2nd National Conference Human Retroviruses and Related Infections Washington, DC - January 29 - February 2, 1995

Natl Conf Hum Retrovir Relat Infect 1995 Jan 29-Feb 2;2: (abstract no. 34)

Zhu M, Duan L, Pomerantz RJ
The Dorrance H. Hamilton Laboratories, Jefferson Medical College Thomas Jefferson University, Philadelphia. PA

The molecular mechanisms involved in the replication of human immunodeficiency virus type 1 (HIV-1) may differ in various cell types and with various exogenous stimuli. As we have previously reported, astrocytic glial cells which can support HIV-1 replication in cell cultures and may be infected in vivo, are demonstrated to provide a cellular milieu in which TAR-mutant HIV-1 viruses may replicate. In further support of this molecular model, human hepatocytes, which can be infected by HIV-1, were used for this study. Using transfections of various TAR, Tat, or TAR/Tat mutant HIV-1 proviral constructs, we demonstrate TAR-independent replication in unstimulated human hepatocytes, via HIV-1 p24 antigen production. Remarkably, in human hepatocytes, HIV-1 replication is not only independent of TAR but also is independent of Tat expression. As a control, a Rev-mutant proviral construct was also transfected into hepatocytes. No viral replication can be detected in these Rev-mutant experiments. We further demonstrate, using EMSA (electrophoretic mobility shift assays), that human hepatocytes contain novel endogenous unidentified proteins which can trans-activate HIV-1 LTR-directed gene expression through binding to the TAR region and down-stream of the TAR region. This alternative regulatory pathway of TAR- and Tat- independent viral production may be important in certain cell-types, for therapies which seek to perturb Tat-TAR binding as a strategy to interrupt the viral lytic cycle.

Keywords: Animals, Astrocytes, Gene Products, tat, Genes, tat, HIV Long Terminal Repeat, HIV-1, Hepatocytes, Humans, Liver, Liver Extracts, Neuroglia, Transfection, genetics

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1995-01-29
34

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