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. 2014 Jul 17;9(7):e102795.
doi: 10.1371/journal.pone.0102795. eCollection 2014.

Effects of treatment with suppressive combination antiretroviral drug therapy and the histone deacetylase inhibitor suberoylanilide hydroxamic acid; (SAHA) on SIV-infected Chinese rhesus macaques

Binhua Ling  1 , Michael Piatak Jr  2 , Linda Rogers  3 , Ann-Marie Johnson  3 , Kasi Russell-Lodrigue  3 , Daria J Hazuda  4 , Jeffrey D Lifson  2 , Ronald S Veazey  5
Affiliations

Effects of treatment with suppressive combination antiretroviral drug therapy and the histone deacetylase inhibitor suberoylanilide hydroxamic acid; (SAHA) on SIV-infected Chinese rhesus macaques

Binhua Ling et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests and financial disclosure exist with companies of Leidos Biomedical Research, Inc. and Merck Research Laboratories. There are no other relevant declarations relating to employment, consultancy, patents, products in development or marketed products etc. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Dynamics of SIV plasma viral loads (copy Eq/ml) before and during antiretroviral therapy.
Arrows with numbers below X-axis indicate time of initiation of antiretroviral therapy with RT inhibitors PMPA and FTC, and integrase inhibitor L-870812 (weeks 7 p.i.), addition of integrase inhibitor L-900564 (week 22 p.i.), and protease inhibitor Darunavir with boosting agent Ritonavir (week 30 p.i.). Grey shading shows the period of cART and the red dashed area indicates 3 weeks of SAHA therapy initiated 49 weeks post infection. The limit of detection by standard qRT-PCR is 30 copy Eq/ml (solid line) and ultrasensitive qRT-PCR is 15 copy Eq/ml (dashed line) or 4 copy Eq/ml (dotted line) attained when using larger volumes of plasma. Filled symbols show determined values, and open symbols indicate samples that were below the limit of detection for the indicated level of sensitivity. All tested samples were below the assay threshold sensitivity for the relevant assays from week 22 post infection on.
Figure 2
Figure 2. PBMC cell-associated levels of SIV gag DNA (A), RNA (B), and ratio of RNA/DNA (C) before and during SAHA, with cART throughout.
Figure 3
Figure 3. Dynamics of CD4+ and CD8+ T cell frequencies in the blood, peripheral lymph nodes and gut before and during cART.
The period of treatment is shown in grey shade, and the vertical dashed line indicates the initiation of SAHA treatment.
Figure 4
Figure 4. Dynamics of CD4+ T cell subsets (TN, TCM and TEM) in blood, peripheral lymph nodes and the gut during combination antiretroviral therapy (cART) and addition of SAHA.
The period of treatment is shown in grey shade, and the vertical dashed line indicates the initiation of SAHA treatment.
Figure 5
Figure 5. HLA-DR expression on CD4+ T cells and CD8+T cells in blood, peripheral LN and the gut during combination antiretroviral therapy and addition of SAHA.
The period of treatment is shown in grey shade, and the vertical dashed line indicates the initiation of SAHA treatment.
Figure 6
Figure 6. CD38 expression CD4+ T cells and CD8+T cells in blood, peripheral LN and the gut during combination antiretroviral therapy and addition of SAHA.
The period of treatment is shown in grey shade, and the vertical dash line indicates the initiation of SAHA treatment.
Figure 7
Figure 7. SAHA concentrations in plasma (A), and levels of histone acetylation (Ac-H4) (B and C), and association of Ac-H4 with RNA/DNA ratios (D) during SAHA and antiretroviral therapy.
The limit of detection of SAHA concentrations in plasma was 0.002 µM.
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