Epitope Escape Mutation and Decay of Human Immunodeficiency Virus Type 1-Specific CTL Responses

Abstract

To investigate possible mechanisms behind HIV-1 escape from CTL, we performed detailed longitudinal analysis of Gag (SLYNTVATL)- and RT (ILKEPVHGV)-specific CTL responses and plasma epitope sequences in five individuals. Among those with CTL against consensus epitope sequences, epitope mutations developed over several years, invariably followed by decay of the CTL targeting the consensus epitopes. The maturation state of the CTL varied among individuals and appeared to affect the rate of epitope mutation and CTL decay, despite similar IFN-γ production. Escape mutations were oligoclonal, suggesting fitness constraints. The timing of escape indicated that the net selective advantage of escape mutants was slight, further underscoring the importance of understanding factors determining selective pressure and viral fitness in vivo. Our data show surprisingly consistent decay of CTL responses after epitope escape mutation and provide insight into potential mechanisms for both immune failure and shifting CTL specificities.

Human Immunodeficiency Virus Type 1 Clade B Superinfection: Evidence for Differential Immune Containment of Distinct Clade B Strains

“…Sampling of epitope sequences revealed significant differences between the viruses, suggesting that the mechanism of immune failure was nonrecognition of the second strain. Strikingly, the majority of CTL responses decayed rapidly after superinfection, similar to the observed loss of CTL after epitope mutation and escape occurring in chronically infected persons (19). Furthermore, while new CTL responses were detected after superinfection, these were fewer and failed to contain the second virus.…”

Telomerase activity of HIV-1–specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors

“…In fact, HIV-1-specific CD8 ϩ T cells from controllers are typically maintained in the presence of extremely low or even undetectable HIV-1 antigen concentrations, and the constitutively high activity of telomerase in conjunction with an antigenic peptide-independent, homeostatic pattern of cell turnover might allow for the continuous persistence and proliferation of these cells without loss of telomere length. In contrast, HIV-1-specific CD8 ϩ T cells from progressors tend to rapidly disappear after CTL escape mutations 40 or following exposure to HAART, 41 suggesting that their maintenance and differentiation is critically mediated by chronic antigenic stimulation, which apparently leads to progressive telomere erosion as well as limitations in their ability to up-regulate telomerase activity and ultimately results in lymphocellular exhaustion. Clearly, detailed molecular mechanisms that allow for the antigen-independent maintenance and differentiation of HIV-1-specific CD8 ϩ T cells from controllers with simultaneous up-regulation of constitutive, antigen-independent telomerase activity and resulting protection against telomere loss need to be further investigated.…”

Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag77–85

“…Although the in vivo effectiveness of SL9-specific CTL has been questioned [8][9][10][11][12], there may at least be a partial benefit from these responses. Interestingly, although HLA-A*0201-restricted SL9 responses are often dominant in chronic infection, they are rarely induced during acute HIV infection [11,13].…”