Interactions between HIV-1 and iron

Infection with HIV-1 leads to AIDS. Around the world, the number of people infected with HIV-1 is increasing, and current forms of medicine do not adequately control the spread of the virus. There are clues in previous scientific studies suggesting that HIV-1 needs iron to grow efficiently, and we have found evidence that HIV-1 itself manipulates people?s cells in order to obtain this iron. The research proposal has two parts; the first is to find out how HIV-1 affects the handling of iron by infected cells. The second is to find out if deliberately altering how infected cells obtain iron can reduce the spread of HIV-1. Together the two sections should increase our understanding of the HIV-1/AIDS problem and may suggest more effective methods of controlling the virus.

HIV-1 infections continue to increase; new methods of controlling HIV-1 are desirable. Iron deposits in macrophages are frequently observed in HIV-1 infected patients, and the amount of iron correlates with mortality. Iron favours HIV-1 replication through various mechanisms including NFkappaB activation and nucleotide synthesis. Previously we found the Nef protein of HIV-1 interacts with the macrophage expressed haemochromatosis protein HFE, indicating HIV-1 actively modulates iron metabolism for its own benefit. The first section of this proposal is to study precisely how HIV-1 alters iron transport by macrophages. Macrophages acquire iron from serum transferrin and haemoglobin, and recycle 30mg/day iron into the blood to supply the bone marrow. The iron is released back into serum by the iron efflux protein ferroportin, which is held in check by its inhibitor peptide, the key iron regulatory hormone hepcidin. Experiments will test how HIV-1 affects macrophage iron uptake from transferrin and haemoglobin, iron release via ferroportin, and if HIV-1 regulates the synthesis of hepcidin. The second complementary section of the proposal investigates if modulating macrophage iron levels experimentally affects HIV-1 replication. In particular a panel of iron chelators will be used to in an attempt to reduce HIV-1 growth while not adversely influencing cell viability. The overall aim of the project is to understand how HIV-1 and macrophage iron transport influence each other, and the data obtained may suggest new types of intervention to reduce HIV-1 growth.