Abstract
The combination of host immune responses and use of antiretrovirals facilitate partial control of human immunodeficiency virus type 1 (HIV-1) infection and result in delayed progression to Acquired Immunodeficiency Syndrome (AIDS). Both treatment and host immunity impose selection pressures on the highly mutable HIV-1 genome resulting in antiretroviral resistance and immune escape. Researchers have shown that antiretroviral resistance mutations can shape cytotoxic T-lymphocyte immunity by altering the epitope repertoire of HIV infected cells. Here it was discovered that an important antiretroviral resistance mutation, L90M in HIV protease, occurs at lower frequencies in hosts that harbor the B*15, B*48 or A*32 human leukocyte antigen subtypes. A likely reason is the elucidation of novel epitopes by L90M. NetMHCPan predictions reveal increased affinity of the peptide spanning the HIV protease region, PR 89–97 and PR 90–99 to HLA-B*15/B*48 and HLA-A*32 respectively due to the L90M substitution. The higher affinity could increase the chance of the epitope being presented and recognized by Cytotoxic T-lymphocytes and perhaps provide additional immunological pressures in the presence of antiretroviral attenuating mutations. This evidence supports the notion that knowledge of HLA allotypes in HIV infected individuals could augment antiretroviral treatment by the elucidation of epitopes due to antiretroviral resistance mutations in HIV protease.
Highlights
Infection by Human Immunodeficiency Virus-1 (HIV-1) leads to the debilitating condition known as Acquired Immunodeficiency Syndrome (AIDS) [1]
Values of deminished Human Leukocyte Antigen (HLA) subtype associated residues are included for reference purposes elsewhere in the article. doi:10.1371/journal.pone.0071888.t002
It was discovered that certain HLA subtypes associated mutations were enriched in sequence sets from drug exposed individuals that are devoid of L90M
Summary
Infection by Human Immunodeficiency Virus-1 (HIV-1) leads to the debilitating condition known as Acquired Immunodeficiency Syndrome (AIDS) [1]. Infection is hallmarked by a steady decline in the T-helper cells and failure of adaptive immunity leading to an increased susceptibility to opportunistic infections. Initial immune responses are effective in the control HIV-1 infection. An important defense against HIV-1 infection, is the destruction via apoptosis of infected T-helper cells and has been shown as a major contributor to the control of viremia [2]. The effectors of the response, Cytotoxic T-lymphocytes (CTLs), scrutinize nucleated cells in the body and induce apoptosis in cells that present foreign peptides, usually 9–11 amino acids in length, on the cell membrane by Human Leukocyte Antigen (HLA) class I. Extraction of peptides from a parent protein that is presented by HLA-class I usually involve proteasomal digestion of the parent protein, followed by transport of the resultant fragments into the endoplasmic reticulum where final trimming and loading of the peptide onto the HLA-class I binding groove occurs [3]
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