CCR5Delta32 and susceptibility to HIV infection

CCR5 acts as an important co-receptor used by HIV for cellular entry into TCD4+ lymphocytes. The presence of a natural 32 base pair deletion in the CCR5 gene, known as CCR5Delta32, produces a truncated receptor that is not expressed on the surface of lymphocytes, thus preventing viral access and conferring resistance to infection.

The HIV virus continues to be one of the major global public health problems involving 1.5 million newly diagnosed individuals in 2020, and a mortality of 680000 during the same year, despite improvements in transmission measures and knowledge of HIV biology. HIV invades and destroys TCD4+ (also called Th) lymphocytes and to a lesser extent other cells of the immune system. Over time the infection progresses to immune system failure, allowing opportunistic infections and life-threatening cancers to develop, in the form of the disease known as Acquired Immune Deficiency Syndrome (AIDS).

To invade Th lymphocytes, HIV-1 (the most frequent) can employ the co-receptors CCR5, CXCR4, or both. However, the amount of CCR5 on the surface of CD4+ T cells is a key regulator of cellular unafectability, and a critical determinant of disease progression. CCR5 is a receptor for chemokines, molecules responsible for the attraction of other cell types to certain parts of the body, mainly involved in immune surveillance and inflammatory response.

The expression of the CCR5 co-receptor on the cell surface can be prevented by a natural genetic variant consisting of a 32 base pair deletion. This variant generates a non-functional entry co-receptor for HIV that does not favor fusion between the virus and the target cell membrane, thus preventing infection and pathogenesis. Carriers of two copies (1% of Europeans) are highly protected from infection, although it is not complete, as rare cases of infection have been reported in these individuals. In the case of presenting a single copy of this variant, it seems to be associated with a reduced viral load, a slower rate of lymphocyte loss and thus a delayed progression to AIDS. In addition, they would show a better virological response to antiretroviral therapy.

CCR5Delta32 is mainly observed in European populations (10%), especially in the north, such as Finland and Russia (16%), Iceland (15%), Sweden (14%), Denmark (13%), northern France (14%) or Norway (10%), while it has a lower incidence in the south and the Mediterranean, such as Spain (7%), Italy (5% 6%), Portugal (5.2%) or Sardinia (4%). It has also been observed in other populations of European descent related to migratory movements in South Africa (13%) or Chile (12%), as well as in African Americans, although with a low incidence (2%) and in some Jewish populations, especially Ashkenazi (11-20%). It is practically absent in sub-Saharan Africans, Asians and Native Americans.