HIV-1 escape from the HLA-B27 and HLA-B57 restricted CTL response

Abstract

Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS), a condition in humans characterised by a progressive loss of CD4+ T-cells. The course of HIV-1 infection is highly variable between individuals and is influenced by both viral and host factors, such as the HLA class I genotype. HLA-B57 and HLA-B27 are most strongly associated with a protective effect against HIV-1 infection. Because of the high immune pressure provided by HLA-restricted CTLs in HIV-1 progression, escape from the CTL mediated immune response is a major mechanism of adaptation of HIV-1. In CTL escape mutations can target peptide processing, the binding of the peptide to the HLA molecule, or recognition of the presented peptide by T-cells. This results in loss, or reduction of peptide presentation by the HLA molecule, thereby inhibiting proper activation of the HIV-1 CTL response. The in vivo benefits of escape from the HLA-restricted CTL response may be severely limited by the loss of fitness that is often the result of the development of the escape mutations. However, the replication-impaired phenotype of the escape variants is often followed by the appearance of compensatory mutations, which restore the viral replication capacity. In HIV-1 infected individuals expressing the protective HLA-B27 and –B57 alleles, the CTL response is mainly targeted against Gag p24, the capsid protein that encapsulates the genomic RNA-nucleocapsid complex in the HIV-1 virion. Escape mutations in the epitopes restricted by HLA-B27 and –B57 thus can affect capsid structure and stability. Conservation of the escape and compensatory mutations upon transmission to a new host can eventually result in accumulation of these mutations in the population. The loss of epitopes able to elicit a CTL response will result in the emergence of less immunogenic HIV-1 variants, which could pose difficulties in developing new therapy options.