Genetic Polymorphisms in the Chemokine and Chemokine Receptors: Impact on Clinical Course and Therapy of the Human Immunodeficiency Virus Type 1 Infection (HIV-1)

Abstract

The natural history and pathogenic processes of infection by the human immunodeficiency virus type 1 (HIV-1) are complex, variable, and dependent upon a multitude of viral and host factors and their interactions. The CCR5-Delta32 allele remains the most important genetic factor known to be associated with host resistance to the HIV-1 infection. However, other mutations in the CCR5, CCR2, CX(3)CR1, CXCL12 (SDF1), and CCL5 (RANTES) genes have been identified and associated with host resistance and/or susceptibility to HIV-1 infection and disease progression. Some studies have also suggested that chemokine receptor gene polymorphisms may affect response to potent antiretroviral therapy. This article reviews the polymorphisms already described in the mutant chemokine receptors or ligands and their impact on the host susceptibility to HIV-1 infection and on the clinical course of the disease, as well as the development of new anti-HIV therapies that takes into account these potential targets in the host. These genetic polymorphisms could be used as genetic markers to detect individuals at higher risk of developing either a faster disease progression or therapeutic failure. Once these individuals are identified, therapeutic strategies based on either different, more aggressive drugs or combinations of drugs can be used, either alone or in combination with shorter intervals for therapeutic monitoring. Pharmacogenetics is very likely to underlie future therapies for HIV-1 infection, and current patients with multi-resistance to the existing antiretroviral agents could also benefit from this approach. These developments also underscore the importance of continuing the investigation of new therapies targeted to the host in order to inhibit the HIV-1 entry into the host cells.

A Single-Amino-Acid Substitution in the Tvb S1 Receptor Results in Decreased Susceptibility to Infection by Avian Sarcoma and Leukosis Virus Subgroups B and D and Resistance to Infection by Subgroup E In Vitro and In Vivo

“…This is the first reported example of a mutation in the ASLV receptors that results in a quantitative effect on ASLV susceptibility and pathogenesis. Various levels of resistance to human immunodeficiency virus type 1 infection have been reported that are explained by polymorphisms in the CD4 receptor and/or the viral coreceptors that result in a significant reduction in the efficiency of the human immunodeficiency virus type 1 glycoprotein interaction with the mutant receptor (23). Therefore, one mechanism whereby this initial interaction between the receptor and virus required for entry can cause selective pressure on the virus population is the interaction of the viral glycoproteins with variant receptors, resulting in quantitative differences in host sensitivity.…”

Association of Chediak-Higashi Syndrome and Human Immunodeficiency Virus Type 1 Acute Infection

“…The control of the infection progression is regulated by the balance between host and viral factors. Human allelic variants do not only interfere in the susceptibility to HIV-1 infection, but also in the subsequent rates of disease progression towards AIDS [13][14][15][16][17][18][19]. Regarding the association of the CHS with HIV-1, studies have reported that the secretory pathway in CD4 + T cells supports HIV-1 cell-to-cell spread at the virological sinapse [20,21].…”

Novel Probes Establish Mas-Related G Protein-Coupled Receptor X1 Variants as Receptors with Loss or Gain of Function

“…For example, loss of function mutations in the melanocortin 4 receptor may account for up to 6% of individuals with severe, early-onset obesity (Loos, 2011). Additionally, polymorphisms in chemokine receptors CCR5 and CCR2 have been linked to delayed progression of AIDS after human immunodeficiency virus (HIV) infection (Reiche et al, 2007). Furthermore, changes in chemosensory response to sweet and savory tastes are associated with single-nucleotide polymorphisms in the GPCRs TAS1R1 and TAS1R3 (Hayes et al, 2013).…”