Figure 1.
Clinical measures and summaries of CTL recognition and emergence of mutational variants in recognized epitopes.
A) Twenty-five epitopes were recognized in this subject during the four-years of evaluation. CTL responses to all 25 founder epitopes were examined at 14 time points, with a subset of epitopes also examined at up to another seven time points. The number of epitopes recognized and the total magnitudes of CTL responses of the 14 time points are shown. Viral sequences encompassing 24 epitopes (not including Pol NL8, for which less data was available) were obtained from the 14 time points, including 13 at which CTL responses were measured. The percentage of epitopes of which the founder sequence was dominant (over 50%) in the sampled viral population is also shown, thus reflecting the cumulative escape of epitopes through time. B) Viral load and CD4+ T cell counts over time.
Figure 2.
Dynamics of CTL responses to persistent viral epitopes.
Longitudinal changes in the magnitudes of CTL responses and sequence frequencies of the founder epitopes. Green lines represent the sequence frequencies of the founder epitopes and red lines represent the magnitude of the corresponding CTL responses.
Figure 3.
Dynamics of CTL responses to evolving viral epitopes.
See legend to Figure 2 for conventions. Panels A to H, evolving epitopes experiencing strong selection; panels I to R, evolving epitopes experiencing weak selection. In panel I, the blue line represents the sequence frequency of the founder epitope with its C-terminal flanking sequence intact (ETINEEAAEWdrv, the lower case letters indicate the flanking sequence, and the underlined letter is the location of the escape mutation that impaired epitope processing).
Figure 4.
CTL recognition of persistent and evolving epitopes through time.
Proportion in A) total number and B) total magnitude of CTL responses against persistent, and strongly and weakly selected evolving epitopes. Data included were from the 14 time points where CTL responses to all 25 founder epitopes were examined. C) Relationship between the emergence of epitope variants and decline of CTL responses. All 18 evolving epitopes were examined.
Figure 5.
Relationship between the dynamics of CTL responses and selection strength.
A) The time of the initial detection of CTL responses to an epitope, and the time of the first observation of a response over 1000 SFC/106 PBMC, each as a function of s (selection coefficient). B) The time interval between the initial detection of CTL responses to an epitope and the first observation of magnitude over 1000 SFC/106 PBMC as a function of s value. C) The time interval between the initial detection of CTL responses to an evolving epitope and the first observation of responses declined from the peak, below 50% and below 20% of the peak magnitude as a function of s. D) The time interval between the peak CTL responses to an evolving epitope and the first observation of responses declining below 50% and 20% of the peak magnitude as a function of s. For Gag QW11, cross-reactivity to the founder epitope from the de novo CTL responses to its mutant was observed from 769 DPS onward. Therefore, only data before 769 DPS were used for this epitope.
Figure 6.
Dynamics of CTL responses to major variants of evolving epitopes.
CTL responses to all major variants of these epitopes were marginal or undetectable throughout the course of study. See legend to Figure 2 for conventions. Each column of panels represent analysis of a single epitope and its major variants. The underlined amino acid corresponds to the position responsible for mutation from the founder sequence shown in the top panels.
Figure 7.
Dynamics of CTL responses to major variants of evolving epitopes.
See legend to Figure 6 for conventions. CTL responses to the major variants of these epitopes were similar in magnitude over time to those observed for the founder epitopes and tended to eventually become marginal or undetectable.
Figure 8.
Dynamics of CTL responses to major variants of evolving epitopes.
See legend to Figure 6 for conventions. Strong and specific CTL responses to some major variants of these epitopes were observed after the sequences of the founder epitopes became undetectable or minor in the sampled viral population.
Figure 9.
Variants of Nef WW9 recognized by CTL at 1501 DPS.
A) Sequence evolution of variants of Nef WW9 observed through the course of study. The arrow indicates the time point 1501 DPS, when the CTL responses against Nef WW9 variants were examined. B) CTL responses against Nef WW9 variants at 1501 DPS. Black bars represent variants whose sequences were observed at 1501 DPS. Grey bars represent variants whose sequences were observed only before 1501 DPS. White bars represent variants whose sequences were not observed in this subject.