HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects

Buzón, María J.; Massanella, Marta; Llibre, Josep M; Esteve, Anna; Dahl, Viktor; Puertas, María C.; Gatell, Josep M.; Domingo, Peré; Paredes, Roger; Sharkey, Mark E.; Palmer, Sarah; Stevenson, Mario; Clotet, Bonaventura; Blanco, Julià; Martínez-Picado, Javier

doi:10.1038/nm.2111

Cited by 482 publications

(388 citation statements)

References 32 publications

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“…This is at variance with a recent report by Lorenzo-Redondo et al [25] and a few earlier reports [23,24], but agrees with several other earlier studies [5,13,[17][18][19][20][21]. Lorenzo-Redondo et al [25] compared genetic diversity in samples HIV-1 RNA in plasma at start of therapy with HIV-1 DNA sequences obtained from blood and tissues at baseline, three and six months after the start of treatment.…”

Section: Discussionsupporting

confidence: 81%

“…Most studies indicate that the HIV-1 reservoir is maintained by the physiological homeostasis of CD4 memory that in part involves occasional expansions and contractions of individual CD4 cell clones [5,12,22]. However, some studies have suggested that persistent virus replication may be an important contributor to the maintenance of the HIV-1 reservoir [23,24]. In particular, Lorenzo-Redondo et al [25] recently reported evidence of rapid HIV-1 evolution in lymphoid tissue reservoirs.…”

Section: Introductionmentioning

confidence: 99%

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Establishment and stability of the latent HIV-1 DNA reservoir

Brodin

Zanini

Thebo

et al. 2016

Preprint

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HIV-1 infection currently cannot be cured because the virus persists as integrated proviral DNA in long-lived cells despite years of suppressive antiretroviral therapy (ART). To characterize establishment, turnover, and evolution of viral DNA reservoirs we deep-sequenced the p17gag region of the HIV-1 genome from samples obtained from 10 patients after 3-18 years of suppressive ART. For each of these patients, whole genome deep-sequencing data of HIV-1 RNA populations before onset of ART were available from 6-12 longitudinal plasma samples spanning 5-8 years of untreated infection. This enabled a detailed analysis of the dynamics and origin of proviral DNA during ART. A median of 14% (range 0-42%) of the p17gag DNA sequences were overtly defective due to G-to-A hypermutation. The remaining sequences were remarkably similar to previously observed RNA sequences and showed no evidence of evolution over many years of suppressive ART. Most sequences from the DNA reservoirs were very similar to viruses actively replicating in plasma (RNA sequences) shortly before start of ART. The results do not support persistent HIV-1 replication as a mechanism to maintain the HIV-1 reservoir during suppressive therapy. Rather, the data indicate that viral DNA variants are turning over as long as patients are untreated and that suppressive ART halts this turnover.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Establishment and stability of the latent HIV-1 DNA reservoir

Brodin

Zanini

Thebo

et al. 2016

Preprint

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“…(30,31), suggesting that cART is effective in preventing viral replication in these anatomical sites. In contrast, increased numbers of 2-long terminal repeat circles in peripheral blood mononuclear cells and decreased amounts of unspliced HIV-1 RNA in CD4 + T cells isolated from the terminal ileum have been reported during raltegravir intensification, supporting the concept that some viral replication can occur despite suppressive cART (32,33). Thus, the role of on-going replenishment via cycles of replication as a cause of persistence is not fully understood.…”

Section: Significancementioning

confidence: 99%

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

Josefsson

Stockenström

Faria

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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250

296

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Significance Identifying the source and dynamics of persistent HIV-1 during combinational antiretroviral therapy (cART) is crucial for understanding the barriers to curing HIV infection. Through genetic characterization of HIV-1 DNA in infected cells from peripheral blood and gut-associated lymphoid tissue from patients after long-term suppressive cART, our study reveals that the primary barrier to a cure is a remarkably stable pool of infected memory CD4 + T cells. Through in-depth phylogenetic analyses, we determined that the HIV-1 reservoir in these cells from eight patients is kept stable during long-term cART and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.

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“…This hypothesis builds first on the link between the size of the reservoir and the degree of inflammation, arguing that persistent virus production during ART could sustain immune activation (IA) and downstream pathological consequences (23, 24), and second on drug distribution studies in animal models of AIDS in which drug concentrations in tissues have been shown to differ from PB levels (25,26). Supporting this argument is the observation that some (but not all) intensification schemes with the integrase inhibitor raltegravir demonstrated a transient increase in 2LTR circles and decreases in IA, suggesting ongoing replication in a tissue site that is not reflected by measures in PB (27,28).We prospectively treated 12 subjects with ARVs and performed multiple samplings of LN, ileum and rectum, and PB after initiating ART to determine intracellular (IC) concentrations of the ARVs in these tissues and to assess the impact of treatment on virus production, measured by reduced numbers of productively infected HIV-1-RNA + cells and HIV-1 RNA in virions associated with the FDCn. Ten of the subjects were naïve to ART, and two subjects had been previously treated but had been off therapy for >1 y.…”

mentioning

confidence: 99%

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Fletcher

Staskus²,

Wietgrefe³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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583

608

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Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution.drug levels | pharmacokinetics | FDC network C ombination antiviral therapy (ART) to suppress HIV-1 replication and reduce plasma viremia to below the limits of detection in peripheral blood (PB) has reduced mortality and dramatically improved quality of life for patients. However, immune reconstitution, measured by changes in the size of populations of CD4 T cells, is often incomplete, even after years of therapy (1-3). During apparently effective therapy, CD4 T-cell populations in PB mononuclear cells (PBMCs), lymph node (LN), and gut-associated lymphoid tissue (GALT) remain abnormally low and innate and adaptive immunity is not fully restored (4). Levels of T-cell activation and innate system activation are often higher than that observed in well-matched uninfected adults (5, 6). These persistent abnormalities may contribute to abnormal vaccine responses (7, 8), a higher than normal incidence of non-AIDS-related cancers (9, 10) and increased risk for clinical conditions associated with chronic inflammation (e.g., cardiac disease, clotting disorders, pulmonary hypertension, emphysema, and stroke) (11-18). Thus, improvements over current approaches to treatment of HIV infection that more fully restore normal immune function might significantly improve health and life expectancy.To that end, we explore here the hypothesis that antiretroviral drug (ARV) concentrations might be insufficient to fully suppress replication in the lymphoid tissue compartments, which are the principal sites where virus is produced, stored as complexes on the follicular dendritic cell network (FDCn) (19-21), and persists in latently infected cells during ART (19,20,22). This hypothesis builds first on the link between the size of the reservoir and the degree of inflammation, arguing that persistent virus production during ART could sustain immune activation (IA) and downstream pathological consequences (23, 24), and second on drug distribution studies in animal models of AIDS in which ...

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HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects

Cited by 482 publications

References 32 publications

Establishment and stability of the latent HIV-1 DNA reservoir

Establishment and stability of the latent HIV-1 DNA reservoir

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

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