parallel with the decline in CD4+ T cells. Activated CD4+ T helper cells are a major source of endogenous IL-2 which is required for the immunoregulation of both antigen-specific B cells and CD8+ T cells. HIV-specific T cell proliferative responses are said to be weak and inconsistent, even during the asymptomatic phase of disease. We thus wished to determine how exogenous IL-2 affected HIV-specific T cell proliferation at different stages of the disease. Our cohort of 81 included both asymptomatic and symptomatic HIV-infected patients as well as uninfected normal donors. Proliferative responses of peripheral blood mononuclear cells (PBMC) that were elicited during culture with an immunodominant gp41-derived synthetic peptide, gp41[8], and which were known to be CD8+ cell-associated in asymptomatics only, were used to analyse the effects of exogenous IL-2. IL-2 had three main effects on HIV-specific proliferation, namely (i) an additive effect, (ii) a synergistic effect, and (iii) an induced effect. More specifically, low dose exogenous IL-2 frequently augmented lymphoproliferation in both asymptomatic and symptomatic gp41[8] responders. In most symptomatics, however, who were predominantly gp41[8] non-responders, exogenous IL-2 induced lymphoproliferation. Flow cytometric analyses using dual immunofluorescence were used to analyse the T cell subset distribution of proliferating PBMC cultures. During culture with gp41[8], both CD4+ and CD8+ T cell numbers increased. However, after the addition of exogenous IL-2 to gp41[8]-containing cultures, CD8+ cell-associated lymphoproliferative responses were preferentially augmented. These results suggest that in symptomatics there is an inadequate supply of endogenous IL-2 to help maintain the strong and effective CD8+ cell-associated anti-viral immunity, and an exogenous supply of IL-2 may be required.

Flow Cytometry

Definition of an immunodominant T cell epitope contained in the envelope gp41 sequence of HIV-1.

The majority of the immunodominant amino acid sequences of HIV-1 that have been characterized to date are coded for by hypervariable gene sequences. These variable sequences are however interspersed with sequences that are highly conserved between HIV strains. Immunogenic viral products with amino acid sequences that vary minimally between strains, and that consistently elicit both humoral and cellular immune responses, may be ideal for inclusion in a subunit vaccine. We studied HIV-seronegative and HIV-infected persons, classified as asymptomatic (AS), ARC or AIDS. Initially, we assessed the cellular immune status of each subject from results of T cell phenotype analyses, assays for serum levels of surrogate markers of disease progression, and responses to mitogens and recall antigen. In addition, we tested whether three short synthetic peptides derived from the conserved sequences of the envelope gp120 (aa 262-284) and gp41 (aa 579-601), and core p17 (aa 106-125) regions of the HTLV-IIIB isolate, could elicit B cell as well as T cell responses in HIV-infected subjects. Only the gp41-derived sequence was immunogenic at both B and T cell levels. To further characterize the gp41 epitope, we used a series of overlapping synthetic peptides derived from a conserved region of the envelope gp41 (aa 572-613). We thus identified an immunodominant 12-mer peptide sequence, gp41(8)(aa 593-604), which consistently elicited both T cell blastogenic and B cell (antibody) responses in AS HIV-seropositive individuals but not in ARC and AIDS patients. Linear regression analysis showed that in AS persons there was a strong positive correlation (P less than 0.0005) between the absolute CD8+ T cell numbers and the magnitude of blastogenic responses to the gp41(8)(aa 593-604). Furthermore, those AS subjects with T cells that proliferated in response to this gp41 analogue also had significantly greater serum levels of antibody to the same short peptide sequence than symptomatic ARC and AIDS patients. These results suggest that cellular responses to the immunodominant and highly conserved envelope sequences of HIV-1, associated with increased CD8+ T cells, may be important in the pathogenesis of HIV disease.

Amino Acid Sequence

Effect of the revised CDC case definition of AIDS on the number of AIDS cases in the Sydney AIDS Prospective Study.

