Dynamics of Viral Evolution and CTL Responses in HIV-1 Infection

Improved understanding of the dynamics of host immune responses and viral evolution is critical for effective HIV-1 vaccine design. We comprehensively analyzed Cytotoxic T-lymphocyte (CTL)-viral epitope dynamics in an antiretroviral therapy-naïve subject over the first four years of HIV-1 infection. We found that CTL responses developed sequentially and required constant antigenic stimulation for maintenance. CTL responses exerting strong selective pressure emerged early and led to rapid escape, proliferated rapidly and were predominant during acute/early infection. Although CTL responses to a few persistent epitopes developed over the first two months of infection, they proliferated slowly. As CTL epitopes were replaced by mutational variants, the corresponding responses immediately declined, most rapidly in the cases of strongly selected epitopes. CTL recognition of epitope variants, via cross-reactivity and de novo responses, was common throughout the period of study. Our data demonstrate that HIV-specific CTL responses, especially in the critical acute/early stage, were focused on regions that are prone to escape. Failure of CTL responses to strongly target functional or structurally critical regions of the virus, as well as the sequential cascade of CTL responses, followed closely by viral escape and decline of the corresponding responses, likely contribute to a lack of sustainable viral suppression. Focusing early and rapidly proliferating CTL on persistent epitopes may be essential for durable viral control in HIV-1 infection

Regularity of center-of-pressure trajectories depends on the amount of attention invested in postural control

The influence of attention on the dynamical structure of postural sway was examined in 30 healthy young adults by manipulating the focus of attention. In line with the proposed direct relation between the amount of attention invested in postural control and regularity of center-of-pressure (COP) time series, we hypothesized that: (1) increasing cognitive involvement in postural control (i.e., creating an internal focus by increasing task difficulty through visual deprivation) increases COP regularity, and (2) withdrawing attention from postural control (i.e., creating an external focus by performing a cognitive dual task) decreases COP regularity. We quantified COP dynamics in terms of sample entropy (regularity), standard deviation (variability), sway-path length of the normalized posturogram (curviness), largest Lyapunov exponent (local stability), correlation dimension (dimensionality) and scaling exponent (scaling behavior). Consistent with hypothesis 1, standing with eyes closed significantly increased COP regularity. Furthermore, variability increased and local stability decreased, implying ineffective postural control. Conversely, and in line with hypothesis 2, performing a cognitive dual task while standing with eyes closed led to greater irregularity and smaller variability, suggesting an increase in the “efficiency, or “automaticity” of postural control”. In conclusion, these findings not only indicate that regularity of COP trajectories is positively related to the amount of attention invested in postural control, but also substantiate that in certain situations an increased internal focus may in fact be detrimental to postural control

Increasing cognitive load with increasing balance challenge: recipe for catastrophe

The variety of sometimes contradictory results of studies of the impact of secondary cognitive tasks on postural balance may be attributed to the heterogeneity of balance challenges and tasks deployed and frequent lack of quantitative comparability of tasks. We deployed a wide range of quantitatively graded difficulties of both balance challenge and cognitive tasking to obtain an overview of the spectrum of their interactions in a multi-tasking situation. A differential comparison of the effects of verbally versus spatially loaded tasks, balanced for difficulty, was made and unlike any other study, we contrived to incorporate falls as an experimental variable. In the first study subjects stood in tandem on beams of either 2, 3 and 6 cm or 3, 6 and 8 cm width (according to 'best performance' ability) while performing mental verbal or spatial 'Stroop' tasks. The design was a between groups (sixteen subjects each) comparison (to reduce learning effect) of sway, fall rate and task error, balanced for order. Measurements were taken of centre of pressure, sway velocity at the hip and head displacement. For any beam width there were no within-subject correlations between sway magnitudes and frequency of falls. Spatial task errors increased with balance challenge (hence with magnitude of sway) but verbal performance was maintained independently of balance challenge. The results of the first study provided statistical power estimates for the design of the second focussed experiment which made a within group (twenty four subjects) comparison of the impact of spatial versus verbal tasks on balancing on the hardest beam. The spatial task significantly elevated the incidence of falls whereas the verbal task had no effect on fall rate. The spatial task raised the incidence of falling by 50% (P = 0.0008) in comparison with 'no task'. The verbal task had no effect (P = 0.07). We conclude that sway magnitude is a poor index of multi-task load. Multi-tasking can increase the chance of falling and spatial processing may have a specific impact on balance. The significant elevation of fall frequency during cognitive tasking shows that the 'posture first' principal can be transgressed although the necessary condition for transgression may be that the subject is willing to take risks believing that he can arrest any fall