CD8+ T-cell responses to different HIV proteins have discordant associations with viral load

Abstract

Selection of T-cell vaccine antigens for chronic persistent viral infections has been largely empirical. To define the relationship, at the population level, between the specificity of the cellular immune response and viral control for a relevant human pathogen, we performed a comprehensive analysis of the 160 dominant CD8(+) T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa. Of the HIV proteins targeted, only Gag-specific responses were associated with lowering viremia. Env-specific and Accessory/Regulatory protein-specific responses were associated with higher viremia. Increasing breadth of Gag-specific responses was associated with decreasing viremia and increasing Env breadth with increasing viremia. Association of the specific CD8(+) T-cell response with low viremia was independent of HLA type and unrelated to epitope sequence conservation. These population-based data, suggesting the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection, are of relevance to HIV vaccine design and evaluation.

CD8 + T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

“…4C to F), with bVC groups possessing significantly broader Gag than Nef responses. Taken together, these observations are consistent with previous findings indicating that broad targeting of Gag but not Nef may contribute to HIV control among viremic controllers (4,(38)(39)(40).…”

“…We demonstrated that virologic control in subjects with protective HLA class I alleles was associated with greater breadth of CD8 ϩ T cell responses to Gag, consistent with previous data on the importance of Gag-specific responses in chronic HIV infection (4,38). In addition, we observed a bias toward targeting of greater breadth of HIV Gag epitopes compared to Nef indepen- dently of protective HLA class I allele expression among controllers.…”

“…Seventy HIV-1 subtype C-chronically infected participants from the Sinikithemba (SK) cohort in Durban, South Africa (3,4,32), were included in the current study. Participants were ART naive at all the time points analyzed.…”

“…Understanding the mechanisms of natural viral control in HIV infection is crucial for the identification of correlates of immune protection and for the design of an effective HIV vaccine. Previous studies have linked HIV control to a number of immunological factors, particularly HIVspecific CD8 ϩ cytotoxic T lymphocytes (CTLs), which have been demonstrated to play an important role (2)(3)(4)(5). However, virusspecific CD8 ϩ T cell immune responses are not equally effective in HIV control, as the majority of infected individuals progress to disease despite the presence of these cells.…”

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

“…58–67 Failure to contain viral replication in macaques correlated with the emergence of viral mutants that escaped from CTL immune surveillance. 68 , 69 In humans, CD8 + T cells targeting Gag are inversely associated with virus load, 70 including in long-term non-progressors, 71 and Gag T cell breadth has been associated with reduced plasma viremia. 72 …”