Comprehensive epitope analysis of cross-clade Gag-specific T-cell responses in individuals with early HIV-1 infection in the US epidemic.
To elucidate the mechanisms underlying cross-clade T-cell reactivity, we evaluated responses to Gag peptides based on clades A, B, C, and M-group sequences at the epitope level by IFN-gamma ELISpot assay in 25 subjects following primary clade B infection. T-cell reactivity to CON (consensus), COT (center of tree), and ANC (most recent common ancestor) B peptides was similar and a high level of cross-reactivity was noted to clade A, C, and M-group peptides. T-cell responses to 15 of the 16 epitopes reacted with at least 1 of the 2 heterologous peptides (A or C or both) and 7 epitopes were invariant across all 3 clades. The remaining 9 epitopes were associated with a total of 11 variant sequences, and with the exception of 1, all substitutions were outside the HLA anchor positions. We conclude that Gag-specific cross-clade T-cell responses producing IFN-gamma can be detected in primary HIV-1 infection. Cross-reactivity is attributable to the recognized epitopes being either invariant across clades or differing by single amino acid substitutions outside the HLA anchor sites. Semi-conservative and non-conservative substitutions that presumably involve the T-cell receptor contact sites have significant effects on T-cell recognition. Finally, further studies are needed to determine if the detection of cross-clade IFN-gamma T-cell responses indeed translates to cross-reactive antiviral activity.
Malhotra
Uma
U
Program in Infectious Diseases, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N. D3-100, Seattle, WA 98109, USA. uma@u.washington.edu
Nolin
Jessica
J
Mullins
James I
JI
McElrath
M Juliana
MJ
D000163:Acquired Immunodeficiency Syndrome / Q000453:epidemiology / Q000276:immunology*; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D013997:Time Factors; D014481:United States / Q000453:epidemiology
D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag