Norman P. Salzman

Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection : a preliminary study

BACKGROUND Interleukin-2 is an important regulatory cytokine of the immune system, with potent effects on T cells, B cells, and natural killer cells. In vitro, interleukin-2 can induce the proliferation and differentiation of peripheral-blood mononuclear cells from patients infected with the human immunodeficiency virus (HIV). METHODS We treated 25 HIV-infected patients with interleukin-2 administered as a continuous infusion at a dosage of 6 to 18 million IU per day for 5 days every 8 weeks during a period of 7 to 25 months. All patients also received at least one approved antiviral agent. Immunologic and virologic variables were monitored monthly. RESULTS In 6 of 10 patients with base-line CD4 counts higher than 200 per cubic millimeter, interleukin-2 therapy was associated with at least a 50 percent increase in the number of CD4 cells. Changes ranged from -81 to +2211 cells per cubic millimeter. Interleukin-2 therapy resulted in a decline in the percentage of CD8 lymphocytes expressing HLA-DR and an increase in the percentage of CD4 lymphocytes that were positive for the p55 chain of the interleukin-2 receptor. Four patients had a transient but consistent increase in the plasma HIV RNA level at the end of each infusion. In the remaining 15 patients, who had CD4 counts of 200 or fewer cells per cubic millimeter, interleukin-2 therapy was associated with increased viral activation, few immunologic improvements, and substantial toxic effects. CONCLUSIONS Intermittent courses of interleukin-2 can improve some of the immunologic abnormalities associated with HIV infection in patients with more than 200 CD4 cells per cubic millimeter.

Increasing Viral Burden in CD4+ T Cells from Patients with Human Immunodeficiency Virus (HIV) Infection Reflects Rapidly Progressive Immunosuppression and Clinical Disease

OBJECTIVE To determine over time the relation between viral burden and immunologic decline in patients with asymptomatic human immunodeficiency virus (HIV) infection. DESIGN Blind analysis of cell samples from matched cohorts for HIV proviral DNA by polymerase chain reaction, retrospective analysis of clinical data on patients, and prospective follow-up of patients seropositive for the human immunodeficiency virus type 1 (HIV-1). SETTING National research clinic and academic medical centers. PATIENTS Cohort 1 included 12 healthy HIV-1-seropositive patients (average follow-up, 14 months): Six patients had stable disease and 6 developed rapidly progressive disease. Cohort 2 included 15 healthy HIV-1-seropositive patients from the Multi-center AIDS Cohort Study (average follow-up, 32 months): Eight patients had stable disease and 7 developed rapidly progressive disease. LABORATORY STUDIES: Quantitative polymerase chain reaction was done to determine the HIV-1 viral burden in sort-purified CD4+ T cells obtained from patients at various timepoints. MEASUREMENTS AND MAIN RESULTS In patients who remained asymptomatic, frequencies of HIV-infected CD4+ T cells were low (less than 1/10,000 to 1/1000) at study entry and increased only minimally (none higher than 1/1000). In contrast, among patients who developed HIV-related symptoms including the acquired immunodeficiency syndrome (AIDS) despite having similar CD4 counts, frequencies of HIV-infected CD4+ T cells were higher at entry (greater than 1/1000) and increased substantially (greater than 1/100) in most within 3 months of developing progressive disease. This increase in HIV burden coincided with a significant decline over time in the percent of T4 cells (31% to 16%), whereas the percent of T4 cells was unchanged in persons who remained asymptomatic (33% to 34%). CONCLUSIONS Increasing viral burden in peripheral blood CD4+ T-cells is directly associated with a progressive decline in CD4+ T cells and deteriorating clinical course in HIV-infected patients.

ANTI-RETROVIRAL EFFECTS OF INTERFERON-α IN AIDS-ASSOCIATED KAPOSI'S SARCOMA

Abstract 21 patients with AIDS and Kaposis sarcoma were enrolled in an open therapeutic trial to determine the in vivo anti-retroviral activity of recombinant interferon-α (IFN-α). 8 (38%) showed a complete or partial anti-tumour response. The mean pretreatment CD4 count for the responders was 399 cells/μl vs 154 cells/μl for the non-responders. All 5 of the patients with more than 400 CD4 cells/μl pretreatment showed a significant reduction in tumour, whereas none of the 7 patients with under 150 CD4 cells/μl had any response. 5 of the 6 complete or partial responders with greater than 50 pg/ml of human immunodeficiency virus (HIV) p24 before IFN therapy showed a 75% or greater reduction by 12 weeks of therapy, with 3 patients having persistently negative HIV cultures. The anti-viral effects were also most pronounced in the patients with the highest CD4 counts. These data demonstrate the potential benefits, both anti-tumour and anti-retroviral, of treatment with IFN-α in the early stages of HIV infection and Kaposis sarcoma.

