Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection

Abstract

CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load ‫؍‬ 142,000 copies/ml; median CD4 count ‫؍‬ 71/l) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/10 6 peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P ‫؍‬ 0.032) and magnitude (P ‫؍‬ 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferonpositive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques.

Targeting HIV-1 Gag into the Defective Ribosomal Product Pathway Enhances MHC Class I Antigen Presentation and CD8+ T Cell Activation

“…Regardless of all of the efforts spent, there is a certain need to improve current strategies for protective or therapeutic vaccinations against HIV-1. Although high-frequency T cell responses can be observed in HIV-1-infected individuals, even in those with progressing disease (49), there is evidence that virus-specific CD8…”

Epitope Cross-Reactivity Frequently Differs between Central and Effector Memory HIV-Specific CD8+ T Cells

“…Recent studies have begun to assess multiple parameters of HIV-specific CD8 ϩ T cell responses (19,20). This is in part because although CD8 ϩ T cells can contain HIV replication in some cases (21)(22)(23), ongoing viral replication and disease have also been found in the face of seemingly robust CD8 ϩ T cell responses (24,25). Several studies have found a lack of correlation between IFN-␥ responses and viral load, even using whole HIV proteome screening (26 -28).…”

The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection

“…Several studies have documented very slow escapes and slow sequence evolution during chronic infection (12)(13)(14)(15)(16). The consensus interpretation of these slow takeover rates during chronic infection is that even the dominant CTL clonotypes impose a very minor selection pressure and play a very minor role in controlling the virus (12).…”

“…All in all, this was taken as evidence suggesting that the virus is largely controlled by other mechanisms during chronic infection (12). However, it is known that CTL responses persist (14,15), and that new CTL responses develop in chronically infected patients (11). Another major aim of this work is to show that the minor selection pressure was to be expected when several CTL clonotypes together control the infection, and, although each of them has very little impact on the control of the infection, they together can play an essential role.…”