Characterization of HIV-specific CD4+ T cell responses against peptides selected with broad population and pathogen coverage.
CD4+ T cells orchestrate immunity against viral infections, but their importance in HIV infection remains controversial. Nevertheless, comprehensive studies have associated increase in breadth and functional characteristics of HIV-specific CD4+ T cells with decreased viral load. A major challenge for the identification of HIV-specific CD4+ T cells targeting broadly reactive epitopes in populations with diverse ethnic background stems from the vast genomic variation of HIV and the diversity of the host cellular immune system. Here, we describe a novel epitope selection strategy, PopCover, that aims to resolve this challenge, and identify a set of potential HLA class II-restricted HIV epitopes that in concert will provide optimal viral and host coverage. Using this selection strategy, we identified 64 putative epitopes (peptides) located in the Gag, Nef, Env, Pol and Tat protein regions of HIV. In total, 73% of the predicted peptides were found to induce HIV-specific CD4+ T cell responses. The Gag and Nef peptides induced most responses. The vast majority of the peptides (93%) had predicted restriction to the patient's HLA alleles. Interestingly, the viral load in viremic patients was inversely correlated to the number of targeted Gag peptides. In addition, the predicted Gag peptides were found to induce broader polyfunctional CD4+ T cell responses compared to the commonly used Gag-p55 peptide pool. These results demonstrate the power of the PopCover method for the identification of broadly recognized HLA class II-restricted epitopes. All together, selection strategies, such as PopCover, might with success be used for the evaluation of antigen-specific CD4+ T cell responses and design of future vaccines.
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Marcus
M
Buggert
Melissa M
MM
Norström
Chris
C
Czarnecki
Emmanuel
E
Tupin
Ma
M
Luo
Katarina
K
Gyllensten
Anders
A
Sönnerborg
Claus
C
Lundegaard
Ole
O
Lund
Morten
M
Nielsen
Annika C
AC
Karlsson
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry; D006801:Humans; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D019562:Viral Load; D055815:Young Adult; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D054298:Human Immunodeficiency Virus Proteins; D010455:Peptides; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus