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. 2024 Sep 11;15(9):e0163224.
doi: 10.1128/mbio.01632-24. Epub 2024 Aug 13.

Analysis of the effect of HDAC inhibitors on the formation of the HIV reservoir

Lijun Ling  1   2   3   4 , Manse Kim  1   2   3   4 , Andrew Soper  1   2   3 , Martina Kovarova  1   2   3 , Rae Ann Spagnuolo  1   2   3 , Nurjahan Begum  1   2   3 , Jennifer Kirchherr  5 , Nancie Archin  2   5 , Diana Battaglia  1   2   3   4 , Dave Cleveland  6 , Angela Wahl  1   2   3   4 , David M Margolis  2   5   7 , Edward P Browne  2   5   7 , J Victor Garcia  1   2   3   4
Affiliations

Analysis of the effect of HDAC inhibitors on the formation of the HIV reservoir

Lijun Ling et al. mBio. .

Abstract

The HIV reservoir is more dynamic than previously thought with around 70% of the latent reservoir originating from viruses circulating within 1 year of the initiation of antiretroviral therapy (ART). In an ex vivo model system of HIV latency, it was reported that early exposure to class I histone deacetylase (HDAC) inhibitors might prevent these more recently infected cells from entering a state of stable viral latency. This finding raises the possibility that co-administration of HDAC inhibitors at the time of ART initiation may prevent the establishment of much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and panobinostat co-administered at the time of ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. As previously shown, SAHA and panobinostat were well tolerated in humanized mice. Unexpectedly, co-administration of SAHA resulted in an increase in the frequency of CD4+ cells carrying HIV DNA but did not alter the frequency of cell-associated HIV RNA in HIV-infected, ART-treated humanized mice. Co-administration of panobinostat did not alter levels of cell-associated HIV DNA or RNA. Our in vivo findings indicate that co-administration of HDAC inhibitors initiated at the same time of ART treatment does not prevent recently infected cells from entering latency.IMPORTANCECurrent antiretroviral therapy (ART) does not eradicate cells harboring replication-competent HIV reservoir. Withdrawal of ART inevitably results in a rapid viremia rebound. The HIV reservoir is more dynamic than previously thought. Early exposure to class I histone deacetylase (HDAC) inhibitors inhibit these more recently infected cells from entering a state of stable viral latency in an ex vivo model of latency, raising the possibility that co-administration of HDAC inhibitors at the time of ART initiation may reduce much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid or panobinostat during ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. Our in vivo study indicates that in contrast to in vitro observations, the co-administration of HDAC inhibitors at the same time of ART initiation does not prevent recently infected cells from entering latency.

