Yukl, SA, Shergill, AK, McQuaid, K, Gianella, S, Lampiris, H, Hare, CB et al.. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS 24: 2451-2460

San Francisco VA Medical Center (SFVAMC) and University of California, San Francisco (UCSF), San Francisco, California, USA.
AIDS (London, England) (Impact Factor: 5.55). 10/2010; 24(16):2451-60. DOI: 10.1097/QAD.0b013e32833ef7bb
Source: PubMed


To determine whether raltegravir-containing antiretroviral therapy (ART) intensification reduces HIV levels in the gut.
Open-label study in HIV-positive adults on ART with plasma HIV RNA below 40 copies/ml.
Seven HIV-positive adults received 12 weeks of ART intensification with raltegravir alone or in combination with efavirenz or darunavir. Gut cells were obtained by upper and lower endoscopy with biopsies from duodenum, ileum, colon, and rectum at baseline and 12 weeks. Study outcomes included plasma HIV RNA, HIV DNA and RNA from peripheral blood mononuclear cells (PBMC) and four gut sites, T-cell subsets, and activation markers.
Intensification produced no consistent decrease in HIV RNA in the plasma, PBMC, duodenum, colon, or rectum. However, five of seven participants had a decrease in unspliced HIV RNA per 10 CD4(+) T cells in the ileum. There was a trend towards decreased T-cell activation in all sites, which was greatest for CD8(+) T cells in the ileum and PBMC, and a trend towards increased CD4(+) T cells in the ileum.
Most HIV RNA and DNA in the blood and gut is not the result of ongoing replication that can be impacted by short-term intensification with raltegravir. However, the ileum may support ongoing productive infection in some patients on ART, even if the contribution to plasma RNA is not discernible.

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    • "However, the source of this residual viremia remains controversial, with competing arguments supporting its origin from incompletely suppressed viral replication (especially in tissues), vs. suggestions that it arises from stochastic reactivation of latently infected cells, or from persistently infected cells not susceptible to inhibition by cART, and/or resistant to immune clearance. Numerous cART intensification studies have attempted to address this question, with most showing no impact, although a couple of studies have demonstrated apparent effects of treatment intensification, particularly when adding integrase inhibitors to base regimens including protease inhibitors [28], [29] [30]. "
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    ABSTRACT: Objectives Viral reservoirs–persistent residual virus despite combination antiretroviral therapy (cART)–remain an obstacle to cure of HIV-1 infection. Difficulty studying reservoirs in patients underscores the need for animal models that mimics HIV infected humans on cART. We studied SIV-infected Chinese-origin rhesus macaques (Ch-RM) treated with intensive combination antiretroviral therapy (cART) and 3 weeks of treatment with the histone deacetyalse inhibitor, suberoylanilide hydroxamic acid (SAHA). Methods SIVmac251 infected Ch-RM received reverse transcriptase inhibitors PMPA and FTC and integrase inhibitor L-870812 beginning 7 weeks post infection. Integrase inhibitor L-900564 and boosted protease inhibitor treatment with Darunavir and Ritonavir were added later. cART was continued for 45 weeks, with daily SAHA administered for the last 3 weeks, followed by euthanasia/necropsy. Plasma viral RNA and cell/tissue-associated SIV gag RNA and DNA were quantified by qRT-PCR/qPCR, with flow cytometry monitoring changes in immune cell populations. Results Upon cART initiation, plasma viremia declined, remaining <30 SIV RNA copy Eq/ml during cART, with occasional blips. Decreased viral replication was associated with decreased immune activation and partial restoration of intestinal CD4+ T cells. SAHA was well tolerated but did not result in demonstrable treatment-associated changes in plasma or cell associated viral parameters. Conclusions The ability to achieve and sustain virological suppression makes cART-suppressed, SIV-infected Ch-RM a potentially useful model to evaluate interventions targeting residual virus. However, despite intensive cART over one year, persistent viral DNA and RNA remained in tissues of all three animals. While well tolerated, three weeks of SAHA treatment did not demonstrably impact viral RNA levels in plasma or tissues; perhaps reflecting dosing, sampling and assay limitations.
    PLoS ONE 07/2014; 9(7):e102795. DOI:10.1371/journal.pone.0102795 · 3.23 Impact Factor
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    • "Because HIV-1 might replicate in tissue reservoirs where drug concentrations are suboptimal (Fletcher et al., 2014), such as lymph nodes, gut associated lymphoid tissues, bone marrow and the central nervous system, some RAL intensification studies assessed the immunologic and virologic responses in tissues. Yukl et al., showed reduction in unspliced HIV RNA, T cell activation and a trend towards CD4 þ T cell increases in ileum, suggesting that this tissue may be an important site for ongoing replication in some patients on cART (Yukl et al., 2010). In contrast, therapy intensification with RAL did not impact cerebrospinal viral loads (Dahl et al., 2011) or isolated HIV semen shedding (Osborne et al., 2013). "
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    ABSTRACT: Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) in recent years have transformed HIV infection into a chronic disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.
    Virology 04/2014; 454-455(1). DOI:10.1016/j.virol.2014.02.021 · 3.32 Impact Factor
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    • "In support of full suppression of viral replication with cART, patients with good adherence to treatment do not show evidence of viral evolution and treatment failure; also no further decrease of residual viremia is seen with intensification of cART regimens [5-7]. However, recent treatment intensification studies with the Integrase Inhibitor (INI) Raltegravir have noted an increase in episomal DNA and a reduction in the size of the latent reservoir [2-4]. These studies suggest that there is ongoing residual viral replication, which may be suppressed by addition of INIs to existing treatment regimens. "
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    ABSTRACT: The Human Immunodeficiency Virus type-1 (HIV-1) spreads by cell-free diffusion and by direct cell-to-cell transfer, the latter being a significantly more efficient mode of transmission. Recently it has been suggested that cell-to-cell spread may permit ongoing virus replication in the presence of antiretroviral therapy (ART) based on studies performed using Reverse Transcriptase Inhibitors (RTIs). Protease Inhibitors (PIs) constitute an important component of ART; however whether this class of inhibitors can suppress cell-to-cell transfer of HIV-1 is unexplored. Here we have evaluated the inhibitory effect of PIs during cell-to-cell spread of HIV-1 between T lymphocytes. Using quantitative assays in cell line and primary cell systems that directly measure the early steps of HIV-1 infection we find that the PIs Lopinavir and Darunavir are equally potent against both cell-free and cell-to-cell spread of HIV-1. We further show that a protease resistant mutant maintains its resistant phenotype during cell-to-cell spread is transmitted more efficiently than wild-type virus in the presence of drug. By contrast we find that T cell-T cell spread of HIV-1 is 4-20 fold more resistant to inhibition by the RTIs Nevirapine, Zidovudine and Tenofovir. Notably, varying the ratio of infected and uninfected cells in co-culture impacted on the degree of inhibition, indicating that the relative efficacy of ART is dependent on the multiplicity of infection. We conclude that if the variable effects of antiviral drugs on cell-to-cell virus dissemination of HIV-1 do indeed impact on viral replication and maintenance of viral reservoirs this is likely to be influenced by the antiviral drug class, since PIs appear particularly effective against both modes of HIV-1 spread.
    Retrovirology 12/2013; 10(1):161. DOI:10.1186/1742-4690-10-161 · 4.19 Impact Factor
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