TRANSCELLULAR ACTIVATION OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 LONG TERMINAL REPEAT IN COCULTURED LYMPHOCYTES

One of the unexplained aspects of the progression of AIDS is that immunological abnormalities are detectable before CD4+ T-helper cell depletion occurs (A. R. Gruters, F. (.. Terpstra, R. De Jong, C.J. M. Van Noesel, R. A. W. Van Lier, and F. Miedema, Eur. J. Immunol. 20:1039-1044, 1990; F. Miedema, A. J. Chantal-Petit, F. G. Terpstra, J. K. M. E. Schattenkerk, F. de Wolf, B. J. M. Al, M. Roos, J. M. A. Lang, S. A. Danner, J. Goudsmit, and P. T. A. Schellekens, J. Clin. Invest. 82:1908-1914, 1988; G. M. Shearer, D. C. Bernstein, K. S. Tung, C. S. Via, R. Redfield, S. Z. Salahuddin, and R. C. Gallo, J. Immunol. 137:2514-2521, 1986). In this report, we describe a mechanism by which human immunodeficiency virus type 1 (HIV-1)-infected cells can influence neighboring HIV-1-infected T lymphocytes and uninfected T cells as well. We have examined the interaction of T-cell and macrophage cell lines that are transfected with HIV-1 DNA by using cocultured lymphocytes. The HIV-1 constructs we used lack a functional pol gene and therefore do not produce infectious virus. Cocultivation results in the transcellular activation of the HIV long terminal repeat in the cocultured T cells. This transcellular activation is evident in as little as 3 h of cocultivation, at ratios of HIV-expressing cells to target cells as low as 1:1,000, and is dependent on the Tat-responsive element. The demonstration that a small number of HIV-expressing cells can affect a large number of uninfected bystander cells in a short period of time suggests a mechanism by which global immune dysfunction can precede the high prevalence of infected cells.