Ruy Soeiro

Human immunodeficiency virus-1 infection of the nervous system: An autopsy study of 268 adult, pediatric, and fetal brains

The central nervous system (CNS) of 221 adults and 31 infants or children with the acquired immunodeficiency syndrome (AIDS) was examined with immunocytochemistry for infectious agents and for human immunodeficiency virus-1 (HIV-1) antigen (gp41). Since the major risk factor in this population was intravenous drug abuse, there were more female and pediatric patients than in other neuropathology autopsy series. Although children had a different spectrum of pathologic changes, including less frequent opportunistic infections, women did not differ from men in terms of types or incidence of opportunistic infections, vascular disease, neoplasia, and subacute AIDS encephalitis (SAE). Subacute AIDS encephalitis was detected in 26% of adult and 48% of pediatric brains. Immunocytochemical analysis of 100 adult and 20 pediatric brains revealed gp41 immunoreactivity in 78% and 40%, respectively. Virtually all adult brains with SAE had gp41 immunoreactivity in macrophages and microglia. Even brains with no significant pathology had frequent gp41 immunoreactivity, especially in the basal ganglia. In pediatric brains, including cases with SAE, gp41 immunoreactivity was less abundant, suggesting the possibility of latent infection or viral clearance. Spinal cords with vacuolar myelopathy or corticospinal tract degeneration had only rare gp41-positive cells. Brains from 16 aborted fetuses from HIV-1-seropositive women were all negative for gp41 immunoreactivity, but 12 brains were positive for HIV-1 by the polymerase chain reaction. These results may indicate that HIV-1 infection in fetal brains is below the limits of detection of immunocytochemistry. The differences noted between adults and children suggest that adults more often have productive CNS HIV-1 infection.

Comparison of Three Regimens for Treatment of Mild to Moderate Pneumocystis carinii Pneumonia in Patients with AIDS A Double-Blind, Randomized Trial of Oral Trimethoprim-Sulfamethoxazole, Dapsone-Trimethoprim, and Clindamycin-Primaquine

