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The HIV-1 genome encodes a protease that is required for viral processing of the precursor polyproteins Pr55gag and Pr160gag-pol. Interference with this process in human lymphocytes inhibits production of infectious virus. We tested the ability of several protease inhibitors to decrease replication of HIV-1BaL in human monocytes and peritoneal macrophages. The compounds tested are oligopeptide analogs of HIV-1 protease substrates in which the scissile dipeptide has been replaced by a hydroxyethylene isostere. The protease inhibitors were added only once, 1 hr prior to inoculation with virus. Every 3-5 days, half the medium was replaced with fresh medium. Inhibition of virus production was assessed by measuring reverse transcriptase (RT) activity in supernatant medium 14 days after infection. The concentration of drug required to inhibit infection by 50% (IC50) in monocytes ranged from 0.17 to 2.99 microM; IC50 values for peritoneal macrophages ranged from 0.21 to 1.9 microM. The IC50 values for these compounds were 1.1- to 10-fold higher when tested in monocytes compared to their inhibitory effect in lymphocytes, although still potently effective in the dosage range that appeared nontoxic to cells. Cell toxicity was seen only at concentrations greater than 10 microM, and varied among the drugs tested. Immunoblot analysis of two of the drugs (SB205700 and SB108922) confirmed inhibition of polyprotein processing. In control cells, 22% of viral protein pr55 was processed to p24 by 24 hr, and 51% was processed by 48 hr. In cells treated with the protease inhibitors (2 microM), Pr55 processing was inhibited 77% at 24 hr and 89% at 48 hr. Thus, these synthetic peptide analogs potently inhibit productive infection of mononuclear phagocytes by HIV-1. Drugs of this class may be useful for the treatment of HIV-1 infection in humans.

CD4 is the predominant cell membrane protein that binds human immunodeficiency virus type 1 (HIV-1) gp120 and facilitates HIV-1 infection, but other membrane-associated molecules may be involved in determining HIV-1 cellular infection. Our prior work had suggested that CD44, the transmembrane receptor for hyaluronan, might play a role in the infection of mononuclear phagocytes with HIV-1. In the present work, we have used cells of the CD4-positive, CD44-negative human T-lymphoblast cell line Jurkat to study the role of CD44 in HIV-1 infection and tropism. Cells were transfected with cDNA for the standard (S, or hematopoietic) CD44 isoform CD44S or the epithelial isoform CD44E. The resultant lines expressed appropriate CD44S or CD44E mRNA and protein. While the parent Jurkat cells, those transfected with vector alone, and those transfected with CD44E could be productively infected with only the lymphocytotropic strain HIV-1-LAI, cells transfected with CD44S were rendered susceptible to productive infection with the monocytotropic strains HIV-1-BaL and HIV-1-ADA. Also, CD44S-transfected cells displayed higher levels of infection with HIV-1-LAI than did the other transfected Jurkat cells. The transfected cell line cells all had comparable growth rates and expressed similar levels of the membrane antigens CD4, CD7, major histocompatibility complex (MHC) class I, MHC class II, and CD11a, while levels of CD3 were slightly higher in cells transfected with vector alone and in one of the clones transfected with CD44S. Hyaluronan binding was increased in cells transfected with either CD44S or CD44E. Mouse NIH 3T3 fibroblasts transfected with human CD4, human CD44S, or both human CD4 and CD44S displayed the appropriate antigens, but they could not be productively infected with lymphocytotropic or monocytotropic strains of HIV-1. The results indicate that in human leukocytes, CD44S is an important determinant of HIV-1 productive infection and may be involved in viral cellular tropism.

Hospice care for patients with AIDS often differs from care provided to patients with other terminal illnesses, such as cancer. We designed a seminar series to educate regional hospice staff about these differences and subsequently determined if the educational intervention was associated with improvements in their AIDS-related knowledge, attitudes, or behaviors toward patients with AIDS. Quantitative and qualitative data were collected from seminar participants (n = 63) and a similar comparison group (n = 18) at several time points. Seminar participants significantly improved their AIDS-related behaviors (p.05); and there was a trend toward knowledge improvement. Qualitative data shed light on the quantitative findings. Participants verbalized better understanding of the relatively aggressive care often given to terminally ill patients with AIDS when it enhanced quality of life.

Setting: Large academic medical center in Tanzania., Objectives: To determine the etiologies and outcomes of large pericardial effusions in HIV-infected and uninfected patients., Design: Prospective cohort study of patients admitted with new large pericardial effusions, confirmed echocardiographically. Patients had pericardial biopsies and drainage with extensive analysis of tissue and fluid specimens, and were followed with clinical and echocardiographic examinations., Results: Of 28 patients with large pericardial effusions, 19 were infected with HIV-1. 22 had invasive diagnostic procedures: 14 of 14 HIV-infected patients, but only 4 of 8 non-HIV-infected patients, had tuberculous pericarditis (P = 0.01). All but 1 of the HIV-infected patients had strongly positive tuberculin skin tests, and short-term outcomes were similar in the 2 groups., Conclusion: TB is the predominant cause of large pericardial effusion in HIV-infected patients in this setting; non-HIV-infected patients are more likely to have other etiologies. These patients were at an early stage of HIV infection and responded well to treatment. In settings where microbiological studies are not routinely available, HIV-infected patients with large pericardial effusions may be treated empirically for tuberculosis and monitored for improvement. If improvement does not follow within 2-4 weeks further studies are indicated. HIV-negative patients should undergo diagnostic evaluation initially.