Keywords: histone deacetylase inhibitors; human immunodeficiency virus; latency; reservoir.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig 1
Fig 1
In vitro- and in vivo-sustained release of SAHA is achieved using an ISFI. (A) In vitro daily cumulative SAHA release from the SAHA-ISFI formulation (30 µL) (n = 3). (B) In vitro daily SAHA release from the SAHA-ISFI formulation in A (n = 3). (C) In vivo serum concentration of SAHA in BALB/c mice (n = 4) after a single subcutaneous injection (50 µL) of the SAHA-ISFI. Data are expressed as mean ± SEM.
Fig 2
Fig 2
SAHA-ISFI treatment at the same time of ART initiation increases the levels of cell-associated HIV DNA but does not alter the levels of cell-associated HIV RNA in the peripheral blood cells of HIV-infected ART-treated humanized mice. (A) Experimental design. Humanized mice were exposed to HIV on day −61 and then were treated with either SAHA-ISFI plus ART or ART alone on day 0. ART was administered via FTC (1,500 mg/kg), TDF (1,560 mg/kg), and RAL (600 mg/kg). Longitudinal assessment of plasma viral loads as groups (B) and for individual animals (C) over the course of the experiment. The plasma viral load limit of detection (693 copies/mL) is indicated by a dashed line. Longitudinal detection of cell-associated (CA) viral RNA as groups (D) and for individual animals (E) in HIV-infected mice after treatment with SAHA-ISFI plus ART (red, n = 5) or ART alone (black, n = 5). Longitudinal detection of CA viral DNA as groups (F) and for individual animals (G) in HIV-infected mice after treatment with SAHA-ISFI plus ART (red, n = 5) or ART alone (black, n = 5). One animal from the SAHA-ISFI plus ART group was found dead on day 40. One animal from the ART alone group became ill and was euthanized on day 24. Data were collected for those two animals from our analysis of peripheral blood until the last timepoint before death. Blue arrows indicate the time of the SAHA-ISFI administration. Shaded gray areas depict ART treatment. Data are expressed as mean ± SEM. Open symbols in panels E and G indicating the limit of detection. Statistical analyses were performed using unpaired two-sided Mann-Whitney U-tests. Statistical significance was considered when P < 0.05.
Fig 3
Fig 3
SAHA-ISFI treatment at the same time of ART initiation results in an increase in the systemic levels of cell-associated HIV DNA but does not alter the levels of cell-associated HIV RNA in the tissues of HIV-infected ART-treated humanized mice. CA viral RNA (A) and DNA (B) were detected in the tissues of HIV-infected mice after treatment with SAHA-ISFI plus ART (red, n = 4) or ART alone (black, n = 4). BM, bone marrow; LIV, liver; LN, lymph nodes; LNG, lung; SPL, spleen, ORG, human thymic organoid. Combined: all individual tissues from all animals graphed together. Open symbols in panels A and B indicate samples with numbers below the limit of detection. Data are expressed as mean ± SEM. Statistical analyses were performed using unpaired two-sided Mann-Whitney U-tests. Statistical significance was considered when P < 0.05.
Fig 4
Fig 4
Panobinostat treatment at the time of ART initiation does not alter cell-associated HIV DNA and RNA levels in the peripheral blood cells from HIV-infected ART-treated humanized mice. (A) Experimental design. Humanized mice were exposed to HIV on day −28 and then were treated with either panobinostat plus ART or ART alone on day 0. Panobinostat was administered intraperitoneally at 2 mg/kg every 3 or 4 days for a total of 10 doses. ART was administered via FTC (1,500 mg/kg), TDF (1,560 mg/kg), and RAL (600 mg/kg). Longitudinal determination of the plasma viral loads as groups (B) and for individual animals (C) over the course of the experiment. The plasma viral load limit of detection (693 copies/mL) is indicated by a dashed line. Longitudinal measurements of CA viral RNA as groups (D) and for individual animals (E) in HIV-infected mice after treatment with panobinostat plus ART (red, n = 8) or ART alone (black, n = 8). Longitudinal measurements of CA viral DNA as groups (F) and for individual animals (G) in HIV-infected mice after treatment with panobinostat plus ART (red, n = 8) or ART alone (black, n = 8). Blue arrows at the bottom indicate the administration of panobinostat. Shaded gray areas depict ART administration. Open symbols in panel G indicate samples with numbers below the limit of detection. Data are expressed as mean ± SEM. Statistical analyses were performed using unpaired two-sided Mann-Whitney U-tests. Statistical significance was considered when P < 0.05.
Fig 5
Fig 5
Panobinostat treatment at the time of ART initiation does not alter systemic cell-associated HIV DNA and RNA levels in the tissues of HIV-infected ART-treated humanized mice. (A) Cell-associated HIV RNA and (B) DNA levels in the tissues of HIV-infected mice after treatment with panobinostat plus ART (red, n = 8) or ART alone (black, n = 7). Combined: all individual tissues from all animals graphed together. (C) The frequency of intact, 5’ def and 3’ def HIV-1 proviruses per million CD4+ T cells was detected in the tissues of HIV-infected mice after treatment with panobinostat plus ART (red, n = 7) or ART alone (black, n = 6). BM, bone marrow; LIV, liver; LN, lymph nodes; LNG, lung; SPL, spleen, ORG, human thymic organoid. Open symbols in panels A and B indicate samples with numbers below the limit of detection. Data are expressed as mean ± SEM. Statistical analyses were performed using unpaired two-sided Mann-Whitney U-tests. Statistical significance was considered when P < 0.05.
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