Abstract
The existence of long-lived reservoirs of latently infected CD4+ T cells is the major barrier to curing HIV, and has been extensively studied in this light. However, the effect of these reservoirs on the evolutionary dynamics of the virus has received little attention. Here, we present a within-host quasispecies model that incorporates a long-lived reservoir, which we then nest into an epidemiological model of HIV dynamics. For biologically plausible parameter values, we find that the presence of a latent reservoir can severely delay evolutionary dynamics within a single host, with longer delays associated with larger relative reservoir sizes and/or homeostatic proliferation of cells within the reservoir. These delays can fundamentally change the dynamics of the virus at the epidemiological scale. In particular, the delay in within-host evolutionary dynamics can be sufficient for the virus to evolve intermediate viral loads consistent with maximising transmission, as is observed, and not the very high viral loads that previous models have predicted, an effect that can be further enhanced if viruses similar to those that initiate infection are preferentially transmitted. These results depend strongly on within-host characteristics such as the relative reservoir size, with the evolution of intermediate viral loads observed only when the within-host dynamics are sufficiently delayed. In conclusion, we argue that the latent reservoir has important, and hitherto under-appreciated, roles in both within- and between-host viral evolution.
Highlights
After the introduction of anti-retroviral therapy (ART) to treat HIV infected individuals, viral reservoirs, in the form of long-lived CD4+ T cells containing integrated proviral DNA, were identified in infected patients [1,2]
Latent reservoirs might affect viral dynamics during untreated infection, because they provide an archive of old viral variants that can re-enter circulation at a later time upon activation of latently infected cells
We developed a mathematical model to investigate how reservoir dynamics affect the evolution of the virus within single hosts, and find that the presence of a latent reservoir can severely delay within-host evolutionary dynamics
Summary
After the introduction of anti-retroviral therapy (ART) to treat HIV infected individuals, viral reservoirs, in the form of long-lived CD4+ T cells containing integrated proviral DNA, were identified in infected patients [1,2]. These reservoirs are established soon after infection [3,4], are long-lived [5], and virus can re-emerge from the reservoirs after months or even years of latency [6]. The reservoir is likely to provide an archive of “ancestral” viral strains that were circulating earlier during the infection If these archived viruses are reactivated months, or even years, after infection, their presence might have a profound influence on within- and between-host dynamics. There has been speculation that the transmission of ancestral strains could explain the lower rates of HIV evolution observed at the epidemiological scale compared to within individuals [16,17,18,19], and the unexpectedly high heritability of HIV set-point viral load despite considerable within-host evolution between transmission events [20,21]
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