Mutations that Prevent HIV Infection

Various ethnic populations have been of interest because of an apparent resistance to human immunodeficiency virus (HIV) infection among some individuals. Receptors on the T cells have been considered potential genetic factors in this resistance.

HIV is a retrovirus spread by body fluids when they come into contact with other body fluids – blood to blood contact, breast feeding, and sexual transmission. HIV attacks and infects the cells of the immune system, particularly T cells, based on the recognition of cell surface proteins by the virus. Viral replication destroys the infected cells, spreading HIV throughout the system to further infect the cells of the immune system. Eventually, the T cells are depleted and immunodeficiency allows opportunistic infections to take hold in the infected individual. The occurrence of these opportunistic infections in the presence of anti-HIV antibodies and/or a low white blood cell count, the precursors to T cells, is defined as acquired immune deficiency syndrome (AIDS), the final stage of HIV infection. There is no cure for the disease and it manifests differently in different patients. The only current treatment is antiretroviral therapy, which targets the enzymes specific to HIV replication. AIDS killed an estimated 2 million people in 2008, the last year for which data has been released by UNAIDS. At that time, an estimated 33 million people worldwide were living with HIV, 2.1 million of which were children, and 2.7 million new infections occurred worldwide.

Individuals who are resistant to HIV infection fall into two groups: highly exposed, sero-negative (ESN), and long-term non-progressors (LTNP). Those in the ESN group are not infected with HIV despite repeated exposure to the virus, sometimes in the form of an HIV-positive partner. The individuals carrying such a designation fall into many categories of exposure that have made it difficult and unsuccessful to determine the genetic basis of their protection. The LTNP group includes less than 2 percent of HIV-positive individuals. The individuals in this group are actually not resistant to HIV infection, but are resistant to the progression of the disease to AIDS. The patients are infected with HIV, but have an almost indiscernible viral load and no immune deficiency.

Some genetic similarities between ESN and LTNP backgrounds are of interest in the search for new therapies, including the delta32 mutation of CCR5, the R5-HIV co-receptor, other CCR5 variants and polymorphisms (though some also result in increased progression), CCR2 variants, CX3CR1 variants, the CXCR1 and CXCR2 locus, and altered CXCR4 binding.

CCR5 is a chemokine receptor on macrophages that is recognized by HIV and used as a co-receptor to infect the immune cells. Macrophages are targeted by certain strains of HIV, and chronic HIV infection upregulates CCR5, increasing the rate of infection of new macrophages. The delta32 mutation, which is thought to be Scandinavian in origin, leaves the CCR5 receptor functional, but it is no longer recognizable by HIV. In the few individuals with the mutation, macrophage-tropic HIV strains cannot infect the cells even if they are exposed to the virus. The CXCR receptors are co-receptors on T cells, and CXCR4 was the first to be recognized. Both CCR5 and CXCR4 are co-receptors for HIV binding the main receptor, CD4, on the immune cells the virus intends to infect.

Studies are currently attempting to find ways to pharmacologically block the co-receptors to utilize what has been learned from the genetic protections against HIV, that is prevent the spread of the virus in the exposed individual. Those who possess a mutation may be less susceptible to infection with particular HIV strains, but can still contract other HIV strains. Prevention is still necessary among all populations.

Studies of interest:

Arenzana-Seisdedos and Parmentier. Genetics of resistance to HIV infection: Role of co-receptors and co-receptor ligands. Seminars in Immunology, 18, 2006.

Piacentini et al. Genetic correlates of protection against HIV infection: The ally within. Journal of Internal Medicine, 265, 2008.