Suraiya Rasheed

CHARACTERIZATION OF A NEWLY DERIVED HUMAN SARCOMA CELL LINE (HT-1080)

A tumor cell line was derived from the fibrosarcoma of a 35‐year‐old Caucasian man who died without having received chemotherapy or radiotherapy. The in vitro growth properties and transplantability into antithymocytic sera treated mice were characteristic of these malignant cells. An aberrant karyology with marker chromosomes was present. No virus particles were detected.

The Relation of Virologic and Immunologic Markers to Clinical Outcomes after Nucleoside Therapy in HIV-Infected Adults with 200 to 500 CD4 Cells per Cubic Millimeter

BACKGROUND We studied measures of human immunodeficiency virus (HIV) replication, the viral phenotype, and immune function (CD4 cell counts) and the relation of changes in these indicators to clinical outcomes in a subgroup of patients in a controlled trial of early antiretroviral treatment for HIV, the AIDS Clinical Trials Group Study 175. METHODS The 391 subjects, each of whom entered the study with a single screening CD4 cell count of 200 to 500 per cubic millimeter, were randomly assigned to receive zidovudine alone, didanosine alone, zidovudine plus didanosine, or zidovudine plus zalcitabine. Plasma concentrations of HIV RNA were assessed in 366 subjects, and viral isolates from 332 subjects were assayed for the presence of the syncytium-inducing phenotype. RESULTS After eight weeks, the mean (+/-SE) decrease from base line in the concentration of HIV RNA, expressed as the change in the base 10 log of the number of copies per milliliter, was 0.26+/-0.06 for patients treated with zidovudine alone, 0.65+/-0.07 for didanosine alone, 0.93+/-0.10 for zidovudine plus didanosine, and 0.89+/-0.06 for zidovudine plus zalcitabine (P<0.001 for each of the pairwise comparisons with zidovudine alone). Multivariate proportional-hazards models showed that higher base-line concentrations of plasma HIV RNA, less suppression of plasma HIV RNA by treatment, and the presence of the syncytium-inducing phenotype were significantly associated with an increased risk of progression to the acquired immunodeficiency syndrome and death. After adjustment for these measures of viral replication and for the viral phenotype, CD4 cell counts were not significant predictors of clinical outcome. CONCLUSIONS Both the risk of the progression of HIV disease and the efficacy of antiretroviral therapy are strongly associated with the plasma level of HIV RNA and with the viral phenotype. The changes in the plasma concentration of HIV RNA predict the changes in CD4 cell counts and survival after treatment with reverse-transcriptase inhibitors.

A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome

Abstract Background. The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity. Methods. To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262). Results. The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the st...

Human immunodeficiency virus‐related lymphoma. Prognostic factors predictive of survival

In an attempt to determine factors predictive of survival in patients seropositive for human immunodeficiency virus (HIV) with acquired immune deficiency syndrome (AIDS)‐related lymphoma, the authors studied 60 such patients, all of whom were treated with curative intent. Eleven patients presented with lymphoma primary to the brain (P‐CNS); the remaining 49 had systemic AIDS‐related lymphoma. Patients with P‐CNS lymphoma had more severe underlying HIV‐related disease than did patients with systemic lymphoma as evidenced by a higher incidence of AIDS before the diagnosis of lymphoma (73% versus 37%; P = 0.04), and lower median number of CD‐4–positive lymphocytes in peripheral blood at diagnosis of lymphoma (30/dl versus 189/dl; P = 0.005). Median survival of such patients was 2.5 months versus 6.0 months for patients with systemic lymphoma (P = 0.04). Forty patients with systemic AIDS‐related lymphoma have died; three factors were strongly associated with shorter survival: (1) Karnofsky performance status (KPS) of less than 70% (multivariate relative survival risk [RSR] = 3.1); (2) history of AIDS before the diagnosis of lymphoma (multivariate RSR = 3.0 for opportunistic infection plus Kaposis sarcoma); and (3) bone marrow involvement (RSR = 3.1)). All three factors (KPS of less than 70%, prior AIDS diagnosis, and marrow involvement) were associated with early demise attributed to AIDS, whereas death attributed to lymphoma per se was associated with only two factors (KPS of less than 70% and marrow involvement). In the absence of all three risk factors, a “good prognosis” group of 17 patients was defined, with a median survival of 11.3 months; the median survival of the remaining patients (“poor prognosis”) was 4.0 months (P = 0.0002). Attainment of complete response to therapy (CR) was strongly related to prolonged survival in the patients in the good prognosis group (17.8 months in patients with CR versus 5.0 months in those with less than CR); however, such meaningful prolongation of survival was not seen in patients with poor prognosis who attained CR (6.3 months versus 3.4 months). The patients with poor prognosis may be unable to tolerate the insult of multiagent chemotherapy, experiencing low CR rates (25%) and death caused by lymphoma and AIDS. However, patients in either prognostic category who attained CR remained at risk for dying of AIDS while the lymphoma was in remission. Thus, it is apparent that meaningful prolongation of survival in the patient with AIDS‐related lymphoma will require not only effective antineoplastic intervention, but also control of the underlying HIV infection. In addition, future therapeutic trials should stratify patients based upon the prognostic factors defined here in an attempt to clarify the results obtained. 68:2466‐2472, 1991.

