CD8 T-Cell Recognition of Multiple Epitopes within Specific Gag Regions Is Associated with Maintenance of a Low Steady-State Viremia in Human Immunodeficiency Virus Type 1-Seropositive Patients

Abstract

The importance of HLA class I-restricted CD8 T-cell responses in the control of human immunodeficiency virus (HIV) infection is generally accepted. While several studies have shown an association of certain HLA class I alleles with slower disease progression, it is not fully established whether this effect is mediated by HIV-specific CD8 T-cell responses restricted by these alleles. In order to study the influence of the HLA class I alleles on the HIV-specific CD8 T-cell response and on viral control, we have assessed HIV-specific epitope recognition, plasma viral load, and expression of HLA class I alleles in a cohort of HIV-seropositive bar workers. Possession of the HLA class I alleles B5801, B8101, and B0702 was associated with a low median viral load and simultaneously with a broader median recognition of Gag epitopes compared to all other HLA alleles (twofold increase) (P ‫؍‬ 0.0035). We further found an inverse linear relationship between the number of Gag epitopes recognized and the plasma viral load (R ‫؍‬ ؊0.36; P ‫؍‬ 0.0016). Particularly, recognition of multiple epitopes within two regions of Gag (amino acids [aa] 1 to 75 and aa 248 to 500) was associated with the maintenance of a low steady-state viremia, even years after acute infection.

Broad, high-magnitude and multifunctional CD4+ and CD8+ T-cell responses elicited by a DNA and modified vaccinia Ankara vaccine containing human immunodeficiency virus type 1 subtype C genes in baboons

“…Studies in chronic HIV infection have not been able to establish a relationship between overall breadth or magnitude of the IFN-c T-cell response to HIV and viral control (Addo et al, 2003;Masemola et al, 2004). With regard to the specificity of the response, only preferential targeting of Gag, and the breadth of the Gag response, has been correlated with superior viral control in large chronic HIV cohorts, as well as in elite controllers Geldmacher et al, 2007;Pereyra et al, 2008). How readily these lessons from chronic HIV infection should be applied to vaccine design and evaluation is not known.…”

“…These include preserved proliferative capacity (Day et al, 2007;Migueles et al, 2002;Rosenberg et al, 1997) and the ability to secrete multiple cytokines (CKs) (Betts et al, 2006;Harari et al, 2004;Kannanganat et al, 2007b). The specificity of the HIV proteins targeted by the T-cell response appears to be important, with a greater breadth of CD8 + epitopes targeted in Gag (Geldmacher et al, 2007;Kiepiela et al, 2007;Pereyra et al, 2008) or high-avidity CD8 + epitopes (Almeida et al, 2007) correlating with greater viral control. These and other features may be important attributes of a successful T-cell vaccine.…”

Magnitude, Breadth, and Functional Profile of T-Cell Responses during Human Immunodeficiency Virus Primary Infection with B and BF Viral Variants

“…Although the importance of CD8 T cells in controlling HIV replication is widely accepted, earlier reports have failed to show either a positive or negative correlation between viral load and the breadth or magnitude of CTL responses. Now it is known that Gag-specific responses are associated with low viremia (29,38,61), which can be explained by the capacity of Gag-specific CTLs to kill very recently infected cells, even before the viral genome integrates into the host genome (55). Also, it was shown that the functional profile of HIV-specific CD8 T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8 T cells (12).…”

“…However, the predicted minimal epitope is in a different position in each peptide (i.e., it is offset). Therefore, we ascribe the lack of recognition of peptides NefBF 28 and NefBF 29 to the offsetting of the minimal epitope within those peptides. Similarly, we found that other reasons for nonrecognition were polymorphism within the optimal epitope (which may affect interaction to the T-cell receptor and thus effector response) and on epitope anchor positions.…”

SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection

“…1,2 While several lines of evidence indicate that human immunodeficiency virus (HIV)-specific CD8 ϩ T cells are involved in the control of HIV replication, [3][4][5][6][7][8][9][10] several reports have focused on intrinsic defects in these cells to explain their failure to clear the virus, thereby leading to progression to acquired immunodeficiency syndrome (AIDS) in all infected individuals. [11][12][13][14] Similarly, simian immunodeficiency virus (SIV)-specific CD8 ϩ T cells contribute substantially to the partial control of viremia in rhesus macaques; depletion of CD8 ϩ T cells results in increased viremia in SIV-infected animals, 15,16 while viral escape at targeted epitopes accelerates disease progression and death in vaccinated animals.…”