Clustering Patterns of Cytotoxic T-Lymphocyte Epitopes in Human Immunodeficiency Virus Type 1 (HIV-1) Proteins Reveal Imprints of Immune Evasion on HIV-1 Global Variation

Abstract

The human cytotoxic T-lymphocyte (CTL) response to human immunodeficiency virus type 1 (HIV-1) has been intensely studied, and hundreds of CTL epitopes have been experimentally defined, published, and compiled in the HIV Molecular Immunology Database. Maps of CTL epitopes on HIV-1 protein sequences reveal that defined epitopes tend to cluster. Here we integrate the global sequence and immunology databases to systematically explore the relationship between HIV-1 amino acid sequences and CTL epitope distributions. CTL responses to five HIV-1 proteins, Gag p17, Gag p24, reverse transcriptase (RT), Env, and Nef, have been particularly well characterized in the literature to date. Through comparing CTL epitope distributions in these five proteins to global protein sequence alignments, we identified distinct characteristics of HIV amino acid sequences that correlate with CTL epitope localization. First, experimentally defined HIV CTL epitopes are concentrated in relatively conserved regions. Second, the highly variable regions that lack epitopes bear cumulative evidence of past immune escape that may make them relatively refractive to CTLs: a paucity of predicted proteasome processing sites and an enrichment for amino acids that do not serve as C-terminal anchor residues. Finally, CTL epitopes are more highly concentrated in alpha-helical regions of proteins. Based on amino acid sequence characteristics, in a blinded fashion, we predicted regions in HIV regulatory and accessory proteins that would be likely to contain CTL epitopes; these predictions were then validated by comparison to new sets of experimentally defined epitopes in HIV-1 Rev, Tat, Vif, and Vpr.

An Endogenous HIV Envelope-derived Peptide without the Terminal NH3+ Group Anchor Is Physiologically Presented by Major Histocompatibility Complex Class I Molecules

“…In addition, some loci such as HLA-B35 (8) and -B27 (9) are individually associated with faster and slower development of AIDS, respectively. The virus escapes this CTL response (10,11), which confirms that CD8 ϩ T lymphocytes exert an immunological pressure (12). This evidence indicates a protective role of CTL in preventing and controlling HIV infection.…”

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

“…Obviously, the specificity of the immunoproteasome could be even higher; however, this creates an easy immune evasion pathway for the pathogens. We recently showed that rapidly evolving viruses, such as HIV, adapt to evade degradation by the immunoproteasome in parts of their genome, but fail to do so in more conserved regions that appear as clusters of epitopes (Yusim et al 2002). Only in rare cases can a virus evolve a protein that can escape proteasomal degradation, like the Epstein-Barr virus (EBV) encoded nuclear antigen (EBNA) 1 (Levitskaya et al 1997).…”

MHC polymorphism under host-pathogen coevolution

“…Another example is HIV-1, which reaches a higher viral load in individuals with common MHC molecules (Trachtenberg et al 2003). HIV-1 has also evolved protein regions devoid of T-cell epitopes, because they lack immuno-proteasome cleavage sites, generate peptides that are poorly presented by MHC molecules, or evade effective immune responses (Korber et al 2001;Moore et al 2002;Yusim et al 2002).…”