Activation of infectious virus from latent human immunodeficiency virus infection of monocytes in vivo.

Individuals infected with HIV may be asymptomatic for years before progressing to overt AIDS. Since HIV can latently infect monocytoid cell lines, we examined whether HIV latency occurs in monocytes in vivo. Freshly isolated monocytes from asymptomatic seropositive individuals examined before and after culture were positive for HIV DNA, but not RNA, as measured by polymerase chain reaction, showing that HIV latency occurs in monocytes in vivo. Coculture of these latently infected monocytes with Con A-activated T cells from HIV-negative normal donors stimulated 90% of the patients' samples and latently infected THP-1 to produce infectious virus. Neither Con A, resting T cells, nor T cell supernatants induced virus. Plasma membranes from activated T cells stimulated HIV production, suggesting cell contact induces factor(s) in monocytes to overcome latency. Thus, monocytes in AIDS patients harbor latent HIV inducible during an immune response, leading to T cell infection and viral-induced pathology.

Nephrotic syndrome associated with a clonal T-cell leukemia of large granular lymphocytes with cytotoxic function.

A 51-year-old man presented with a T-cell leukemia of large granular lymphocytes and rapidly developed a nephrotic syndrome due to presumptive minimal-change glomerulopathy. The E-rosette+, Ia+ cells demonstrated cytotoxic activity similar to that of natural killer lymphocytes but lacked other T-subset markers, except that one third of them bore Fc(IgG) receptors. Cytogenetic analysis revealed loss of chromosome 10 and the translocation (1;10)(p11;q11) in all metaphases. Regression of the leukemia after chemotherapy was accompanied by a dramatic resolution of the nephrotic syndrome, suggesting that the activated granular lymphocytes induced the renal lesion. The close association of a clonal T-lymphoproliferative disorder with minimal-change nephrotic syndrome lends further support to current views implicating activated T cells or their products in the pathogenesis of this glomerulopathy.

Thymic peptide hormones: basic properties and clinical applications in cancer.

The manuscript will provide an in-depth and critical review of the nomenclature, biochemistry, biological properties, and a summary of published and on-going clinical trials with all reported thymic preparations, including both partially purified thymic factors (e.g., thymosin fraction 5, thymostimulin) as well as purified and synthesized thymic peptides (e.g., thymosin alpha 1, thymulin). Particular emphasis will be placed on which thymic peptides should be categorized as true hormones. In addition, the comparative biochemistry and biological activity in animals will be summarized and contrasted for all the currently available thymic factors. The effects, in vitro of thymic factors, on peripheral blood lymphocytes isolated from normal donors and patients with primary immunodeficiency disorders, autoimmune disorders, and neoplastic disorders will also be reviewed. Finally, a detailed critical summary of the clinical trials performed with each of the thymic preparations will be presented with an emphasis on treatment of patients with cancer.

Low-dose multidrug chemotherapy plus Pneumocystis carinii pneumonia prophylaxis for HIV-related Kaposi's sarcoma.

Treatment of advanced HIV-related Kaposi's sarcoma (KS) with combination chemotherapy yields a high tumor regression rate but also a high incidence of opportunistic infections (OIs), most notably Pneumocystis carinii pneumonia (PCP). We attempted to maintain a high response rate and minimize the likelihood for developing PCP by designing a flexible low-dose weekly multidrug chemotherapy regimen that alternates two myelotoxic with one to two nonmyelotoxic drugs, concurrently with prophylactic aerosolized pentamidine. Eighteen homosexual men were treated, all of whom had had prior OIs or exhibited advanced mucocutaneous or visceral disease and/or systemic symptoms. In 17 evaluable patients, 16 partial responses but no complete responses were observed (objective response rate = 94%). Median time to response and response duration were 2 and 8 months, respectively. Toxicity was limited to a reversible sensory neuropathy in three patients, and five required blood transfusions. With a median follow-up time of 17 months, two cases of PCP and six other OIs occurred. Overall median survival was 12 months, with most of the deaths (8 of 14) secondary to recurrent KS. Weekly low-dose multidrug chemotherapy + PCP prophylaxis yields a high response rate but high relapse rate, a low incidence of PCP, and comparable or better survival to other regimens not employing PCP prophylaxis. Our results suggest that the optimal combined modality approach for patients with advanced HIV-KS should include a more intensive multidrug chemotherapy regimen in combination with a vigorous, broad-scoped prophylactic regimen for PCP and other potential OIs.

