The human immunodeficiency virus (HIV) continues to plague the world, with nearly 37 million people living with the virus today. Although antiretroviral therapy has somewhat contained the virus by “prolonging survival times, reducing viral load and alleviating suffering,” it remains unaffordable for most of the developing world (Pan, 2013). A recent study performed by Professor Shokrollah Elahi and his team at the University of Alberta identified a drug that may be effective from both a medicinal and economic standpoint. In a recent article in Aids, Elahi and colleagues explain how the drug induces resistance to the HIV virus via gene expression.
A major indication of acquired immunodeficiency (AIDs) virus is the depletion of white blood cells within the body known as CD4+ T-cells. This occurs by a process known as pyroptosis, in which CD4+ T-cells release inflammatory signals that cause uncontrolled cell death. Massive CD4+ T-cell destruction occurs in the early stages of infection, although disease progression can take many years. In an attempt to counter this effect, the body normally releases memory CD4+ T-cells to preserve the immune response; however, this process is ineffective in an individual with HIV/AIDS because the immune system is not able to restore a stable population of these cells. Thus, immune deficiency appears to be linked with the dynamics of T-cell population within the body.
In an attempt to counter this effect, the body normally releases memory CD4+ T-cells to preserve the immune response; however, this process is ineffective in an individual with HIV/AIDS because the immune system is not able to restore a stable population of these cells.
The current antiretroviral therapy for HIV has significantly improved survival times for HIV-infected individuals. Current treatments suppress viral replication and restore CD4+ memory T cells in the body. However, in many HIV-affected individuals the treatment fails to restore pre-infection CD4+ T-cell levels.
Elahi used Green Fluorescent Protein (GFP), which fluoresces when the target gene is expressed, to investigate gene expression in CD4+ T-cells. They spliced GFP into the region of the DNA that expresses the p24 gene, which enables the HIV virus to insert into its host (resting, non-virus replicating CD4+ T- cells). In the presence of a drug known as atorvastatin, they observed that there was a remarkable decrease in the expression of the p24 gene in the CD4+ T-cells, indicating reduced HIV insertion. In the absence of atorvastatin, these cells underwent pyroptosis, eventually resulting in cell death.
This is a major breakthrough in the scientific community because previous treatments largely targeted active, replicating CD4+ T-cells. Activated CD4+ T-cells comprise a major reservoir for HIV infection, because the virus is efficiently able to replicate inside these cells. On the other hand, resting CD4+ T-cells are infected by HIV, but are not responsible for actively producing HIV. However, once these cells are reactivated, the virus is able to replicate. Treatments such as antiretroviral therapy, are ineffective for many individuals because they are unable to target the reservoir of resting CD4+ T-cells. Now scientists have identified a new treatment that inhibits the ability of HIV to expand in CD4+ T-cells.
Elahi also observed the impact of atorvastatin on receptors within CD4+ T-cells. He identified that the expression of the CCR5 receptor, which allows the HIV to bind to an active, replicating CD4+ T-cell, is downregulated by nearly 60-80% compared to a cell that is untreated. He also observed that the cell surface area that is populated by the CCR5 receptor decreased substantially, reducing HIV infection rates in active T-cells. On the other hand, the drug upregulates the expression of a receptor known as TIGIT, which prevents the HIV virus from binding to a CD4+ active T-cell due to its increased surface area. Thus, atorvastatin’s mechanism includes the ability to regulate the abundance and distribution of cell surface receptors on T-cells in order to limit HIV binding.
Thus, atorvastatin’s mechanism includes the ability to regulate the abundance and distribution of cell surface receptors on T-cells in order to limit HIV binding.
Not only does atorvastatin reduce infection among CD4+ cells, but it may also serve as a preventive measure. Elahi discovered that atorvastatin upregulated the p21 gene, which created resistance against HIV. Upon inserting a p21 inhibitor into the cells, they found that the protein encoded by the p21 gene degraded in the presence of enzymes known as ubiquitin, and that the CD4+ T cells were no longer able to maintain their resistance against the virus. Thus, if scientists expand their research on the regulation of the p21 gene and atorvastatin, it may lead to more effective preventive care against HIV.
Unfortunately, many economic barriers serve as major limitations to HIV prevention and treatment in poorer countries.
The ongoing research in this field is promising, especially because HIV/AIDS is one of the most devastating pandemics in recorded history. Unfortunately, many economic barriers serve as major limitations to HIV prevention and treatment in poorer countries. For countries in sub-Saharan Africa, the cost of HIV treatment may rise to nearly three times its GDP. Swaziland’s economic growth is projected to decrease until 2017, limiting health care spending. In addition, external borrowing does not seem to be an option because many of the African countries are in a significant amount of debt. However, atorvastatin could be cost-effective because it can provide additional benefits and act as a preventative measure against HIV infection for many patients. The study by Elahi demonstrates that it can serve as an antiretroviral therapy by targeting the active CD4+ T-cells. According to the study, it also targets resting CD4+ T-cells and decreases susceptibility to infection. Thus, with funding from developed countries, atorvastatin could substantially lower HIV infection in developing countries in the future. As scientists acquire more knowledge of the pathogenesis of the disease, research should be aimed towards cheaper treatment and prevention, with hopes of improving the outcomes of HIV victims.
Elahi, S., Weiss, R. H., & Merani, S. (2016). Atorvastatin restricts HIV replication in CD4 T cells by upregulation of p21. Aids, 30(2), 171-183.
Other Information Gathered From
HIV and AIDS in sub-Saharan Africa regional overview | AVERT. (n.d.). Retrieved January 28, 2016, from http://www.avert.org/professionals/hiv-around-world/sub-saharan-africa/overview
Pan, X., Baldauf, H., Keppler, O. T., & Fackler, O. T. (2013). Restrictions to HIV-1 replication in resting CD4 T lymphocytes. Cell Research, 23(7), 876-885.