Sickle-cell disease (SCD) is a hereditary disorder that affects approximately 100,000 people in the USA, primarily of African descent. Single E6V mutation in b-globin gene leads to the production of hemoglobin S (HbS) and development of chronic hemolytic anemia. Our recent analysis of a national hospital discharge survey showed an association of SCD with lower frequency of HIV-1 diagnosis (odds ratio 0.33) suggesting that SCD might offer a protection from HIV-1. We hypothesize that hemolytic anemia in SCD leads to inhibition of HIV-1 transcription through the activation of heme-, iron and oxygen-dependent pathways. Heme induces transcription of iron regulatory genes in macrophages, including heme oxygenase-1 (HO-1), ferritin and iron export protein, ferroportin leading to the increased iron export and reduction of cellular iron. In SCD, expression of HO-1 is increased whereas expression of hepcidin that regulates internalization and degradation of ferroportin is decreased (and also our preliminary data). Induction of HO-1 by heme inhibits HIV-1 infection in macrophages and T-cells in vitro and in HIV-1 infected humanized mice. We have previously shown that HIV-1 transcription is inhibited by iron chelators or ferroportin. Iron chelators inhibi cellular activities of CDK2 and CDK9, both critical for HIV-1 transcription. Our recent findings demonstrate that CDK2 directly phosphorylates CDK9's Ser90 resulting in the activation of HIV-1 transcription. We, therefore, hypothesize that increased blood heme concentration, ischemia and decreased hepcidin will elevate levels and activity of HO-1 and ferroportin, reduce cellular iron and upregulate HIF-1 pathway leading to the induction of Egr-1, p21 and inhibition of CDK2 and CDK9. Upregulation of this protein network will lead to the inhibition HIV-1 transcription and viral replication in SCD condition.
In Specific Aim 1, we will analyze HIV-1 inhibition in SCD and SCD trait.
In Specific Aim 2, we will analyze molecular mechanisms of HIV-1 inhibition in SCD and SCD trait.
In Specific Aim 3, we will analyze novel inhibitors HO-1, ferroportin and hepcidin pathways in vivo. Collectively, our proposed research is designed to elucidate the molecular mechanisms of HIV-1 inhibition in the settings of SCD and SCD trait. Our studies will uncover novel mechanisms of HIV-1 regulation by heme, ferroportin, hepcidin, and iron. Our proposed studies are significant because they may lead to novel therapeutics, such as the use of hemin and iron chelators.
Sickle Cell Disease is a hereditary disorder which protects against malaria and may have a protective effect against HIV-1 infection. This is an example of selective human mutation that is restrictive to HIV-1. The proposed research is relevant to public health because it is aimed at understanding the mechanism of protection against HIV-1 in the setting of Sickle Cell Disease. Uncovering the mechanism of HIV-1 resistance is likely to generate novel therapeutic approaches, and thus the proposed research is relevant to the NIH mission that pertains to a reduced vulnerability of the population to viral infections that include infection with HIV-1.
|Kumari, Namita; Iordanskiy, Sergey; Kovalskyy, Dmytro et al. (2014) Phenyl-1-Pyridin-2yl-ethanone-based iron chelators increase I?B-? expression, modulate CDK2 and CDK9 activities, and inhibit HIV-1 transcription. Antimicrob Agents Chemother 58:6558-71|