ART Suppresses Plasma HIV-1 RNA to a Stable Set Point Predicted by Pretherapy Viremia

Abstract

Current antiretroviral therapy is effective in suppressing but not eliminating HIV-1 infection. Understanding the source of viral persistence is essential for developing strategies to eradicate HIV-1 infection. We therefore investigated the level of plasma HIV-1 RNA in patients with viremia suppressed to less than 50–75 copies/ml on standard protease inhibitor- or non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy using a new, real-time PCR-based assay for HIV-1 RNA with a limit of detection of one copy of HIV-1 RNA. Single copy assay results revealed that >80% of patients on initial antiretroviral therapy for 60 wk had persistent viremia of one copy/ml or more with an overall median of 3.1 copies/ml. The level of viremia correlated with pretherapy plasma HIV-1 RNA but not with the specific treatment regimen. Longitudinal studies revealed no significant decline in the level of viremia between 60 and 110 wk of suppressive antiretroviral therapy. These data suggest that the persistent viremia on current antiretroviral therapy is derived, at least in part, from long-lived cells that are infected prior to initiation of therapy.

Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy

“…Our earlier studies revealed a highly significant association between low-level viremia at week 60 and baseline HIV RNA levels, as well as a lack of association of this viremia on therapy with treatment regimen, suggesting that persistent viremia arises from reservoirs of long-lived cells infected before the initiation of therapy (4). The model used to fit the biphasic decay in the current study provides a mechanism to estimate individual patient parameter values, allowing us to further evaluate this theory.…”

“…R eduction of HIV-1 RNA levels to Ͻ50 copies per ml is frequently achieved with combination antiretroviral therapy, but residual low-level viremia has been detected, using ultrasensitive assays, despite such therapy (1)(2)(3)(4)(5). The source and dynamics of this residual viremia are currently unknown.…”

“…The source and dynamics of this residual viremia are currently unknown. Viremia could arise from ongoing cycles of viral replication in a sanctuary site where there is suboptimal drug penetration, from long-lived productively infected cells, or from activation of virus expression from latently infected cell reservoirs (1,4,(6)(7)(8)(9).…”

“…Using a recently developed real-time HIV RNA assay with single-copy sensitivity (10), our prior work has shown that Ͼ80% of patients on suppressive standard protease inhibitor or nonnucleoside reverse transcriptase inhibitor-containing antiretroviral therapy for 60 weeks had measurable levels of persistent viremia (4). These therapies suppress plasma viremia to a new setpoint that correlates with baseline pretherapy plasma HIV-1 RNA levels but not with treatment regimen.…”

Un virus tapi dans l’ombre : les bases moléculaires de la latence du VIH-1

“…Quelques exemples de molécules, à même de réactiver l'expression du virus et donc utilisables en vue d'une stratégie de purge des réservoirs, sont représentés en rouge : activateurs de la voie de la signalisation cellulaire menant à NF-B (prostatin), inhibiteurs des histones déacétylases (HDACi) et activateurs du complexe P-TEFb (HMBA, hexaméthylène bisacétamide). a permis de détecter une virémie résiduelle [11][12][13]. Le problème de l'origine de cette virémie résiduelle était à nouveau au centre des débats, et les tenants d'une réplication rési-duelle chronique à nouveau sur le devant de la scène.…”