Persistent HIV-1 replication maintains the tissue reservoir during therapy

Abstract

Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site of viral production, storage of viral particles in immune complexes, and viral persistence. Whilst combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. A spatial dynamic model of persistent viral replication and spread explains why the development of drug resistance is not a foregone conclusion under conditions where drug concentrations are insufficient to completely block virus replication. These data provide fresh insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and refill the viral reservoir despite potent antiretroviral therapy.

No evidence of HIV replication in children on antiretroviral therapy

“…and Figure 3A) revealed obvious topological differences ( Figure 3C) and indicated that the evolutionary rate reported in ref. 10 was grossly overestimated. To show that our simulation model accurately reflects the accumulation of mutations in vivo, we performed the same simulation for the children (ZA001 and ZA002) who served as replication controls using evolutionary rates calculated from the change in the root-to-tip distances over time for these children.…”

“…The failure to detect any significant change in the HIV population for 7 to 9 years in children on ART with sustained suppression of viremia provides strong evidence against ongoing replication of HIV-1 either in the blood or in sanctuary sites with subsequent trafficking of infected cells peripherally, as is expected (10). These findings directly refute those purported to show HIV evolution in patients on ART (10) and confirm that the HIV reservoir is likely maintained largely, if not solely, by the persistence and expansion of cells that were infected prior to the initiation of treatment in individuals on ART with sustained suppression of viremia.…”

“…There has been continued debate about whether the HIV reservoir is maintained through the persistence and proliferation of cells infected before the initiation of ART (1)(2)(3)(4)(5), or from ongoing viral replication in potential ART sanctuary sites, such as lymph nodes (LNs) (6)(7)(8)(9)(10), with subsequent trafficking of recently infected cells into the blood (10,11). If ongoing replication in tissues maintains the HIV reservoir, then preventing infection of new cells by developing antiretrovirals that better penetrate sanctuary sites such as LNs would be a high priority.…”

“…Prior studies addressing the question of ongoing replication have analyzed the evolution of virion RNA or proviral DNA sequences in chronically infected adults as a function of the duration of ART (3,10,(12)(13)(14)(15). Such studies have ascribed the success of ART to its ability to effectively prevent the infection of new cells by reducing the in vivo reproductive rate to less than 1 and effectively halting viral evolution and preventing the associated development of drug resistance (3,16,17).…”

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

“…If the latent compartment declines because of HIV reactivation and death of latently infected cells but is also partially maintained by different self-renewal mechanisms, like homeostatic proliferation (25,26) or infection of new cells (27), then its natural decay would be the sum of the HIV reactivation rate and the net loss due to the balance of the death and renewal rates (Fig. 1C).…”