If left untreated, the human immunodeficiency virus (HIV) usually leads to AIDS 10-15 years after infection. AIDS is a serious disease of the immune system that leads to barely controllable infections with microorganisms or malignant tumors due to a loss of function of the T4 helper cells. According to the UNAIDS organization, almost 37 million people worldwide are living with an HIV infection and are potential virus carriers. The virus enters the host cell by interacting with its main receptor CD4 and (depending on the cell) one of the two coreceptors CCR5 and CXCR4. Both co-receptors are membrane-bound chemokine receptors that are down-regulated by the cell surface after binding a lingand (SDF-1, MIP-1 or RANTES).
Genetic variants (polymorphisms) both in the chemokine receptors and in the chemokines themselves are associated with individual differences in susceptibility to HIV infection and response to HIV therapy. Approximately 25-30% of HIV-infected long-term survivors (>15 years without AIDS) are carriers of the CCR5-delta32bp polymorphism (rs333). Although 1-5% of the uninfected, HIV-exposed population are homozygous for this variant, this 32bp deletion is rarely found in HIV-infected individuals (<0.1%). Heterozygosity also appears to offer some protection against HIV infection, as there are fewer heterozygotes in the HIV-1-infected population than in the normal population. The onset of AIDS is also delayed by 2-4 years. In addition, the V64I polymorphism in the membrane receptor CCR2 (rs1799864) and the 3'A polymorphism in the soluble cofactor SDF1 (rs1801157) appear to influence the risk of infection and the course of the disease, which explains the very different individual clinical courses. The protective effect of SDF1, for example, is particularly pronounced in individuals who have been infected with HIV-1 for a long time. By determining the genetic variants, it is possible to derive a statement about the individual disposition for HIV infection and therapy management.
The HLA system also appears to play a role in the progression of AIDS. Patients who are carriers of the HLA-B*35 subtypes B*35:02/35:03/35:04/53:01 (so-called B*35-PX allele) have a more severe course than patients who are carriers of the B*35:01 type (so-called B*35-PY allele). It is possible that the presentation of viral epitopes via B35-PX and the resulting immunological synapse leads to more effective transmission of the virus to activated T cells or to less effective control of infected cells. In carriers of the HLA-B*57:01/57:03 subtype, the course of HIV infection is delayed, probably due to an effective presentation of viral epitopes. At the same time, the B*57:01 allele is important for therapy, as 48% to 61% of patients with this subtype develop hypersensitivity to the nucleoside analog abacavir, compared to 0% to 4% of patients who are HLA-B*57:01 negative. According to the Federal Institute for Drugs and Medical Devices, every HIV-infected patient should be tested for the presence of the HLA-B*57:01 allele before starting treatment with abacavir. Patients with HLA-B*57:01 should not use abacavir.
References
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