Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses
Hancock, Gemma (University of Oxford)
Yang, Hongbing (University of Oxford)
Yorke, Elisabeth (University of Toronto)
Wainwright, Emma (Royal Berkshire NHS Foundation Trust (Reading, Gran Bretanya))
Bourne, Victoria (University of Oxford)
Frisbee, Alyse (Duke University (Durham, Estats Units d'Amèrica))
Payne, Tamika L. (Duke University (Durham, Estats Units d'Amèrica))
Berrong, Mark (Duke University (Durham, Estats Units d'Amèrica))
Ferrari, Guido (Duke University (Durham, Estats Units d'Amèrica))
Chopera, Denis (University of Cape Town)
Hanke, Tomáš (University of Oxford)
Mothe, Beatriz (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Brander, Christian (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
McElrath, M. Juliana (Fred Hutchinson Cancer Research Center (Seattle, Estats Units d'Amèrica))
McMichael, Andrew (University of Oxford)
Goonetilleke, Nilu (University of North Carolina School of Medicine)
Tomaras, Georgia D. (Duke University (North Carolina, Estats Units d'Amèrica))
Frahm, Nicole (Fred Hutchinson Cancer Research Center (Seattle, Estats Units d'Amèrica))
Dorrell, Lucy (University of Oxford)

Fecha:	2015
Resumen:	Abstract. Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.
Nota:	Ajuts: R01/R56 NIH Grant AI-52779 (GDT), NIH F31 Fellowship (1F31AI106519-01)(TLP), Center for AIDS Research (P30 AI 64518) i Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, grant number UM1-AI100645-01 (AM)
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	PLOS pathogens, Vol. 11 Núm. 2 (february 2015) , ISSN 1553-7374

DOI: 10.1371/journal.ppat.1004658
PMID: 25723536

22 p, 877.6 KB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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