Healthy dynamics of CD4 T cells may drive HIV resurgence in perinatally-infected infants on antiretroviral therapy

Abstract

In 2019 there were 490,000 children under five living with HIV. Understanding the dynamics of HIV suppression and rebound in this age group is crucial to optimizing treatment strategies and increasing the likelihood of infants achieving and sustaining viral suppression. Here we studied data from a cohort of 122 perinatally-infected infants who initiated antiretroviral treatment (ART) early after birth and were followed for up to four years. These data included longitudinal measurements of viral load (VL) and CD4 T cell numbers, together with information regarding treatment adherence. We previously showed that the dynamics of HIV decline in 53 of these infants who suppressed VL within one year were similar to those in adults. However, in extending our analysis to all 122 infants, we find that a deterministic model of HIV infection in adults cannot explain the full diversity in infant trajectories. We therefore adapt this model to include imperfect ART adherence and natural CD4 T cell decline and reconstitution processes in infants. We find that individual variation in both processes must be included to obtain the best fits. We also find that infants with faster rates of CD4 reconstitution on ART were more likely to experience resurgences in VL. Overall, our findings highlight the importance of combining mathematical modeling with clinical data to disentangle the role of natural immune processes and viral dynamics during HIV infection.

Fig 1. Model framework and analysis schematic.

(A) The infection model with rate constants. CD4 target cells (T) are infected by free infectious virus (V_I) and either become productively infected cells (I), die though abortive infection, or become latently infected. Productively infected cells produce both infectious (green) and non-infectious (red) virus, both of which are cleared at rate c, and latently infected cells can become reactivated at a later point to join the productively infected cell population. CD4 target cells also undergo reconstitution and natural decline processes at total net rate θ(t, T). Further details are given in the text. (B) Schematic illustrating the definition of viral resurgence (top) compared to no resurgence (bottom). The timing of resurgence is defined as the time at which viral load first starts increasing (vertical red line), and the size of resurgence is the total integrated viral load during the upslope period (blue shaded region). The dashed horizontal line represents the detection threshold of the assay.

Fig 2. Model fits for viral RNA observations.

Each panel represents a different infant; points represent the data; and solid lines are the model fits. The dashed horizontal line is the detection threshold of the RNA assay, and red crosses are censored observations below this threshold. Panels shaded in red are infants who experienced viral resurgence (i.e. at least one period of increasing VL).

Fig 3. Model fits for CD4 T cell observations.

Each panel represents a different infant, ordered as in Fig 2; points represent the data; and solid lines are the model fits.

Fig 4. VL resurgence is associated with rates of CD4 reconstitution, VL production and decay, and ART history of infant and mother.

(A–B) Relationship between the occurrence of VL resurgence (defined as any increase in VL following initiation of ART) and the CD4 reconstitution rate, r, in cells μl^-1 day^-1 (A) and the ratio of virus production to decay, $\overline{p}=p/c$, in copies ml⁻¹ cell⁻¹ (B). Each point represents a different infant and p < 0.0001(****) in both cases. Seven infants whose resurgence was a viral rebound event are highlighted in orange. (C–D) Relationship between $\overline{p}$ and the size of VL resurgence in RNA copies ml⁻¹ (C) and timing of VL resurgence in days (D). Each point represents an infant who experienced resurgence. Correlations are 0.66 and -0.75, respectively, and p < 0.0001 in both cases. (E) Relationship between the occurrence of VL resurgence and the timing of maternal ART initiation (p < 0.01). The size of each box reflects the proportion of infants in the corresponding category and the numbers show the corresponding sample size. (F) Relationship between infant ART adherence and the occurrence of VL resurgence (p < 0.05 for AZT and LVP/r; p = 0.06 for NVP). Adherence was classified as ‘good’ if the majority of adherence estimates were 90% or more, and ‘poor’ otherwise.