[Show abstract][Hide abstract] ABSTRACT: Most T cell-based HIV-1 vaccine candidates induce responses of limited breadth for reasons that are unclear. We evaluated vaccine-induced T-cell responses in individuals receiving an HIV-1 recombinant adenoviral vaccine. Certain HLA alleles (B27, B57, B35, and B14) are preferentially utilized to mount HIV-specific responses, whereas other alleles (A02 and B07) are rarely utilized (P < 0.001). This preference seems due to 4 following factors individually or in combination: higher affinity of specific peptides to specific HLA alleles; higher avidity of T-cell receptor; HLA and peptide interaction; and/or higher surface expression of certain HLA. Thus, HLA immunodominance plays a substantial role in vaccine-induced T-cell responses.
[Show abstract][Hide abstract] ABSTRACT: HLA alleles B57/58, B27, and B35 have the strongest genetic associations with HIV-1 disease progression. The mechanisms of these relationships may be host control of HIV-1 infection via CD8(+) T-cell responses. We examined these immune responses in subjects from the Seattle Primary Infection Cohort with these alleles. CD8(+) T-cell responses to conserved HIV epitopes within B57/58 alleles (TW10 and KF11) and B27 alleles (KK10 and FY10) delayed declines in CD4(+) T-cell counts (4 to 8 times longer), while responses to variable epitopes presented by B35 alleles (DL9 and IL9) resulted in more rapid progression. The plasma viral load was higher in B57/58(+) and B27(+) subjects lacking the conserved B57/58- and B27-restricted responses. The presence of certain B57/58-, B27-, and B35-restricted HIV-specific CD8(+) T-cell responses after primary HIV-1 infection better defined disease progression than the HLA genotype alone, suggesting that it is the HIV-specific CD8(+) T cells and not the presence of a particular HLA allele that determine disease progression. Further, the most effective host CD8(+) T-cell responses to HIV-1 were prevalent within an HLA allele, represented a high total allele fraction of the host CD8(+) T-cell response, and targeted conserved regions of HIV-1. These data suggest that vaccine immunogens should contain only conserved regions of HIV-1.
Journal of Virology 02/2010; 84(9):4461-8. · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HIV-1-infected persons with HLA-B27 and -B57 alleles commonly remain healthy for decades without antiretroviral therapy. Properties of CD8+ T cells restricted by these alleles considered to confer disease protection in these individuals are elusive but important to understand and potentially elicit by vaccination. To address this, we compared CD8+ T cell function induced by HIV-1 immunogens and natural infection using polychromatic flow cytometry. HIV-1-specific CD8+ T cells from all four uninfected immunized and 21 infected subjects secreted IFN-gamma and TNF-alpha. However, CD8+ T cells induced by vaccination and primary infection, but not chronic infection, proliferated to their cognate epitopes. Notably, B27- and B57-restricted CD8+ T cells from nonprogressors exhibited greater expansion than those restricted by other alleles. Hence, CD8+ T cells restricted by certain protective alleles can resist replicative defects, which permits expansion and antiviral effector activities. Our findings suggest that the capacity to maintain CD8+ T cell proliferation, regardless of MHC-restriction, may serve as an important correlate of disease protection in the event of infection following vaccination.
The Journal of Immunology 12/2006; 177(10):7406-15. · 5.36 Impact Factor