Increased sequence coverage through combined targeting of variant and conserved epitopes correlates with control of HIV replication.
A major challenge in the development of an HIV vaccine is that of contending with the extensive sequence variability found in circulating viruses. Induction of HIV-specific T-cell responses targeting conserved regions and induction of HIV-specific T-cell responses recognizing a high number of epitope variants have both been proposed as strategies to overcome this challenge. We addressed the ability of cytotoxic T lymphocytes from 30 untreated HIV-infected subjects with and without control of virus replication to recognize all clade B Gag sequence variants encoded by at least 5% of the sequences in the Los Alamos National Laboratory HIV database (1,300 peptides) using gamma interferon and interleukin-2 (IFN-γ/IL-2) FluoroSpot analysis. While targeting of conserved regions was similar in the two groups (P = 0.47), we found that subjects with control of virus replication demonstrated marginally lower recognition of Gag epitope variants than subjects with normal progression (P = 0.05). In viremic controllers and progressors, we found variant recognition to be associated with viral load (r = 0.62, P = 0.001). Interestingly, we show that increased overall sequence coverage, defined as the overall proportion of HIV database sequences targeted through the Gag-specific repertoire, is inversely associated with viral load (r = -0.38, P = 0.03). Furthermore, we found that sequence coverage, but not variant recognition, correlated with increased recognition of a panel of clade B HIV founder viruses (r = 0.50, P = 0.004). We propose sequence coverage by HIV Gag-specific immune responses as a possible correlate of protection that may contribute to control of virus replication. Additionally, sequence coverage serves as a valuable measure by which to evaluate the protective potential of future vaccination strategies.
Department of Global Health, University of Washington, Seattle, Washington, USA.
Justine
J
Sunshine
Moon
M
Kim
Jonathan M
JM
Carlson
David
D
Heckerman
Julie
J
Czartoski
Stephen A
SA
Migueles
Janine
J
Maenza
M Juliana
MJ
McElrath
James I
JI
Mullins
Nicole
N
Frahm
D015331:Cohort Studies; D017124:Conserved Sequence; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D019562:Viral Load; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*
D000939:Epitopes; D007376:Interleukin-2; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma