STRUCTURE OF THE HUMAN MILK INHIBITOR OF HIV BINDING

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We have found that human milk inhibits the binding of gp120, the human immunodeficiency virus (HIV) envelope glycoprotein, to CD4, the human host cell receptor; this binding is thought to be an essential first step in HIV infectivity. The inhibitory activity was not found in bovine milk nor in human sera, but the milks of some other species exhibit variable activity. We propose to purify the HIV inhibitory factor(s) in human milk and to define precisely its biochemical, immunological, and biophysical characteristics. Preliminary biochemical and immunological studies indicate that this inhibitory material in its native state is a macromolecular larger than 250 Kd with an isoelectric point of 9.3-9.6, possibly sulfated and glycosylated, but containing neither mannose nor sialic acid. The specific activity of the inhibitor is at least an order of magnitude greater than dextran sulfate, implying a highly specific and potent mechanism. The active factor is associated with milk macromolecules such as glycoproteins, mucins or glycosaminoglycans. We recently found that a mucin complex isolated from human milk fat globule membrane blocks CD4 binding. Inhibitory activity will be determined by the ability of a sample to inhibit binding of the HIV envelope glycoprotein gp120 (or its monoclonal antibody surrogate, OKT4A) to CD4, and to inhibit the replication of HIV in cultured cells. The structural features of the active macromolecules that are associated with the protective activity will be determined. We will develop a solid phase assay for detection and measurement of the active factor in order to seek alternate sources of materials containing the inhibitory molecule(s). Thus the identification of a new class of compounds with anti-HIV therapeutic potential is the major goal of this project. The studies will also provide information for the assessment of the risk factors associated with perinatal HIV infection. Perinatal transmission of HIV is rapidly becoming a major source of new AIDS cases. Pediatric AIDS usually results in failure to thrive, mental retardation, and death. Although human milk is known to contain immunoglobulin and non-immunoglobulin factors that inhibit several microbial pathogens, it is also known to act as the agent of vertical transmission for certain viruses. Breast milk has been suggested as an agent of HIV transmission, raising concerns regarding breast feeding in populations with high incidence of HIV; however, most epidemiologic evidence indicates no breast-feeding-related increase in the rate of vertical transmission by populations of HIV infected mothers. Thus, defining a specific inhibitor of HIV transmission in human milk might contribute information useful in formulating public health policy, in addition to its potential utility for providing a basis for developing a novel family of therapeutic or prophylactic agents with low potential of host toxicity.