Neopterin is a pteridine produced by human mononuclear phagocytes, usually in response to interferon-gamma (IFN-gamma) stimulation. Increasing serum levels of neopterin correlate with clinical progression to AIDS in HIV-infected people, but the factors that contribute to these elevated levels are not established. We performed in vitro experiments to investigate the possibility that HIV-1 infection of mononuclear phagocytes directly induces enhanced neopterin production. We found that HIV-1-infected monocytes and peritoneal macrophages produced neopterin in quantities similar to amounts produced by uninfected cells. The HIV-infected cells responded to stimulation with IFN-gamma as well as uninfected cells, with a 6- to 12-fold increase in neopterin production. We conclude that elevated serum levels of neopterin in HIV-infected individuals are not caused by HIV-1 infection of mononuclear phagocytes but may be a result of the normal response to mononuclear phagocytes to increased levels of IFN-gamma.

Patients undergoing chronic haemodialysis are at increased risk for infection with hepatitis B virus (HBV), but response to currently available vaccines is suboptimal. We undertook a 4-year prospective study of the efficacy of hepatitis B vaccine in patients with renal insufficiency, who were not yet dialysis-dependent. A booster dose of Recombivax HB was given at 3 or 4 years to those whose antibody levels fell below a predetermined point. Progression to dialysis was associated with poorer initial response to vaccination compared with those remaining dialysis-independent, but response to booster immunization was favourable in both groups. It is concluded that immunization of predialysis patients and subsequent booster vaccine results in a more favourable antibody response than has been seen historically in haemodialysis patients. Local endemicity and cost of vaccine should be considered when determining the best strategy for HBV immunization of patients with chronic renal failure.

Human immunodeficiency virus type 1 (HIV-1) infects mononuclear phagocytes, cells that may serve as a reservoir for viral persistence. Infection with HIV-1 leads to progressive compromise of the immune system, resulting in infections with opportunistic pathogens and eventual death. Experiments were designed to determine if in vitro HIV-1 infection of mononuclear phagocytes would diminish their oxidative capabilities, thus decreasing their antimicrobial effectiveness. Blood monocytes and peritoneal macrophages were obtained from uninfected donors and inoculated with a monocytotropic strain of HIV-1. Hydrogen peroxide production and reduction of nitroblue tetrazolium were measured after acute stimulation of cells with PMA or a phagocytic stimulus. Despite vigorous virus production, no difference was seen in oxidative burst between uninfected cells and infected cells or between monocyte-derived and peritoneal macrophages. In conclusion, reduced antimicrobial activity of HIV-infected mononuclear phagocytes is probably not secondary to decreased ability to generate reactive oxygen species.

Objective: To determine whether specific intestinal parasites are associated with HIV infection in Tanzanian children with chronic diarrhea., Design: A prospective, cross-sectional study., Setting: Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania., Subjects: All children aged 15 months to 5 years admitted with chronic diarrhea, and age-matched controls., Methods: Standardized history, physical examination, HIV serology, and stool parasitology were evaluated for all subjects. We compared three groups: HIV-infected and non-HIV-infected children with chronic diarrhea and controls without diarrhea., Main Outcome Measures: Fecal parasites and nutritional status., Results: Chronic diarrhea accounted for one-quarter of all cases of diarrheal disease in the defined age range, and children with chronic diarrhea were severely malnourished. Forty per cent of subjects with chronic diarrhea were HIV-seropositive. Although intestinal parasites were detected in approximately 50% of all three groups, diarrheagenic parasites were detected in up to 40% of children with chronic diarrhea. Blastocystis hominis was detected only in HIV-infected patients., Conclusions: HIV infection was common in children with chronic diarrhea, and parasitic agents of diarrhea may be important in children with chronic diarrhea both with and without HIV infection in this setting. B. hominis was more frequent in HIV-infected children. The immunocompromising effects of severe malnutrition may have diminished the difference between HIV-infected and non-HIV-infected children.

Concurrent infection with HIV-1 and Mycobacterium tuberculosis is increasingly common in East Africa. In the past, a drug regimen consisting of 2 months of intramuscular streptomycin plus 12 months of isoniazid and thiacetazone has been used in tuberculosis control programs with acceptable efficacy and low incidence of adverse reactions. Anecdotal reports of increasing cases of Stevens-Johnson syndrome prompted a 2 month prospective search for cases of severe cutaneous hypersensitivity reactions at Muhimbili Medical Centre in Dar es Salaam, Tanzania. Five such patients were admitted to a single ward during this time, 4 of whom were HIV-seropositive and all of whom were being treated with isoniazid and thiacetazone. These findings have implications for the management of tuberculosis in East Africa and perhaps other countries with high prevalence of both HIV-1 and tuberculosis.

Women using estrogen-progestin oral contraceptive agents have a marked decrease in the activity of hepatic triglyceride lipase, an enzyme believed to be involved in the catabolism of lipoprotein remnants. The hypothesis that women receiving these agents have defective remnant processing resulting in elevated chylomicron remnant concentrations in plasma was tested. Retinyl esters, which in humans are transported by intestinally-derived lipoproteins, were used to estimate chylomicron and chylomicron remnant concentrations. Women on a variety of oral contraceptive agents had increased plasma triglyceride concentrations, but only minimally increased fasting retinyl ester concentrations. Retinol and retinyl binding protein were elevated to about 150% of controls (p less than 0.001). Retinyl ester concentrations during active fat absorption were then measured in a second group of women taking a single preparation. Three-hour retinyl ester levels were lower in the treated group than control (p less than 0.05), but the difference had disappeared at six hours. Postheparin plasma hepatic triglyceride lipase was reduced by 46% in the treated group (p less than 0.05). Thus despite reduction in hepatic lipase activity, there was no accumulation of retinyl esters in the contraceptive-treated women to suggest impaired remnant processing.