For HIV entry to take place, the virus must bind to cell receptors so that it can be brought into the cell. In brief, HIV infects white blood cells, because the proteins HIV binds to for entry are specific to those cells. HIV entry occurs after HIV binds to a protein known as CD4 as well as to a co-receptor - which varies by the strain of the virus. The co-receptor is generally either CCR5 or CXCR4.
Scientists actually classify immune cells by looking at the proteins expressed on their surfaces. Thus T-cells are cells that are CD4 or CD8 positive. CD4 T-cells can then be further subdivided into classes by what other proteins they express. Not all CD4 cells have the same function, and those functions are controlled by the different proteins in the cell and on its surface. This variation in proteins is also why different CD4 cells also have different susceptibility to HIV infection. HIV only infects those T-cells that express both CD4 and CCR5 or CXCR4.
CCR5 and CXCR4 are cytokine receptors. Cytokines are small proteins used for communication by the immune system, controlling everything from antibody production to regulation of certain types of blood cells. Cytokine receptors are actually present on numerous types of cells; they can be found on any type of cell that the immune system might need to communicate with. However, the two cytokine receptors that have been shown to be important for HIV entry - CCR5 and CXCR4 - only put cells at risk of infection when CD4 is also present.
HIV entry into white blood cells requires the virus binding to both CD4 and, depending on the HIV strain, either CCR5 or CXCR4. CCR5 HIV strains seem to be somewhat more common than CXCR4 strains, which may potentially be useful for prevention and treatment since CXCR4 is more critical for immune function and can not be safely blocked. In contrast, CCR5 is a popular target for drug development. Scientists have spent years developing numerous CCR5 blockers to help reduce the transmission of HIV or slow its progress. The first CCR5 antagonist - Maraviroc - was approved in the United States in 2007.
There is also another side to the story of the CCR5 HIV link. Research into the relationship between CCR5 and HIV has led to some fascinating discussions about the probable history of the HIV epidemic and why some populations seem to be at greater or lesser risk of HIV infection. In particular, there has been a great deal of interest in the role of CCR5 mutations in resistance to HIV infection.
Scientists have found that individuals with certain mutations in the CCR5 gene - mutations that are more common in European populations - are resistant to infection with any of the CCR5 HIV strains but not to infection with the CXCR4 HIV strains. There has also been research suggesting that other diseases, such as smallpox, that interact with the CCR5 receptor may also affect individuals' susceptibility to CCR5 HIV, and that the distribution of these diseases across the globe may have affected the shape of the HIV epidemic.
The CCR5-related changes in HIV susceptibility are mediated by the role of CCR5 in HIV entry, but they have not only inspired research in prevention and treatment. Research based on the CCR5 HIV link has also provided scientists with useful insights about the nature of HIV disease that go beyond the basics of HIV biology and extend into the role of public health decision making in the spread of epidemics.
Alkhatib G. The biology of CCR5 and CXCR4. Curr Opin HIV AIDS. 2009 Mar;4(2):96-103.
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Moore JP et al. The CCR5 and CXCR4 Coreceptors—Central to Understanding the Transmission and Pathogenesis of Human Immunodeficiency Virus Type 1 Infection. AIDS Res Hum Retro. 2004 January; 20(1): 111-126
Weinstein RS et al. Significantly reduced CCR5-tropic HIV-1 replication in vitro in cells from subjects previously immunized with Vaccinia Virus. BMC Immunology 2010, 11:23