We sought to evaluate the potential impact of a proposed revision in the case definition of acquired immunodeficiency syndrome (AIDS) (from a clinical case definition to one also including subjects with HIV infection who have an absolute number of peripheral CD4+ cells of less than 200 x 10(6)/L) among 512 HIV-seropositive homosexual/bisexual who were reviewed between 1984 and 1991. According to the current case definition, 151 (30%) of 512 at-risk subjects developed AIDS between 1984 and August 1, 1991. Of the 361 at-risk subjects who were not classified as AIDS by the current definition, 47 (13%; 95% CI 9-17%) were classified as AIDS according to the revised definition. The median time to development of AIDS according to the revised definition was 288 weeks and that according to the current definition was 338 weeks. Data on clinical status were available for 34 of the new cases at the time of their diagnosis according to the proposed case definition: 16 (47%) of these were asymptomatic, 10 (29%) had persistent generalised lymphadenopathy and eight had minor infectious diseases. Of the 151 cases diagnosed according to the current definition, 78 (52%) had an antecedent CD4+ cell count that met the criteria for AIDS under the revised definition a median of 59 weeks before their diagnosis according to the current definition. These data indicate an appreciable increase in the number of cases of AIDS in this cohort when the revised case definition was applied. These findings have important implications for the surveillance, and for the clinical monitoring and treatment, of patients with HIV disease in Australia.

Acquired Immunodeficiency Syndrome

Anxiety, depression and HIV related symptomatology across the spectrum of HIV disease.

Levels of anxiety and depression were assessed for 207 HIV seropositive homosexual/bisexual men (AIDS = 34, ARC = 72, asymptomatic HIV infection = 101), and 36 seronegative controls. Lymphocyte subset enumeration, history of opportunistic infections, and occurrence of HIV-related symptoms were recorded at the time of assessment. No differences between groups were found on age, educational level, state/trait anxiety or depression scores. Neither the number of symptoms reported, their duration, severity, frequency of occurrence, nor the proportion of patients who reported a specific symptom was different between the three HIV seropositive groups. Severity of anxiety and depression was related to the magnitude of symptomatology, but not associated with either degree of immunodeficiency, number of opportunistic infections or diagnostic group. Principal component analysis extracted five symptom factors (cognitive, affective, psychosocial, neurological and physical), none of which predicted state anxiety scores. However, affective and psychosocial symptom factors predicted trait anxiety and depression scores. The results indicate that ratings of anxiety and depression are independent of stage of HIV infection, may be in part mediated by constitutional and physical symptoms of HIV disease, but are primarily associated with the presence of psychological and psychosocial symptoms.

AIDS Dementia Complex

Subtypes of Epstein-Barr virus in human immunodeficiency virus-associated non-Hodgkin lymphoma.

Biopsy samples obtained from 20 patients with human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) were assessed for evidence of Epstein-Barr virus (EBV) and HIV sequences. DNA was extracted from formalin-fixed, paraffin-embedded NHL tissue and specific viral gene sequences were sought using the polymerase chain reaction (PCR). EBV sequences were found in 10 NHL samples (50%), with five tumors showing A-type and five B-type sequences. By serologic testing, 18 of 19 patients had antibodies to EBV, with 14 patients having antibodies to A-type EBV and 11 to B-type EBV. Serology confirmed the high prevalence of type B EBV in HIV-infected patients, but was not a reliable indicator of the EBV subtype present in the lymphomas. HIV sequences were present in biopsy tissue but at a level consistent with an origin from bystander HIV-infected cells. All 20 patients were negative by enzyme-linked immunosorbent assay for antibodies to human T-cell leukemia virus-type I. The high prevalence of type B EBV in these tumors is similar to the findings in endemic Burkitt's lymphoma, where 40% of the tumors have type B viral sequences. In normal populations, type B EBV is rarely found outside the nasopharynx. These studies support the hypothesis that EBV is an important cofactor in NHL in HIV-infected persons. The finding that B-type EBV is present in 25% of HIV-associated NHL suggests that this EBV subtype may be an important human pathogen with a wider geographic distribution than originally thought.

Antigens, Viral

Culture and properties of cells derived from Kaposi sarcoma.

We describe the establishment of four continuous cell cultures isolated from pleural or peritoneal fluid of patients with Kaposi sarcoma (KS) and show evidence that these cells are derived from vascular endothelium. Although provision of an extracellular matrix (fibronectin, laminin, or matrigel) was essential, the cell cultures were not dependent on exogenously added growth factors (platelet-derived growth factor, epidermal growth factor with or without heparin) for continuous culture. Specific staining for endothelial cell (EC) markers (factor VIII, Ulex europaeus type 1 lectin) and the secretion of endothelin, a vascular EC product, were demonstrated. The KS cells secreted large amounts of cytokines (granulocyte-macrophage-CSF, TNF-alpha, IL-1 beta, and especially IL-6). Conditioned media from the KS cells caused normal capillary EC to proliferate. The KS cells synthesized fibroblast growth activity in amounts sufficient to induce the proliferation of normal EC and fibroblasts. These data support the existence of a paracrine pathway of EC proliferation in KS and suggest that KS cells could sustain their own growth via an autocrine mechanism.

Acquired Immunodeficiency Syndrome