*For additional members of the ACTG 108 study group, see the Appendix. In 1994, 15 440 cases of Pneumocystis carinii pneumonia occurring in the United States were reported to the Centers for Disease Control and Prevention [1]. Thus, despite the advent of prophylactic agents to prevent this infection, the need for effective and nontoxic therapeutic regimens remains. Increased physician and patient awareness, along with improved methods of diagnosis, have made earlier institution of ambulatory therapy with oral medications a feasible alternative to hospitalization for inpatient treatment in many instances. Previous studies [2-8] suggest that the efficacy of trimethoprim-sulfamethoxazole, available since 1968, is equivalent or superior to that of all alternative therapies for P. carinii pneumonia. However, rates of treatment-limiting toxicity ranging from 20% to 57% in patients with the acquired immunodeficiency syndrome (AIDS) who receive this regimen [2, 3, 5, 7, 8] have necessitated a continued search for better-tolerated regimens. In one study [9], the combination of dapsone and trimethoprim was successfully used to treat 15 patients with a first episode of P. carinii pneumonia. In a subsequent randomized trial [5], this combination was compared with trimethoprim-sulfamethoxazole in 60 patients with arterial oxygen pressures of 60 mm Hg or greater. In this latter study, the efficacy of dapsone-trimethoprim was similar to that of trimethoprim-sulfamethoxazole (93% compared with 90%), but dapsone-trimethoprim was associated with a lower frequency of major toxicities (30% compared with 57%). The combination of clindamycin with primaquine has shown excellent activity against P. carinii in in vitro studies and in an experimental rat model [10]. Successful use of this regimen in the treatment of P. carinii pneumonia, generally with intravenous administration of clindamycin for all or part of therapy, has been described since 1989 [11-15]. In one study of 60 patients with an alveolar-arterial oxygen difference (PAO2-PaO2) of 40 mm Hg or less [15], the administration of intravenous or oral clindamycin and oral primaquine was associated with therapeutic success in 92% of patients and with doselimiting toxicity in 15% of patients. A randomized trial [16] compared intravenous clindamycin and oral primaquine with intravenous or oral trimethoprim-sulfamethoxazole in 49 patients with a first episode of P. carinii pneumonia and an arterial oxygen pressure of 50 mm Hg or greater; 90% of patients in each group were classified as having successful therapy, and dose-limiting toxicity occurred in 18% and 20% of patients, respectively. Thus, although dapsone-trimethoprim and clindamycin-primaquine have gained widespread use in the treatment of P. carinii pneumonia, their relative efficacies have not yet been validated in a large controlled trial, and their toxicity profiles have not been directly compared. To guide the clinician in selecting the optimal oral therapy for patients with AIDS and mild to moderate P. carinii pneumonia, we compared the toxicities and efficacies of trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine in a randomized, doubleblind multicenter trial. Methods Beginning in May 1991, patients were enrolled at 24 centers participating in the AIDS Clinical Trials Group (ACTG) of the National Institutes of Allergy and Infectious Diseases (NIAID). Each sites institutional review board approved the study (ACTG trial 108), and all participants gave informed consent before the study drug was administered. Patients Eligible patients had human immunodeficiency virus (HIV) infection, were older than 13 years of age, weighed 35 to 100 kg, and had symptoms or signs of P. carinii pneumonia, such as cough, shortness of breath, or an abnormal chest radiograph. Enrollment was limited to patients whose room air PAO2-PaO2 was 45 mm Hg or greater. Morphologic confirmation of the diagnosis by visualization of P. carinii in induced sputum, bronchoscopic lavage, or transbronchial biopsy specimens was required within 10 days of study entry. Treatment of P. carinii pneumonia lasting no more than 24 hours was permitted before randomization. Exclusion criteria were concurrent pulmonary pathologic conditions that could obscure the evaluation of response to therapy; the third trimester of pregnancy; receipt of systemic corticosteroids within 7 days of study entry; deficiency of glucose-6-phosphate-dehydrogenase (G6PD) or nicotinamide adenine dinucleotide methemoglobin reductase; hemoglobin M abnormality; previous enrollment in the study; inability to receive oral therapy; and serum creatinine level greater than 152.5 mol/L, hemoglobin level less than 80 g/L, absolute neutrophil count less than 0.75 109/L, platelet count less than 50 109/L, or alanine aminotransferase levels greater than 7.5 times the upper limit of normal. Randomization and Dosing Patients were assigned to treatment on the basis of a permuted block randomization. Randomization was stratified by treatment center and by the use of antipneumocystis prophylaxis within 30 days and was accomplished by computerized linkage to a central data management center. Active study drug and placebo assignments were implemented by each sites pharmacist, who labeled the bottles in a blinded manner. The Burroughs Wellcome Company (Research Triangle Park, North Carolina), the Jacobus Pharmaceutical Company (Princeton, New Jersey), the Upjohn Company (Kalamazoo, Michigan), and Sterling-Winthrop Pharmaceuticals (New York, New York) provided the study drug. The dosages of the study drugs were as follows: dapsone, 100 mg daily; clindamycin, 600 mg three times daily; and primaquine base, 30 mg daily. The dosages of trimethoprim and sulfamethoxazole were based on patient weight: Patients weighing 51 to 80 kg received two double-strength trimethoprim-sulfamethoxazole tablets (320:1600 mg) three times daily or trimethoprim (300 mg) three times daily with dapsone once daily. Patients weighing 36 to 50 kg received 240:1200 mg of trimethoprim-sulfamethoxazole (1.5 double-strength tablets) three times daily or 200 mg of trimethoprim three times daily with dapsone once daily. Patients weighing 81 to 99 kg received 400:2000 mg of trimethoprim-sulfamethoxazole (2.5 double-strength tablets) three times daily or 400 mg of trimethoprim three times daily with dapsone once daily. To maintain a doubleblind status, all patients received one active regimen and one placebo regimen. Patients with a PAO2-PaO2 of 35 to 45 mm Hg received adjunctive prednisone, 40 mg twice daily for 5 days, then 40 mg daily for 5 days, then 20 mg daily until antipneumocystis therapy was discontinued [17]. Patients with a history of intolerance to trimethoprim-sulfamethoxazole were enrolled beginning in September 1992 and were randomly assigned to one of the other treatment arms. Therapy was administered for 21 1 days. For patients with dose-limiting toxicity, the protocol specified either double-blind crossover to an alternative regimen (according to a second randomized list) or the substitution of intravenous pentamidine (3 to 4 mg/kg of body weight daily). Antipneumocystis therapy could be terminated if the patient had received therapy for at least 14 days and if clinical signs and symptoms had remitted. Patients meeting criteria for therapeutic failure (see below) were to receive intravenous pentamidine to complete therapy. We did not permit concurrent therapy with zidovudine, ganciclovir, colony-stimulating factors, rifampin, rifabutin, folinic acid, investigational agents other than triazole antifungal agents, and other medications potentially effective against P. carinii (such as pyrimethamine and sulfadiazine). Clinical and Laboratory Assessments At baseline, physical examination, venipuncture (for complete blood count with differential; reticulocyte count; and determination of creatinine, aminotransferase, and lactic acid dehydrogenase levels), measurement of room air arterial blood gas, and chest radiography were done. Physical examination and venipuncture were repeated on days 0, 3, 7, 10, 14, and 21 of therapy; arterial blood gas determination was repeated on days 7 and 21; and chest radiography was repeated on day 7. Serum methemoglobin levels were measured on days 3, 7, and 10 of therapy. Physical examination, venipuncture, and chest radiograph were repeated 2 weeks after therapy was completed. Survival status and recurrence of P. carinii pneumonia were determined 60 days after completion of therapy. Secondary antipneumocystis prophylaxis was advised for all patients who completed the study, and each patients primary physician chose the medication. We used a battery of instruments to assess the effect of treatment on patient-reported health status. Physical function was measured using the Duke Activity Status Index [18], a 12-item index weighted on the basis of known metabolic costs of each activity. Energy, pain, and general health perceptions were measured using scales from the Medical Outcomes Study [19], supplemented by four additional general health items [20]. Disability was measured by the number of days spent in bed or the decrease in the number of usual activities the patient could perform [21]. Severity of pulmonary (cough, dyspnea, and chest tightness) and other symptoms (fever, pain, nausea, rash, and dizziness) was assessed using a questionnaire that required approximately 5 minutes to complete and was available in English and Spanish [22]. Definitions of End Points Therapeutic failure at day 7 was defined by one of the following: 1) increase in PAO2-PaO2 of greater than 20 mm Hg over baseline without remission of baseline signs and symptoms; 2) change in antipneumocystis therapy for reasons other than toxicity; 3) intubation; and 4) death. Therapeutic failure at day 21 was defined by any of the above variables or by therapeutic failure at day 7. We used neither persistence of fe

Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus- associated non-Hodgkin's lymphoma

PURPOSE To determine the following: (1) the feasibility of combining the antiretroviral didanosine (ddl) with a 96-hour continuous intravenous (IV) infusion of cyclophosphamide (800 mg/m2), doxorubicin (50 mg/m2), and etoposide (240 mg/m2) (CDE) plus filgrastim in patients with non-Hodgkins lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection; (2) the effect of ddl on CDE-induced myelosuppression and CD4 lymphopenia; and (3) the effect of CDE on serum p24 antigen and quantitative HIV blood cultures. METHODS Twenty-five patients with HIV-related NHL received CDE every 28 or more days. Consecutive patients were assigned in an alternating fashion to group A (ddl given at a standard dose during cycles one, two, five, and six) or group B (ddl given during cycles three, four, five, and six). RESULTS ddl use was associated with less leukopenia (mean nadir, 3.33 v 1.49 x 10(3)/microL; p = .03), neutropenia (2.38 v 1.07 x 10(3)/microL; p = .03), and thrombocytopenia (76 v 48 x 10(3)/microL; p = .059), and fewer RBC (1.6 v 3.1 per cycle; p < .01) and platelet transfusions (0.7 v 1.5 per cycle; p < .01), but had no significant effect on CD4 lymphopenia. Furthermore, lymphomatous bone marrow involvement and low CD4 count were associated with significantly greater myelosuppression. Although there was no substantial change in serum p24 antigen, the HIV blood culture became quantitatively more positive or converted from negative to positive in seven patients (64%). Complete response (CR) occurred in 58% of patients (95% confidence interval, 38% to 78%), median CR duration exceeded 18 months, tumor-related mortality was 20%, and median survival was 18.4 months. CONCLUSION Our results suggest that the CDE and filgrastim regimen is tolerable and effective for patients with HIV-associated NHL, and that combination with ddl is feasible and may result in less myelosuppression.

Detection of HIV in fetal central nervous system tissue

Neurological disease is a common finding in children with AIDS and in others without signs of disease but with evidence of congenital HIV-1 infection. To investigate the possibility that HIV-1 can infect fetal central nervous system (CNS) tissue and therefore possibly serve as the substrate for the abnormal neurodevelopment characteristic of pediatric AIDS, eight abortus CNS samples (one set of twins) from seven HIV-1-seropositive intravenous drug users (IVDUs) and eight control abortus CNS samples from eight HIV-1-seronegative IVDUs were analyzed for HIV-1 infection. HIV-1 nucleic acid was detected only after the use of polymerase chain reaction (PCR) in three of eight CNS samples from HIV-seropositive IVDUs but not in samples from seronegative subjects. In situ hybridization confirmed that HIV-1 DNA sequences were in cells in the CNS parenchyma of two of the three positive samples. This study demonstrates that HIV-1 can infect human fetal CNS tissue in vivo, but that the use of PCR may be necessary for its detection.

Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection

Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.

The Involvement of RNA in Protein Synthesis

Binding of tRNA to Ribosomes The binding of tRNA to ribosomes has been extensively studied with both bacterial and mammalian systems. There is a reaction between the 30S portion of the ribosome, po...

Maternofetal transmission of human immunodeficiency virus-1: the role of antibodies to the V3 primary neutralizing domain.

ABSTRACT: The increase in the number of human immunodeficiency virus-1 (HIV-1)-infected children is a direct consequence of the heterosexual spread of the disease to women and the growing number of HIV-positive i.v. drug users. It is not known how the majority of infants born to HIV-1-infected women escape HIV-1 infection, and, for those infected, the timing of HIV-1 transmission has yet to be determined. In addition, the role of maternal antibodies in the prevention of HIV-1 transmission to the fetus is unclear. We have previously demonstrated a correlation between vertical transmission and the absence of high-affinity/avidity antibodies to a peptide, KRI-HIGPGRAFYT, which corresponds to a region of the primary neutralizing domain of the gp120 V3 loop of HIVMN (MN-PND). The present study examines the correlation between the presence of these high affinity antibodies in women completing a pregnancy or undergoing an elective abortion and the detection of HIV-1 infection in their aborted fetuses. In several instances, transmission occurred despite high-affinity antibodies to the MN-PND. We have, therefore, evaluated the reactivity of sera to different MN-PND variants. In one infant born to a mother with high-affinity/avidity antibodies to KRIHIGPGRAFYT (classic MN-PND), the infected baby developed antibodies to an MN-PND variant peptide against which his mother did not mount a humoral immune response during pregnancy. This finding indicates that fetal infection with MN-PND escape mutants arising during pregnancy may occur during a period when the mother is serologically negative.

Alterations in Human Fetal Hematopoiesis Are Associated with Maternal HIV Infection

ABSTRACT: In the majority of adult and pediatric patients with AIDS, hematologic abnormalities including leukopenia, anemia, and thrombocytopenia are commonly observed. In addition to these findings, changes in hematopoietic progenitor cells occur, including a reduction of multipotential-forming units, granulocyte-macrophages, macrophage as well as eosinophil colony-forming units, and bone marrow erythyroid burst-forming units. This study examined alterations in human fetal liver hematopoiesis in 2nd trimester abortuses from human immunodeficiency virus (HIV)-seropositive women. The differentiation and growth potential of hematopoietic cells in vitro were monitored. Upon initial isolation, some populations of liver hematopoietic cells from abortuses of HIV-sero-positive women were significantly decreased when compared to age-matched samples from fetuses of normal females including the percentage of early T cells [cluster of differentiation (CD)2], B cells (CD19), and early monocytes (CD14). A decrease in multipotent progenitors (CD34), myelomonocytes (CD33), and panleukocytes (CD45) was also observed. In contrast, after 21 d in culture, cells from HIV abortuses demonstrated an increase in the percentage of CD14 cells when stimulated with erythro-poietin and granulocyte-monocyte colony-stimulating factor, as well as an increase in CD45 phenotype after exposure to granulocyte-monocyte colony-stimulating factor alone. These samples showed a persistence of erythropoietic elements (transferrin and CD36 phenotype) when compared to normal controls. No significant difference in the in vitro growth of hematopoietic progenitors (bone marrow erythroid burst-forming units, granulocyte-macrophage colony-forming units, and multipotential forming units) between these samples and normal controls was found. These findings may be the result of transplacental hematopoietic inhibitors produced as a consequence of maternal HIV infection that result in similar hematologic abnormalities in AIDS patients.

Evidence of human immunodeficiency virus infection in human fetal tissues

The majority of children with acquired immunodeficiency syndrome (AIDS) exhibit signs of neurologic dysfunction. It is presently unclear whether the neuropathology of pediatric AIDS is the result of human immunodeficiency virus (HIV) infection of neural cells or the consequence of “bystander” pathogenic mechanisms. AIDS patients can have an array of neuropathologic abnormalities including perivascular inflammation, multinucleated giant cells, and microglial nodules. These findings support a pathogenic role for HIV-infected hematogenous cells invading the central nervous system (CNS) and causing “bystander” pathology. However, CNS tissue from AIDS patients can also show hypertrophy of oligodendrocyte nuclei, demyelination, gliosis, and disseminated necrotic foci, which suggests that neural cells may also be infected by HIV.