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

Abstract

Residual viremia can be detected in most HIV-1-infected patients on antiretroviral therapy despite suppression of plasma RNA to <50 copies per ml, but the source and duration of this viremia is currently unknown. Therefore, we analyzed longitudinal plasma samples from 40 patients enrolled in the Abbott M97-720 trial at baseline (pretherapy) and weeks 60 to 384 by using an HIV-1 RNA assay with single-copy sensitivity. All patients were on therapy (lopinavir/ritonavir, stavudine, and lamivudine) with plasma HIV RNA <50 copies per ml by week 96 of the study and thereafter. Single-copy assay results revealed that 77% of the patient samples had detectable low-level viremia (>1 copy per ml), and all patients had at least one sample with detectable viremia. A nonlinear mixed effects model revealed a biphasic decline in plasma RNA levels occurring over weeks 60 to 384: an initial phase of decay with a half-life of 39 weeks and a subsequent phase with no perceptible decay. The level of pretherapy viremia extrapolated for each phase of decay was significantly correlated with total baseline viremia for each patient (R 2 ‫؍‬ 0.27, P ‫؍‬ 0.001 and R 2 ‫؍‬ 0.19, P < 0.005, respectively), supporting a biological link between the extent of overall baseline viral infection and the infection of long-lived reservoirs. These data suggest that low-level persistent viremia appears to arise from at least two cell compartments, one in which viral production decays over time and a second in which viral production remains stable for at least 7 years.

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…[7][8][9][10][11] Because residual HIV expression continues despite effective ART [12][13][14][15][16] and is required for viral rebound, HIV-infected cells should theoretically be targetable by a T cell therapeutic agent. Several mechanisms are thought to be responsible for the apparent failure of autologous cytotoxic T lymphocytes (CTLs) to clear reactivated cells in HIV-infected individuals: HIV evolution prior to ART quickly selects for CTL escape mutations; [17][18][19] HIV Nef mediates downregulation of major histocompatibility complex class I (MHC-I), 20,21 protecting HIV-infected cells from T cell receptor (TCR)-dependent CTL killing; and HIV-specific CTL responses may be limited by exhaustion 22,23 or peripheral immune tolerance.…”

Quantification of HIV-1 latency reversal in resting CD4 + T cells from patients on suppressive antiretroviral therapy

“…Assays of infectious virus recovery from quiescent CD4 + T cells isolated from patients on ART have revealed the existence of a reservoir of latent, replication competent HIV-1 with a half-life of 44 mo (1)(2)(3)(4). In addition, low-level plasma viremia persists indefinitely on ART (5,6), and the level of virus in plasma rebounds following cessation of ART (7,8). New therapeutic approaches are required to eliminate both persistent low-level viremia and the latent proviral reservoir.…”

A Conserved Hydrogen-Bonding Network of P2 bis -Tetrahydrofuran-Containing HIV-1 Protease Inhibitors (PIs) with a Protease Active-Site Amino Acid Backbone Aids in Their Activity against PI-Resistant HIV

“…Thus, the enhanced replication fitness of HIV A02 in combination with loss of contacts for RTV in the active site of PR A02 may well explain the compromised activity of RTV (EC 50 , Ͼ1 M) against HIV A02 in the antiviral assays. In the case of patients, a study based on the Abbott M97-720 trial showed that low-level viremia could persist at least for 7 years in patients on an LPV/RTV regimen, partially due to latent viral reservoirs (36). Based on our structural analysis, amino acid substitutions (both active site and non-active site) in PR A02 caused an altered binding orientation of RTV in the active site, resulting in a significant loss of contacts in the S2 and S2= binding pockets of PR A02 and, consequently, causing HIV-1 resistance to RTV.…”