Effects of gamma irradiation on the human immunodeficiency virus. A study in frozen human bone-patellar ligament-bone grafts obtained from infected cadavera.

We studied the effects of several different doses of gamma radiation, ranging from 20,000 to 40,000 gray (2.0 to 4.0 megarad), with respect to the inactivation of the human immunodeficiency virus in fresh-frozen, whole bone-patellar ligament-bone grafts. Although the International Atomic Energy Agency has recommended the use of 25,000 gray of gamma radiation for the sterilization of medical products, the dose required for the inactivation of the human immunodeficiency virus in frozen allografts has not been established. Using one of the most sensitive and specific tests for the detection of the human immunodeficiency virus, the polymerase-chain-reaction test, we found that doses of 20,000 or 25,000 gray of gamma radiation did not destroy the genes of the human immunodeficiency virus effectively; DNA of the virus was detectable in the DNA of bone-marrow tissue obtained from grafts treated with these doses. However, DNA of the human immunodeficiency virus was not detectable in the grafts treated with 30,000 or 40,000 gray of gamma radiation. We conclude that a dose of 30,000 gray of gamma radiation or more is necessary for the sterilization of a fresh-frozen bone-patellar ligament-bone allograft, so that it can be used for reconstructive procedures without the risk of transmission of the virus to the recipient.

Prevalence and significance of acquired immunodeficiency syndrome-related retinal microvasculopathy.

We performed ophthalmologic examinations on 127 subjects with or at risk for human immunodeficiency virus (HIV) infection over a one-year period to determine the prevalence and significance of retinal cotton-wool spots and hemorrhages (AIDS-related retinal microvasculopathy). Of 26 asymptomatic homosexual men, of whom 13 were HIV seronegative and 13 were HIV seropositive, none manifested this retinopathy. Three of 34 patients (9%) with AIDS-related complex and 29 of 67 patients (43%) with AIDS manifested retinopathy on the initial examination. This difference in the prevalence of retinopathy between groups was statistically significant (P less than .05). Patients with AIDS demonstrated 7.2 times greater odds of manifesting retinopathy than patients with AIDS-related complex (P less than .05). Within the group of patients with AIDS, the T helper (CD4) to suppressor (CD8) cell ratio was significantly associated with retinopathy at the initial ocular examination. The CD4:CD8 ratio of the total group of AIDS and AIDS-related complex patients with retinopathy was significantly lower than that of patients without retinopathy (P less than .05). There was no significant association between retinopathy and any specific past or concurrent opportunistic infection or neoplasm. The presence of retinopathy was not associated with symptoms in any patient. The lesions of AIDS-related retinal microvasculopathy may be an important finding in the evaluation of patients suspected to have HIV-related disease.

Presence of cell-free human immunodeficiency virus in cervicovaginal secretions is independent of viral load in the blood of human immunodeficiency virus-infected women

OBJECTIVE The purpose of this study was to establish virologic or molecular criteria for evaluating the rate of transmission of human immunodeficiency virus type 1 and for defining the role of virus burden in the development of gynecologic diseases in human immunodeficiency virus-infected women. STUDY DESIGN Paired samples of blood and cervicovaginal secretions from 63 human immunodeficiency virus-seropositive women were evaluated for cell-free and cell-associated virus load by several methods, including quantitative cultures and reverse transcription polymerase chain reaction. RESULTS All women showed evidence of virus infection in both blood and cervicovaginal secretions by a combination of in vitro culture and molecular detection methods. The CD4+ cell counts in these women ranged from < 200/microliter to > 500/microliter. Blood plasma of 26% women (12/46) did not show detectable levels of human immunodeficiency virus ribonucleic acid by reverse transcription polymerase chain reaction (< 10(2)/100 microliters). These same women had significant amounts of human immunodeficiency virus in the cell-free cervicovaginal secretions (10(2) to 10(5) copies per 100 microliters). In contrast, 17% (8/46) women with significant quantity of human immunodeficiency virus ribonucleic acid in the blood plasma had negative results for human immunodeficiency virus in the cervicovaginal secretions. Further, treatment of women with the antiviral drug zidovudine did not change the human immunodeficiency virus-1 detection rate in plasma ribonucleic acid but showed significant reduction in the ability to detect human immunodeficiency virus ribonucleic acid in cell-free cervicovaginal secretions (p = 0.036). CONCLUSIONS We conclude that the replication kinetics of human immunodeficiency virus in the blood and cervicovaginal cells are unrelated, independent events. Further, there is no correlation between the virus load or the CD4+ cell counts in the blood and the presence or absence of quantifiable human immunodeficiency virus in cervicovaginal secretions.

