Publications

Infection of monocyte-macrophages with human immunodeficiency virus may be central to the pathogenesis of the acquired immunodeficiency syndrome. The ability of infected macrophages to prime T cells through IL-1 production was investigated in vitro. Purified human monocytes maintained in suspension culture were infected with strain HIV-DV. Intracellular expression of virus p24 antigen increased from undetectable levels immediately after infection to 13-59% of cells by 10-14 d; infected macrophages remained viable for up to 60 d. Supernatants collected between 14 and 20 d after infection were examined in the murine thymocyte co-mitogenesis assay and demonstrated to contain a potent IL-1 inhibitor, designated contra-IL-1. Contra-IL-1 activity was present in all supernatants examined after 4 d of infection, and peaked coincident with peak p24 antigen expression. Inhibitory activity was not present in uninfected cells. Contra-IL-1 activity eluted after gel filtration with an approximate molecular weight of 9 kD. Inhibitory activity was removed by exposure to heat or acid pH, or by incubation with chymotrypsin or staphylococcal V8 protease. Contra-IL-1 did not inhibit IL-2- or IL-4-dependent proliferation of murine T cell lines. Despite its ability to inhibit IL-1 activity, contra-IL-1 did not interfere with the binding of recombinant IL-1 beta to a fibroblast cell line. Contra-IL-1 inhibited the proliferation of normal peripheral blood mononuclear cells to both concanavalin A and tetanus toxoid; inhibition could be attenuated by the addition of exogenous IL-1. Messenger RNA extracted from infected macrophages was examined by Northern analysis for the presence of message to IL-1 beta. No message was apparent, suggesting that the presence of contra-IL-1 was not obscuring the concomitant release of IL-1. Infected macrophages stimulated with endotoxin generated readily detectable message for IL-1 beta. Spleen macrophages purified from two patients with AIDS complicated by immune thrombocytopenia spontaneously expressed p24 antigen in vitro and released contra-IL-1 activity into the media. Contra-IL-1 may contribute to the immune dysfunction of AIDS.

Although much is known about the natural history of HIV infection, many issues remain unresolved and require additional study. At least four major questions require further investigation. (1) Current data suggest that most HIV-infected persons will eventually develop AIDS. The proportion of all infected persons who will eventually develop AIDS, as well as the average and maximum incubation periods, have not yet been conclusively defined. (2) Certain clinical signs (such as oral candidiasis) or laboratory test results (such as a depressed T4 count) may indicate a poorer prognosis. However, the predictive value of such indicators for a specific patient and in an individual situation varies. Combinations of clinical and laboratory data may help refine estimates of the likelihood of developing AIDS or other HIV-related diseases. (3) Why some HIV-infected persons develop disease and others do not is not completely understood. The role of cofactors for disease progression needs additional investigation. There may be no one universal cofactor for progression but, rather, various agents that cause immune stimulation and reactivation of latent HIV. Therefore, exposure to a variety of infectious or environmental agents (such as through sexually transmitted diseases or injection of iv drugs) may accelerate progression to disease in HIV-infected persons. (4) It is not established whether antiviral agents will prevent or reduce the likelihood of disease progression in asymptomatic HIV-infected persons. If beneficial, should they be given to all HIV-infected persons or only to those whose clinical and laboratory evaluation suggests an increased likelihood of progression? Given these uncertainties, how should the physician or other health care worker evaluate, treat, and counsel the HIV-infected patient? Such patients should receive a comprehensive medical evaluation for both diagnostic and staging purposes; the details of such an evaluation are beyond the scope of this review and have been well described. A few brief points, however, should be emphasized.(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the epidemiology of HIV infection in Asian and Pacific Islander populations in San Francisco, we compared cases of AIDS reported in Asians and Pacific Islanders with those reported in other racial and ethnic groups. The incidence of AIDS in Asians and Pacific Islanders was significantly lower than in Whites, Blacks, Latinos and American Indians and Alaska natives. AIDS cases among Asians and Pacific Islanders have increased 177% since 1985 compared with 54% in other racial and ethnic groups, with the greatest increase in homosexual and bisexual men and transfusion recipients. Among Asian and Pacific Islander ethnic groups, the incidence of AIDS was 168 cases per 100,000 in Polynesians, 141 per 100,000 in Japanese, 92 per 100,000 in 100 Filipinos, 72 per 100,000 in southeast Asians, and 21 per 100,000 in Chinese. We conclude that AIDS cases are disproportionately increasing in Asians and Pacific Islanders in San Francisco.

Stable expression of the 40-kDa transactivator protein (Tax) from the type I human T-cell leukemia virus (HTLV-I) in Jurkat T cells leads to the activation and sustained expression of certain cellular genes that are transiently induced during normal T-cell growth. Cellular genes induced by Tax include those encoding the alpha subunit of the high-affinity interleukin 2 receptor (Tac), interleukin 2, and granulocyte/macrophage colony-stimulating factor. Tax induction of the interleukin 2 gene is synergistically amplified by mitogens that augment cytoplasmic levels of calcium. These changes in the pattern of cellular gene expression reflect a specific action of Tax, as they are undetectable in isogenically matched control cell lines expressing antisense tax cDNA. The spectrum of cellular genes regulated by Tax appears to be restricted: several other T-cell genes, either inducibly or constitutively expressed, are unaffected by this viral protein. These cell lines constitutively expressing Tax provide valuable reagents to explore the molecular basis for Tax action and to delineate the full spectrum of cellular genes regulated by this retroviral gene product.

Extension of mesangial cells (MC) into the pericapillary space is a pathologic response seen in several forms of glomerulonephritis. This process may involve both cytoplasmic extension by MC and actual cellular migration. For investigation of whether extracellular matrix factors could modulate this process, the migratory responses of rat MC were quantitatively examined using a cell culture model. Denuding ("wounding") a portion of a confluent culture of MC was followed by migration of mesangial cells into the denuded area. The expected proliferative response to this treatment was blocked by irradiation. The migratory response began within 8 hours of wounding and continued for at least 80 hours. The MC migratory response was specifically inhibited in a dose-dependent and reversible manner by heparin and heparinlike glycosaminoglycans (GAGs). Chondroitin sulfates and hyaluronic acid did not significantly inhibit MC migration. Glomerular basement membrane heparinlike GAGs may normally prevent MC extension into the pericapillary space. Changes in the density or composition of these substances during glomerular inflammatory processes could permit the development of MC pericapillary extensions and thereby lead to further alterations in basement membrane integrity.

The cell walls of gram-negative bacteria contain several biologically active components, including lipopolysaccharide (LPS), lipoprotein, and protein 1. The effects of these individual components and a synthetic analog of lipoprotein, TPP, on several activation parameters of glomerular mesangial cells (MC) were examined. Prostaglandin secretion, synthesis of the autogrowth factor, mesangial interleukin-1 (IL-1), and new synthesis of cellular proteins were assessed as markers of MC activation. All bacterial cell wall components evaluated were active in varying degrees as stimulants of prostaglandin secretion. In general, PGE was the predominant product. TPP and protein 1 also induced substantial secretion of thromboxane. Each cell-wall component was effective in stimulating mesangial IL-1 secretion. The activation of MC was associated with the enhanced synthesis of many cellular proteins in addition to IL-1. Stimulation by these bacterial components was dependent on the state of the mesangial cell cycle, because nonproliferating cells did not respond to these factors. Activation of MC by gram-negative bacterial cell wall components, with release of vasoactive prostaglandins and peptide mitogens, may be responsible for some of the glomerular hemodynamic alterations and cellular proliferative events associated with sepsis or chronic bacterial infection.