Novel biological means of control of HIV and AIDS.
Int Conf AIDS 1996 Jul 7-12; 11:8 (abstract no. Mo.A.260) Gallo RC; Institute of Human Virology, Medical Biotechnology Center, University of Maryland at Baltimore, Baltimore, MD, USA. Fax: 410-706-1952. E-mail: gallo@umbi.umdl.edu.
1) The C-C Cytokines (Rantes, MIP-1alpha, and MIP-1'): These are a subset of chemokines which in turn are a subset of cytokines. Their known role was in inflammation. Last year we reported the discovery (Science, 270: 1560, 1995) that these molecules were potent inhibitors of HIV-1 and HIV-2 infection. We noted that the inhibition is virus specific (HIV-1, HIV-2, SIV and not other tested viruses), that it worked against all tested field clinical isolates of HIV-1 but not against some CD4 T-cell line adapted strains (like III-B) but still effective against other such strains like RF and MN (all in cell line cultures since 1983 or early 1984 in our laboratory). These and other results suggested that the mechanism of inhibition may involve HIV entry, a concept and new result which will be discussed in this presentation. Our results and those of others also indicated that these molecules (Rantes, MIP-1alpha, and MIP-1') are produced by CD8+ and CD4+ T-cells and macrophages, and that they are the major if not only significant soluble inhibitory factors produced by CD8+ T-cells. Some have argued against this, and repeatedly emphasized that many cytokines increase or diminish HIV replication, and therefore, presumably there is nothing special about these chemokines. Of course many cytokines affect HIV replication. For example IL-2 in promoting T-cell proliferation, will obviously promote more HIV production, whereas, other cytokines can interfere with IL-2 or with T-cell activation or other cellular events and thereby indirectly inhibit HIV production. In this way and by numerous other possible indirect ways, it is evident that many factors influence HIV replication by their effects on cells. These points are irrelevant to the major issue, i.e., the C-C chemokines are the first soluble molecules P to be discovered which directly and specifically inhibit HIV infection since the discovery of antibodies. Indeed, this statement may be true for any virus, i.e. what other soluble specific inhibitors of any virus are known? Moreover, in less than 6 months of our report, other groups, notably those at New York University (Koup et. al; Nature Medicine 1996); and Zagury et. al (submitted for publication) have provided evidence that it is these chemokines which may be protective against infection in HIV-1 hyper-exposed but never infected people. I conclude that it is a moot and irrelevant point whether the C-C chemokines are the sole or key CD8+ T-cell derived HIV suppressive "factor" described by Levy, but presumably not identified now for more than a decade. Whether other cytokines influence virus production (long known) by effecting a variety of cellular events is irrelevant to the discovery of novel, potent, specific naturally occurring anti-HIV molecules, which are already influencing our understanding of HIV infection. Key colleagues in these studies are: Drs. F. Cocchi, A. DeVico, A. Garzino-Demo, and P. Lusso. 2) hCG At the last AIDS International Conference in Yokohama I reported on our model of Kaposi's sarcoma (KS), (in vitro cultures and in vivo transplanted tumors in immune deficient mice), leading us to conclude that KS tumors are composed of hyperplastic (non-malignant) cells and at least in some cases of advanced KS, of neoplastic cells, both likely to be of activated vascular endothelial cell origin. In the course of these studies (key colleagues in these studies were, Drs. Y. Lundari-Iskander, J. Bryant, P. Gill, P. Hermans, O. Picard, J. Besnier, L. Flammand, and D. Poretz) we found that the hormone of early pregnancy, hCG, a glycoprotein heterodimer consisting of 2 chains (alpha and '), kills KS cells by apoptosis. This led us to clinical collaborations and in turn to several other basic laboratory studies and will be discussed. I will summarize the new results of both the clinical and laboratory studies in this presentation.
Keywords: AEGIS, Acquired Immunodeficiency Syndrome, HIV-1, HIV Infections, Macrophage Inflammatory Protein-1, RANTES, Virus Replication, Chemokines, CC, Chemokines, T-Lymphocytes, Macrophages, Antigens, CD4, HIV-2, Cytokines, Interleukin-2, New York, In Vitro, Animal, Mice, Female, Pregnancy, prevention & control, virology, ICA11