Clinical, virologic, and immunologic effects of combination therapy with ribavirin and isoprinosine in HIV-infected homosexual men.

We evaluated the clinical, immunologic, and virologic effects of oral treatment with ribavirin and isoprinosine for up to 3 months in asymptomatic, HIV-culture-positive homosexual men. Fifteen consecutive men received isoprinosine 4 g/day (1 g q.i.d.), and 800 (9 men) or 1,200 mg/day (6 men) of ribavirin. Five men in each ribavirin dosage group completed at least 2 months of treatment. No unexpected toxicities were observed. Eight minor HIV-related events occurred in six men while on study. All men remained HIV-positive, and time to positive culture decreased by at least 4 days in three men from each treatment group. Serum p24 levels did not change in two men who were p24 antigenemic and received 800 mg/day of ribavirin. Treatment was associated with a generalized lymphopenia affecting all lymphocyte subsets including CD4, which was partially reversible 1 month after stopping treatment. Most of the men remained anergic on DTHS skin testing. No improvements were noted in in vitro lymphoproliferative responses to antigens or in NK cell activity (which decreased significantly in the 1,200 mg/day ribavirin group). Although well tolerated at the doses employed, the combination of ribavirin and isoprinosine produced an unexpected generalized lymphopenia and did not exhibit HIV-suppressive or immunorestorative effects.

Effect of lithium carbonate in HIV-infected patients with immune dysfunction.

Ten homosexual men received oral lithium carbonate at doses that maintained their serum lithium concentrations between 0.5 and 1.5 mEq/L. Prior to treatment all patients had HIV isolated from PHA-activated peripheral blood lymphocytes (PBLs) using a quantitative antigen-capture enzyme-linked immunosorbent assay (ELISA) assay for detection, and had an absolute number of CD4 (helper) lymphocytes of less than 300/mm3. Eight of 10 patients developed symptoms of drug toxicity requiring discontinuation of the drug in 7 patients. Two patients completed only 4-5 weeks of lithium therapy, and 5 patients received 7-8 weeks. All patients remained culture positive for HIV during the trial, and viral titers as measured by the antigen capture assay were unchanged or increased. There were no significant changes in the absolute number of CD4 lymphocytes, CD4/CD8 ratio, or phytohemagglutinin (PHA) or tetanus toxoid induced proliferative responses. There was a significant decrease in mixed lymphocyte reaction (MLR). Lithium carbonate demonstrated no immunorestorative or antiviral activity when given in therapeutic doses. Drug toxicity limited therapy in the majority of patients.

Ultrastructural markers in circulating lymphocytes of subjects at risk for AIDS.

One hundred random lymphocytes in each of 168 buffy coat preparations from 59 subjects at risk for AIDS (50 homosexuals, 7 hemophiliacs, and 2 combined, all with T4:T8 ratios of less than or equal to 1.2) were screened for the presence of ultrastructural markers, "tubuloreticular structures" (TRS), and "test tube and ring-shaped forms" (TRF). Twenty-six (44%) of the subjects were TRS positive (71 specimens) and 12 (20%) were TRS/TRF positive (34 specimens). TRF were only observed in TRS-positive specimens. There was an inverse relationship between the incidence and abundance of markers and the T4:T8 ratios, i.e., mean T4:T8 +/- SE for TRS-negative, TRS-positive, and TRS/TRF-positive subjects were 0.59 +/- 0.05, 0.42 +/- 0.05, and 0.19 +/- 0.06, respectively. Markers were present for as long as 16 months before AIDS was diagnosed in four subjects and before the appearance of features suggestive of AIDS in two others. The assessment of TEM markers in peripheral blood lymphocytes is a simple method for screening at-risk subjects in whom AIDS is likely to develop.