Interferon-α in Patients with Asymptomatic Human Immunodeficiency Virus (HIV) Infection: A Randomized, Placebo-Controlled Trial

Abstract Study Objective:To evaluate the toxicity and clinical efficacy of interferon-α2b (IFN-α) in patients with asymptomatic human immunodeficiency virus (HIV) infection. Design:Randomized, plac...

Zidovudine in Patients with Human Immunodeficiency Virus (HIV) Infection and Kaposi Sarcoma: A Phase II Randomized, Placebo-Controlled Trial

STUDY OBJECTIVE To evaluate the toxicity, effects on immune function, antitumor effects, antiretroviral effects, and pharmacokinetics of zidovudine therapy in patients with early human immunodeficiency virus (HIV) infection and Kaposi sarcoma. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING National Institutes of Health, a referral-based research institution (single site). PATIENTS Physician-referred volunteer patients with HIV infection, Kaposi sarcoma, CD4+ lymphocyte counts greater than 0.2 x 10(9)/L, and no systemic symptoms or history of opportunistic infection. Of 41 patients enrolled, 4 had not met all entry criteria and were therefore not evaluable. INTERVENTIONS Patients were randomized to one of four treatment groups for an initial 12-week treatment period: oral placebo (9 patients); zidovudine, 250 mg orally every 4 hours (9 patients); zidovudine, 0.5 mg/kg body weight intravenously every 4 hours (9 patients); and zidovudine, 2.5 mg/kg intravenously every 4 hours (10 patients). After at least 12 weeks of therapy at their assigned dose, patients were treated with oral zidovudine, generally 250 mg every 4 hours, with a mean 42-week follow-up. MEASUREMENTS AND MAIN RESULTS Anemia and granulocytopenia were the major toxicities. Significant increases in platelet counts and declines in serum HIV antigen and IgG and IgM levels occurred in treated patients. Treated patients were more likely than those on placebo to clear HIV from the cerebrospinal fluid. There were no differences in tumor progression or CD4+ or CD8+ lymphocyte counts among the groups. CONCLUSIONS Zidovudine was well tolerated and had antiretroviral activity in patients with early HIV infection and Kaposi sarcoma but it had no significant effect on the extent of Kaposi sarcoma or on immune function.

Detection of HIV in Bone Allografts Prepared From AIDS Autopsy Tissue

Processed bone from an AIDS patient was tested for the presence of the human immunodeficiency virus type 1 (HIV-1). The preliminary procedures used to process bone allografts included removal of adventitious material and two cycles of freeze thawing. Although infectious virus was readily observed in plasma and bone marrow cells taken at autopsy, no infectious virus was detected in processed bone fragments. However, by using the polymerase chain reaction procedure, the presence of proviral HIV DNA could be demonstrated in processed bone allografts from this donor. Whereas the best safeguard against transmission of HIV by allografts is rigorous criteria for the exclusion of seropositive individuals as donors, proper procedures for processing bone allografts can further reduce the possibility of HIV transmission by bone allografts in cases where tissue from an infected donor is collected and processed.

Isolation of HIV-1 from plasma of infected individuals: an analysis of experimental conditions affecting successful virus propagation.

Experimental conditions affecting the successful propagation of HIV-1 from the plasma of seropositive individuals were examined. It was determined that whole blood samples collected with lithium heparin as the anticoagulant, immediate plasma separation, and immediate culturing were best suited for obtaining viable virus from plasma. Virus was isolated by infecting fresh phytohemagglutinin-stimulated normal donor peripheral blood mononuclear cells (PBMCs) with plasma followed by weekly cocultivation with new target cells. The plasma virus isolation rate was the greatest and HIV-1 titers were the highest for those individuals with <200 CD4+ cells/mm3 and decreased as the level of CD4+ cells approached normal values. We were able to obtain positive cultures from 29.5% of those patients with CD4+ counts >500/mm3 HIV-1 titers in plasma also correlated with high serum p24 antigen levels when serum was treated with glycine to dissociate antigen-antibody complexes.