Inhibition of HIV-1 Latency Reactivation by Dehydroepiandrosterone (DHEA) and an Analog of DHEA

Abstract

The initial infection with human immunodeficiency virus type 1 (HIV-1) in most individuals usually results in the establishment of a latent or chronic infection before eventual progression toward acquired immunodeficiency syndrome. HIV-1 can also establish a latent or persistent infection in some T cell lines that show minimal constitutive virus expression. However, activation of the T cell lines leading to enhanced HIV-1 replication can be induced by antigens, mitogens, and cytokines (tumor necrosis factor α [TNF-α], interleukin 1, and interleukin-2). Various gene products from other viruses (HTLV-1, HSV, EBV, CMV, HBV, and HHV-6) can also enhance HIV-1 long terminal repeat (LTR)-driven reporter gene activity. On the basis of these observations, it has been proposed that reactivation of latent HIV-1 harbored in chronically infected T lymphocytes, monocytes, or macrophages plays an important role in the pathogenesis of AIDS. So far, there are no drugs or therapy available that can provide protection against HIV-1 latency reactivation. ACH-2, derived from a human T cell line (CEM), is chronically infected with HIV-1, with low levels of constitutive virus expression. ACH-2 can be converted to productive infection by stimulation of the cells with 12-O-tetradecanoylphorhol-13-acetate (TPA), mitogen or cytokines (TNF-α), or infection with HSV. Therefore the ACH-2 cell line is a good candidate for studying the effects of drugs on HIV-1 activation. Previously, we have reported that DHEA and synthetic analogs of DHEA can be modest inhibitors of HIV-1 IIIB replication in phytohemagglutinin-stimulated peripheral blood lymphocyte cultures. Here we report that DHEA and a synthetic analog of DHEA, 8354, can also reduce HIV-1 latency reactivation in the ACH-2 cell line. The inhibitory effect is not due to cytotoxicity of these drugs. Treatment with DHEA or 8354 resulted in downregulation of HIV-1 latency reactivation in a TPA- or TNF-α-stimulated ACH-2 cell line as measured by syncytium formation and accumulation of reverse transcriptase activity. The mechanisms of inhibition are not clear, but evidence suggests that reduction of NF-κB activation plays a role.