Abstract
Tenofovir (TFV) has been widely used for pre-exposure prophylaxis of HIV-1 infection with mixed results. While the use of TFV in uninfected individuals for prevention of HIV-1 acquisition is actively being investigated, the possible consequences of TFV exposure for the HIV-target cells and the mucosal microenvironment are unknown. In the current study, we evaluated the effects of TFV treatment on blood-derived CD4+ T cells, monocyte-derived macrophages and dendritic cells (DC). Purified HIV-target cells were treated with different concentrations of TFV (0.001-1.0 mg/ml) for 2 to 24hr. RNA was isolated and RT-PCR was performed to compare the levels of mRNA expression of nucleotidases and pro-inflammatory cytokine genes (MIP3α, IL-8 and TNFα) in the presence or absence of TFV. We found that TFV increases 5’-ecto-nucleotidase (NT5E) and inhibits mitochondrial nucleotidase (NT5M) gene expression and increases 5’ nucleotidase activity in macrophages. We also observed that TFV stimulates the expression and secretion of IL-8 by macrophages, DC, and activated CD4+ T cells and increases the expression and secretion of MIP3α by macrophages. In contrast, TFV had no effect on TNFα secretion from macrophages, DC and CD4+ T cells. Our results demonstrate that TFV alters innate immune responses in HIV-target cells with potential implications for increased inflammation at mucosal surfaces. As new preventive trials are designed, these findings should provide a foundation for understanding the effects of TFV on HIV-target cells in microbicide trials.
Highlights
Three decades after the discovery of HIV, with no preventive vaccine available and limited success with microbicides, the HIV pandemic continues to spread with more than 30 million people living with HIV and almost 2.5 million new infections in 2011 [1]
The present study investigated the effects of TFV with respect to its ability to modulate 5’-nucleotidase gene expression, nucleotidase biological activity and chemokine production by CD4+ T cells, macrophages and dendritic cells (DC), the main target cells for HIV-1 infection
We found that TFV altered expression of two of the seven 5’-nucleotidase genes, NT5E (CD73) and NT5M, but had no effect on any of the intracellular 5’-nucleotidases
Summary
Three decades after the discovery of HIV, with no preventive vaccine available and limited success with microbicides, the HIV pandemic continues to spread with more than 30 million people living with HIV and almost 2.5 million new infections in 2011 [1]. Microbicides are compounds that can be applied topically and/or taken orally to prevent sexual transmission of HIV and other sexually transmitted infections (STI) [2]. TVF can be taken orally or administered topically into the vagina in a gel form. The CAPRISA 004 trial (Centre for the AIDS Program of Research in South Africa) tested the efficacy of the vaginal gel containing TFV in preventing HlV-1 acquisition, and found a 39% reduction in infection when the gel was applied before and after sexual intercourse [4]. The VOICE (Vaginal and Oral Interventions to Control the Epidemic) trial, in which the TFV gel was applied to the vagina or taken orally on a daily basis, was discontinued due to lack of efficacy [5]. Lack of adherence was a main factor involved in the failure of the VOICE trial, the possible contribution of changes in the biology of HIV-target cells induced by TFV needs to be explored
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