HIV-1 and SIVmac Repression by Retinoic Acid in Monocyte Cell Lines and Macrophages, and HIV-1 Repression by Interleukin-16 in T Cell Lines: A Dissertation

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Document Type

Doctoral Dissertation


Graduate School of Biomedical Sciences, Program in Immunology and Virology


Tretinoin; Interleukin-16; Monocytes; Macrophages; HIV-1; Academic Dissertations


Human immunodeficiency virus type-1 (HIV-1) is the etiologic agent of acquired immune deficiency syndrome (AIDS). In most cases HIV-1 infection in humans, leads to AIDS, which is characterized by opportunistic infections leading to death. The role various infectable cell types play in the course of infection is unclear. However, it is becoming increasingly more evident that cells of the monocyte/macrophage lineage are very important at several stages of disease. They are involved in the transmission, establishment and dissemination of infection as well as the AIDS related complication of dementia and pulmonary dysfunction. The regulation of virus expression in monocyte/macrophages while maintaining normal cell function would be of great benefit.

Retinoic acid (RA) is a bioactive metabolite of vitamin A, an essential nutrient, and acts as a transcriptional regulator of many genes. RA is also a potent modulator of myeloid cell differentiation and function; it is currently used clinically. Clinical data indicate that serum vitamin A levels are inversely correlated with various aspects of HIV-1 induced disease. Furthermore, work done by several groups has demonstrated that RA directly modulates HIV-1 replication in cells of the myeloid lineage. RA is capable of either stimulating or repressing HIV-1 replication depending on the cell type used. This dichotomy appears to depend upon the differentiation state of the cells. Changes in differentiation states are associated with the altered expression of many cellular proteins including transcriptional regulators. Experiments indicate that the TATA box of HIV-1 is required for full levels of gene expression.

I hypothesized that RA was modulating replication at the level of LTR-directed gene expression, and that the differentiation state of the cell influences the RA modulation. This thesis demonstrates that the RA effect is at the level of gene expression mapping to a promoter proximal element for both HIV-1 and simian immunodeficiency virus (SIVmac.) The ability of RA to stimulate or repress expression depends upon the differentiation state of the cells. Using U937 promonocyte cells, I demonstrate that RA increases SIVmac and HIV-1 transcription. When THP-1 monocytes or primary macrophages are used, I demonstrate that RA induces repression of HIV-1 and SIVmac. This RA modulation of expression is associated with altered complexes binding to the promoter proximal regions of HIV-1 and SIVmac.

There has been a great deal of interest in CD8+ T cell derived factors which modulate HIV-1 replication. Work done by Levy and colleagues over a decade ago demonstrated that factors secreted by CD8+ T cells could block HIV-1 replication. Others have shown that the β-chemokines, released by activated CD8+ T cells, can block the entry of HIV-1 into macrophages. Center and colleagues identified a lymphocyte chemoattractant factor as IL-16. IL-16 is released by activated CD8+ T cells and it's receptor is CD4. IL-16 induces the migration of CD4+ T lymphocytes, and has been shown to activate many signaling pathways in CD4+ T lymphocytes.

Kurth et al. demonstrated that IL-16 blocked the replication of HIV-1 in CD8+ depleted PBMC. In these experiments, it was not determined whether IL-16 was blocking viral entry (preventing viral binding to CD4) or whether IL-16 had inhibitory effects on subsequent steps in the virus life cycle. While IL-16 and HIV-1 share CD4 as their receptor, IL-16 binding was mapped to a separate epitope on CD4 from the HIV-1 binding site. Therefore I began experiments to determine how IL-16 regulates HIV-1 expression in T cells.

I hypothesized that the IL-16 signaling pathway is involved in repressing HIV-1 gene expression. Experiments presented here demonstrate that IL-16 represses LTR-directed gene expression in T cell lines in a CD4 dependent manner. The IL-16 mediated repression is dependent on a DNA binding site contained within the viral core enhancer region. The data are also consistent with IL-16 inducing a repressor which binds within or adjacent to the HIV-1 core enhancer region.


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