Persistence of Wild-Type Virus and Lack of Temporal Structure in the Latent Reservoir for Human Immunodeficiency Virus Type 1 in Pediatric Patients with Extensive Antiretroviral Exposure

Abstract

Although highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection can reduce levels of HIV-1 RNA in plasma to below the limit of detection, replication-competent forms of the virus persist in all infected individuals. One form of persistence involves a stable reservoir of latent but potentially infectious virus that resides in resting memory CD4 ؉ T cells. The mechanisms involved in maintaining this latent reservoir are incompletely understood. In the present study, we examined the dynamic characteristics of this reservoir in a cohort of children who developed drug-resistant HIV-1 as a result of extensive exposure to inadequately suppressive one-or two-drug regimens prior to the advent of HAART. We have previously shown that drug-resistant viruses selected by nonsuppressive pre-HAART regimens can enter and persist in this reservoir. We have extended these findings here by demonstrating that archival wild-type HIV-1 persists in this reservoir despite the fact that in these patients drug-resistant mutants have been favored by the selective conditions for many years. Phylogenetic analysis of replication-competent viruses persisting in resting CD4؉ T cells revealed a striking lack of temporal structure in the sense that isolates obtained at later time points did not show greater sequence divergence than isolates from earlier time points. The persistence of drug-sensitive virus and the lack of temporal structure in the latent reservoir provide genetic evidence for the idea that HIV-1 can persist in a latent form free of selective pressure from antiretroviral drugs in long-lived resting memory CD4 ؉ T cells. Although there may be other mechanisms for viral persistence, this stable pool of latently infected cells is of significant concern because of its potential to serve as a lasting source of replication-competent viruses, including the infecting wild-type form and all drug-resistant variants that have arisen subsequently.

The HBV Drug Entecavir — Effects on HIV-1 Replication and Resistance

“…Phylogenetic analysis suggests that the M184V variants evolved recently, most likely as a result of entecavir treatment. The appearance of M184V could also reflect emergence of an archived variant from the latent reservoir (26), but in either case there is clear evidence that entecavir selected for this variant in patient #1.…”

HIV Pathogenesis: Dynamics and Genetics of Viral Populations and Infected Cells

“…In the chronic infection phase, there is a slow but perceptible turnover of the viral population such that genetically distinct populations arise every few years (F Maldarelli, M Kearney, S Palmer, et al, unpubl.). In contrast, in patients on maximally suppressive therapy, evolution of viral genomes is frozen at the point at which therapy began (Ruff et al 2002;Tobin et al 2005), and no evidence for continuing evolution can be seen even after many years. In patients for which therapy is partially suppressive, ongoing evolution can still be observed (Tobin et al 2005), as is also true in patients known as "elite controllers," who naturally control HIV-1 infection at levels similar to those seen in patients on suppressive antiviral therapy (Mens et al 2010).…”

Stable gene expression occurs from a minority of integrated HIV-1-based vectors: transcriptional silencing is present in the majority

“…6 Genetic studies have shown drug-sensitive archival HIV-1 sequences can be found in T cells in patients who have undergone antiretroviral therapy for up to 5 years. 7 Longitudinal studies in patients undergoing antiretroviral therapy for 2 years found a lack of clinically relevant evolution in the protease gene in HIV recovered from peripheral blood cells. 8 The virus was replication competent but apparently had not been exposed to the selection pressure exerted by the therapy, implying that the virus was not replicating.…”