A novel methodology for quantitating the enhancement of cutaneous delayed-type hypersensitivity by IMREG-1: a measure of the immunopotentiation of cell-mediated immunity.

IMREG-1, a low-molecular-weight immunomodulator derived from normal human leukocyte dialysates, has been shown to enhance cutaneous delayed-type hypersensitivity (DTH) responses to recall antigens. Both IMREG-1 and the biologically active peptides (Tyr-Gly[YG] and Tyr-Gly-Gly[YGG]) identified therein are able to accelerate and enhance DTH in a concentration-dependent manner. In this study, we describe a novel methodology for analyzing and quantitating this response and demonstrate its use with data comparing drug to placebo. Subjects demonstrating prior sensitivity to a recall antigen (tetanus toxoid) received intradermal injections of tetanus toxoid alone (control) and either dilutions of IMREG-1 plus antigen, or placebo plus antigen, on the volar surface of the forearm. The response, as measured by area of erythema, was calculated and plotted as a function of time. The area under the resulting curve (AUC) was then determined by use of the trapezoidal rule, whereby the area of a trapezoid formed between each sequential pair of time points was calculated. The AUC computed for each site receiving a dilution of IMREG-1 or placebo (test) was compared with the AUC computed at the site that received antigen alone (control) by means of a test to control (T/C) ratio. The respective T/C ratios for designated dilutions of IMREG-1 or placebo provided a basis of comparison between responses to IMREG-1 and to placebo, while also controlling for individual sensitivity in response to antigen. We demonstrate in this study that the enhanced response to IMREG-1 plus antigen is statistically different from that seen with placebo plus antigen. This response, as a function to time, predominantly appears in the 12- to 24-hr period after injection, illustrating the ability of the immunomodulator to accelerate, enhance, and sustain a DTH response. We further conclude that the effect of IMREG-1 in this context is one of immunopotentiation of cell-mediated immunity.

HIV retrotransposon activity and the immunopathogenesis of AIDS.

This article presents the new hypothesis that HIV retrotransposon insertional mutagenesis induces genomic effects that bring about immune dysfunction through disruption, deletion or rearrangement of the genome of the host. This activity may be augmented by the action of most, if not all, the cofactors of HIV-induced disease.

Documentation of an AIDS virus infection in the United States in 1968.

The acquired immunodeficiency syndrome was first recognized as a clinical entity in the United States in the early 1980s; however, the issue of when human immunodeficiency virus, the causative agent of the acquired immunodeficiency syndrome, was introduced into at-risk populations in the United States is unresolved. Previously, we reported the case study of a 15-year-old black male who was admitted to St Louis City Hospital in 1968 for extensive lymphedema of the genitalia and lower extremities. Chlamydial organisms were widely disseminated and isolated from numerous body fluids and organs. Over a 16-month clinical course his condition progressively deteriorated, and at autopsy there was widespread Kaposi's sarcoma of the aggressive, disseminated type. Recently performed Western blot and antigen capture assays on serum and autopsy tissue specimens frozen since 1969 have disclosed that this sexually active teenager was infected with a virus closely related or identical to human immunodeficiency virus type 1. The clinical and immunologic findings together suggest that an immunosuppressive retrovirus existed in the United States before the late 1970s.

Cell surface effects of human immunodeficiency virus.

Cell killing by human immunodeficiency virus (HIV) is thought to contribute to many of the defects of the acquired immunodeficiency syndrome (AIDS). Two types of cytopathology are observed in HIV-infected cultured cells: cell-cell fusion and killing of single cells. Both killing processes appear to involve cell surface effects of HIV. A model is proposed for the HIV-mediated cell surface processes which could result in cell-cell fusion and single cell killing. The purpose of this model is to define the potential roles of individual viral envelope and cell surface molecules in cell killing processes and to identify alternative routes to the establishment of persistently-infected cells. Elucidation of HIV-induced cell surface effects may provide the basis for a rational approach to the design of antiviral agents which are selective for HIV-infected cells.

Cell killing by ultraviolet-inactivated human immunodeficiency virus.

Extensive cell killing and cytopathology were observed within 24 hr after exposure of a clonal cell line of human T-4 lymphocytes (RH9) to culture supernatants containing human immunodeficiency virus (HIV). Ultraviolet-irradiated HIV-containing culture fluids were also capable of killing RH9 cells and of inducing specific cytopathic effects which were indistinguishable from those induced by unirradiated virus-containing preparations. The uv-irradiated HIV was incapable of forming proviral DNA using the endogenous virion genomic RNA as a template. The RH9 cells persistently infected with HIV did not release soluble cytotoxic factors to account for the cell killing observed when culture supernatants were added to uninfected RH9 cells. The fraction involved in cell killing had the hydrodynamic properties of a retrovirus. These results suggest that a virion component is responsible for cell killing by HIV.

Inhibition of interleukin 2 production and expression of the interleukin 2 receptor by plasma from acquired immune deficiency syndrome patients.

Plasmas from acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC) patients were screened for their ability to inhibit mitogen-induced proliferation of normal human lymphocytes. Plasmas from 67% of the individuals examined contained significant suppressive activity. Additional studies on the mechanism of action of the plasma inhibitor demonstrated that it functions as a nonlymphotoxic inhibitor of interleukin 2 production by stimulated human lymphocytes, and that this activity is accompanied by suppression of expression of the cell surface receptor for interleukin 2. A more detailed understanding of the action of this activity may aid in the design of therapy to minimize the contribution of this agent to the immune anergy observed in these patients.

Counter inhibitor: a low molecular weight cytokine derived from human leukocyte dialysates reverses antigen dependent PMN and macrophage migration inhibition.

A low molecular weight component, termed counter inhibitor (CI), has been partially purified from human dialyzable leukocyte extracts. Addition of CI to either a direct leukocyte or macrophage migration inhibition system results in reversal of antigen-induced migration inhibition. CI activity requires the presence of antigen for expression, but does not require that the donor of the CI be immune to the antigen used in the migration inhibition assay. Reversal of migration inhibition by CI appears to be a consequence of its ability to prevent PMNs or macrophages from responding to lymphokines which induce migration inhibition.

Isolation from murine myeloma and leukemia cells of a selective inhibitor of DNA polymerases.

An inhibitor of two ribopolymer-transcribing DNA polymerases can be isolated from MOPC-21 myeloma tumors, from the sera of mice bearing these tumors, or from MCDV-12 ascitic leukemia. The peritoneal fluid of mice bearing the latter neoplasm is also a source of the inhibitor. The inhibitor is a small DNA molecule which displays inhibitory activity in both double- and single-stranded form.