Suramin Antiviral Therapy in the Acquired Immunodeficiency Syndrome: Clinical, Immunologic, and Virologic Results

The human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) requires reverse transcriptase for viral replication. We treated 12 patients who had acquired immunodeficiency syndrome and active HTLV-III/LAV viremia with suramin, a potent competitive inhibitor of reverse transcriptase, in six weekly induction doses of 1 g, followed by weekly maintenance doses of 500 mg. Three of eleven evaluable patients had complete inhibition of viral reverse transcriptase levels, lasting at least 18 weeks in each. Two additional patients had marked reduction in reverse transcriptase activity. Nadir serum suramin levels at the end of the induction phase correlated with the level of reverse transcriptase reduction. Toxicity included hepatic transaminase elevation, fever, malaise, rash, proteinuria, paresthesias, reversible neutropenia, and adrenal insufficiency. Objective clinical improvement was documented in 1 patient, but no patient had improvement in immune function and 7 patients had recurrent opportunistic infections. Although suramin may suppress HTLV-III/LAV viremia, its significant toxicity and lack of effect on immune variables indicate that alternative therapy will be required.

HIV Replication Enhances Production of Free Fatty Acids, Low Density Lipoproteins and Many Key Proteins Involved in Lipid Metabolism: A Proteomics Study

Background HIV-infected patients develop multiple metabolic abnormalities including insulin resistance, lipodystrophy and dyslipidemia. Although progression of these disorders has been associated with the use of various protease inhibitors and other antiretroviral drugs, HIV-infected individuals who have not received these treatments also develop lipid abnormalities albeit to a lesser extent. How HIV alters lipid metabolism in an infected cell and what molecular changes are affected through protein interaction pathways are not well-understood. Results Since many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables. Four separate experiments were conducted including one that compared 14 different time points over a period of >3 months. By subtractive analyses of protein profiles overtime, several hundred differentially expressed proteins were identified in HIV-infected cells by mass spectrometry and each protein was scrutinized for its biological functions by using various bioinformatics programs. Herein, we report 18 HIV-modulated proteins and their interaction pathways that enhance fatty acid synthesis, increase low density lipoproteins (triglycerides), dysregulate lipid transport, oxidize lipids, and alter cellular lipid metabolism. Conclusions We conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002–0.01). Translational and clinical studies on the newly discovered proteins may now shed light on how some of these proteins may be useful for early diagnosis of individuals who might be at high risk for developing lipid-related disorders. The target proteins could then be used for future studies in the development of inhibitors for preventing lipid-metabolic anomalies. This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways.

Variability and Prognostic Values of Virologic and CD4 Cell Measures in Human Immunodeficiency Virus Type 1-Infected Patients with 200–500 CD4 Cells/mm3 (ACTG 175)

Virologic measurements are increasingly used to evaluate prognosis and treatment responses in human immunodeficiency virus (HIV) type 1 infection. Markers of HIV-1 replication, including infectious HIV-1 titer from peripheral blood mononuclear cells, serum HIV-1 p24 antigen, plasma HIV-1 RNA, CD4 cell numbers, and viral syncytium-inducing (SI) phenotype, were determined in 391 virology substudy participants in AIDS Clinical Trials Group study 175. The subjects had 200-500 CD4 cells/mm3. All markers of viral replication significantly correlated with one another and were inversely related to CD4 cell number. Disease progression to an AIDS-defining event or death or loss of >50% of CD4 cells was associated with infectious HIV-1 titer (P < .001), HIV-1 RNA (P < .001), and HIV-1 p24 antigen (P = .007). In multivariate proportional hazards models, p24 antigen was never significant when HIV-1 RNA level was included. In a model containing infectious HIV-1 titer (P = .038), HIV-1 RNA (P < .001), SI phenotype (P < .001), and CD4 cell number (P = .18), only the virologic parameters remained significantly associated with progression.