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Twelve healthy, anal-receptive, homosexual Caucasian males who were seronegative for HIV antibody were typed for HLADR antigens. Flow cytometry was used to immunophenotype peripheral blood lymphocytes bearing the CD4, CD8, LEU7, and combined CD8 and LEU7 antigens. These individuals had reported a large number of sexual partners within a five-year period preceding this study. Each individual was assigned a score based on the Hardy- Weinberg frequency of their HLA-DR phenotype in the Caucasian population. The larger the value of this score, the more common the HLA-DR phenotype; the smaller the score, the rarer the phenotype in the population at large. A significant inverse correlation was observed between this score and the proportion of lymphocytes with CD8 and LEU7 antigens. Lymphocytes bearing these two antigens have in vitro suppressor activity and are elevated in patients with human immunodeficiency virus (HIV) infection. The inverse association between CD8+/LEU7+ cells and frequency of HLA-DR phenotypes is consistent with the hypothesis that individuals with rarer phenotypes whose partners are drawn from the population at large are more likely to be challenged during anal insemination, which results in immunosuppression (alloantigenic challenge hypothesis). On the other hand, it is possible that an association exists between certain HLA-DR phenotypes and immune status. Although these observations were made in a very small sample, we believe that the strength of this association provides justification for further investigation into the possibility that alloantigenic challenge may increase the risk for infection, if exposed to HIV, and augment the immunosuppressive action of HIV once significant infection has occurred.