Listeria monocytogenes sepsis and small cell carcinoma of the rectum: an unusual presentation of the acquired immunodeficiency syndrome.

A 26-year-old male homosexual initially presented with Listeria monocytogenes sepsis and a small cell carcinoma of the rectum. His subsequent course included esophageal candidiasis, Pneumocystis carinii pneumonia, and severe T-lymphocyte abnormalities on immunologic testing, consistent with the acquired immunodeficiency syndrome (AIDS). This represents the first case of AIDS associated with this unusual tumor and Listeria infection.

Thymosin in the early diagnosis and treatment of high risk homosexuals and hemophiliacs with AIDS-like immune dysfunction.

PIP: The adnormal levels of thymosin alpha 1 in acquired immunodeficiency syndrome (AIDS) patients, depressed T-cell function, thymus pathology, and the restoration of T-cell function by thymosin fraction 5 (TF5) lend support to the hypothesis that the thymus plays a central role in AIDS. The thymosin alpha 1 assay may provide a means of identifying symptomatic carriers of AIDS. This paper summarizes the current status of diagnostic studies with thymosin alpha 1 in AIDS and reports the 1st clinical trial with thymosin in subjects with AIDS-like immune dysfunction. Serum samples from intravenous drug abusers, homosexuals, and Haitians with AIDS have revealed thymosin alpha 1 levels at least 2 standard deviations from the mean of controls without AIDS. Preliminary data from a pilot study in homosexuals and hemophiliacs at high risk for AIDS suggest that the administration of TF5 may be effective in reconstituting some T-cell mediated specific immune functions, including cell-medicated lympholysis (CML) and the mixed lymphocyte response (MLR), and enhancing the lectin-induced production of T-cell growth factor. On the other hand, TF5 has failed to have any effects on the T4/T8 ratio, absolute lymphocyte counts, or natural killer cell activity.^ieng

Phase II trial of subcutaneous interleukin-2, subcutaneous interferon-alpha, intravenous combination chemotherapy, and oral tamoxifen in the treatment of metastatic melanoma: final results of cancer biotherapy research group 94-11.

BACKGROUND: The treatment of metastatic melanoma remains unsatisfactory despite encouraging results with biotherapy and combination chemotherapy. Combining these two modalities may improve outcomes for such patients. METHODS: Eligible patients had metastatic melanoma, were in good medical condition, and had not been treated previously for metastatic disease. A 42-day treatment cycle consisted of: tamoxifen 10 mg p.o. b.i.d. days 1-42, carmustine 150 mg/m2 i.v. on day three, dacarbazine 220 mg/m2 and cisplatin 25 mg/m2 i.v. q.d. days 3-5, and 24-26, interferon-alpha 2b 6.0 MU/m2 s.c. days 8-12 and 29-33, and interleukin-2 11 MU/m2 s.c. days 8, 10, 12 and 29, 31, 33. In the absence of tumor progression, patients could receive up to six cycles of alternating treatment. Toxicity and tumor response was assessed following each treatment cycle; survival was determined from the first date of treatment. RESULTS: The 28 melanoma patients included 21 men and 7 women, with a median age of 55 years with a range of 26-77. Fifty-four percent were asymptomatic when treatment was initiated. Eighty percent had soft tissue metastases, 32% lung, 28% liver, and 8% bone. There were nine patients with significant tumor responses (three complete, six partial) for a response rate of 32% (18-57% 95% CI) based on intent-to-treat analysis, and 38% (18-57%, 95% CI) for the 24 patients who were evaluable for response. The months of duration of survival for responders were 38.9+, 27.2+, 22.8+, 16.3, 13.2, 9.4, 7.5, 6.5+, and 5.8. At a median follow-up of 31 months, the median duration of event-free survival was 4.6 months; median survival was 9.4 months. The survival rate one year from initiating treatment was 42%; 2-year survival was 14%. The most frequent toxicities were 96% nausea/vomiting, 80% fatigue, 73% thrombocytopenia, 60% neutropenia, and 44% fever. Two patients experienced early death that may have been treatment related; one died of cardiovascular complications and the other of a central nervous system event. CONCLUSION: This outpatient regimen was associated with significant toxicity including a 7% rate of possible treatment-related death. Tumor regression rates and survival were similar to results reported for chemotherapy alone, or inpatient IL-2-based therapy, but did not suggest an improvement in outcome.

Disseminated talc granulomatosis. An unusual finding in a patient with acquired immunodeficiency syndrome and fatal cytomegalovirus infection.

The association of disseminated magnesium silicate talc granulomatosis and acquired immunodeficiency syndrome is reported in a male homosexual who used intravenous drugs and who died of overwhelming cytomegalovirus (CMV) infection. Autopsy findings included widespread deposition of talc crystals in the lungs, liver, lymph nodes, bone marrow, and spleen. Typical CMV inclusions were seen in the lungs, kidneys, adrenal glands, gastrointestinal tract, and right eye. There was no evidence of malignancy. Analysis of peripheral blood neutrophil function revealed impaired chemotaxis and chemokinesis, but opsonophagocytosis had remained normal. The CMV infection in the small bowel was extensive and resulted in severe destruction of the muscularis propria and neural plexi, leading to marked dilatation and persistent diarrhea. The terminal course was marked by intractable hypotension, pneumonitis, and malnutrition, which could be attributed respectively to CMV involvement of the adrenal glands, lungs, and small bowel. The etiology and possible role of systemic talc granulomatosis in the development of immunosuppressive illness is reported herein.

A pilot study of intensive weekly chemotherapy for extensive disease small-cell lung carcinoma.

An intensive weekly chemotherapeutic treatment for extensive disease small-cell lung cancer was piloted in 14 patients. The regimen consisted of 6 drugs. Two drugs were given each week for a total of 12 weeks of treatment. Modifications were required in the protocol to attempt to overcome excessive toxicity. Unexpected toxicity included anemia requiring transfusions in 8 of 10 patients completing treatment, sepsis in 8 of 14 with 3 related deaths, and prolonged grade III motor neurotoxicity in 2 patients. All 3 patients who died of sepsis had shown evidence of response, and 8 of the remaining 11 had 90% or greater tumor shrinkage. Two others had a partial response. Median survival time for all patients was 9.3 months.

Abnormal phytohemagglutinin-induced T-cell proliferative responses in Hodgkin's disease.

Optimal conditions were established for evaluating the phytohemagglutinin-induced proliferative responses of purified peripheral blood T lymphocytes. This assay was utilized to determine whether T cells (in the absence of monocytes and serum inhibitory factors) from patients with Hodgkin's disease were defective in their ability to proliferative in response to optimal (50 microgram/ml) and suboptimal (25 and 12.5 microgram/ml) concentrations of phytohemagglutinin. T cells from 6 of 12 untreated patients exhibited 6-day proliferative responses below the range of 15 control subjects using optimal mitogen concentrations, and 9 of 12 patients exhibited subnormal responses using lower concentrations. Kinetic analyses indicated that the abnormal T-cell proliferative responses were characterized by peak proliferation occurring at day 4 or 5, rather than day 6. The observed abnormalities were not related to elevations in the proportions of T cells bearing surface receptors for IgG (T gamma Cells). Our results suggest that intrinsic functional T-cell defects contribute to the impaired immunity associated with Hodgkin's disease.