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A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge

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Science Translational Medicine  14 Jan 2015:
Vol. 7, Issue 270, pp. 270ra4
DOI: 10.1126/scitranslmed.3010298
  • Fig. 1. GSK744 LA plasma PK profile and tissue distribution in Depo-Provera–treated female rhesus macaques.

    Eight female rhesus macaques were injected intramuscularly with 30 mg of Depo-Provera on weeks −3 and 2 and with GSK744 LA (50 mg/kg) on weeks 0 and 4. (A) GSK744 plasma concentrations from Depo-Provera–treated female rhesus macaques (red) were compared with those from male rhesus macaques (gray) dosed with GSK744 LA (50 mg/kg) on weeks 0 and 4. Means ± SD are shown. Dotted and dashed horizontal lines represent 1× and 4× PAIC90, respectively. (B) Rectal and cervical tissue distribution of GSK744 was assessed from pinch biopsies each week in a subset (n = 4) of Depo-Provera–treated rhesus macaques. Each symbol represents tissue concentrations from an individual macaque. Solid lines represent the mean for the group. Dotted and dashed horizontal lines represent 1× and 4× PAIC90, respectively. (C and D) Correlation of (C) rectal tissue GSK744 or (D) cervical tissue GSK744 and plasma GSK744 concentrations. Each symbol represents the simultaneous plasma and tissue concentrations of an individual macaque.

  • Fig. 2. Monthly injections of GSK744 LA protect rhesus macaques against three intravaginal SHIV challenges.

    (A) Study design. Twelve female rhesus macaques were injected intramuscularly with 30 mg of Depo-Provera on weeks −3 and 2. Eight rhesus macaques were injected intramuscularly in the quadriceps with GSK744 LA (50 mg/kg) at two time points, weeks 0 and 4. Four Depo-Provera–treated rhesus macaques served as controls. All animals were challenged intravaginally on week 1 with 300 TCID50 of SHIV162P3. GSK744 LA–treated rhesus macaques were further challenged on weeks 5 and 7. All rhesus macaques were followed for 24 weeks. (B) Kaplan-Meier plot of GSK744 LA–treated and control rhesus macaques remaining aviremic after three intravaginal SHIV challenges. (C) Viral loads of control rhesus macaques (in gray) and GSK744 LA–treated rhesus macaques (in color). Open symbols represent samples sequenced for the integrase-coding region. Dotted line represents the limit of quantitation (LOQ), >40 SHIV RNA copies/ml plasma. (D) Plasma PK of individual GSK744 LA–treated rhesus macaques throughout the study. Open symbols represent drug concentrations at the time of first vRNA detection. Dotted and dashed horizontal lines represent 1× and 4× PAIC90, respectively. LOQ >0.01 μg/ml.

  • Fig. 3. Phylogram of SHIV162P3 sequences.

    Maximum likelihood phylogenetic tree of SHIV162P3 sequences from viral stock and from each of the six infected rhesus macaques. Hypermutated sequences were excluded. Red and brown circles represent sequences from GSK744 LA–treated rhesus macaques, squares represent sequences from control rhesus macaques, and pink diamonds represent SHIV162P3 viral stock. The vertical scale bar represents 0.0002 nucleotide substitutions per site.

  • Table 1. PK of GSK744 in rhesus macaques dosed with GSK744 LA (50 mg/kg).

    ND, not determined.

    AUC (0−τ)
    (μg × hour/ml)
    Cτ (μg/ml)Cmax (μg/ml)Tmax (day)*t1/2 (day)
    GSK744 LA dose121212122
    50 mg/kg (male)2047 (772)2593 (648)‡§2.66 (1.07)‡§2.62 (1.66)4.53 (2.12)5.17 (1.20)‡§14 (7–28)42 (35–56)8.6 (3.7)
    50 mg/kg (female),
    Depo-Provera–treated (PK study)
    1698 (455)1616 (591)1.20 (0.74)1.29 (0.59)4.21 (0.84)3.47 (1.45)10.5 (7–21)38.5 (35–49)ND||
    50 mg/kg (female),
    Depo-Provera–treated (challenge study)
    1247 (236)1587 (415)0.85 (0.51)1.39 (0.75)3.03 (0.71)3.45 (0.98)14 (7–21)42 (35–49)9.6 (7.8)

    *Tmax reported in median (range) and not subjected to statistical analyses.

    t1/2 estimated for the second dose only because terminal phases were long enough to estimate parameter.

    P < 0.05 when compared with female challenge study.

    §P < 0.05 when compared with female PK study.

    P < 0.05 when compared with female challenge study.

    ||t1/2 was not estimated for PK study because sufficient time points were not collected to estimate parameter.

    Supplementary Materials

    • www.sciencetranslationalmedicine.org/cgi/content/full/7/270/270ra4/DC1

      Fig. S1. Plasma PK of individual GSK744 LA–treated rhesus macaques throughout the PK study.

      Fig. S2. Correlation of rectal tissue GSK744 concentrations by processing method before freezing.

      Fig. S3. Correlation of cervical tissue GSK744 concentrations from individual samples.

      Fig. S4. GSK744 plasma concentrations from Depo-Provera–treated rhesus macaques compared with humans.

      Fig. S5. Consensus sequence analysis of SHIV integrase-coding regions from plasma of infected GSK744 LA–treated macaques.

      Fig. S6. Minimum number of T/F variants was estimated from plasma collected within 1 week of detection of viremia.

      Table S1. Summary of time of detection for plasma vRNA, proviral DNA, and anti-SHIV antibodies (Ab).

      Table S2. Susceptibility of single-cycle recombinant viruses with the integrase-coding regions of SHIV162P3 viral stock, FM26, FG95, and mutants to GSK744.

      Table S3. Env single-genome analysis summary.

    • Supplementary Material for:

      A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge

      Chasity D. Andrews, Yun Lan Yueh, William R. Spreen, Leslie St. Bernard, Mar Boente-Carrera, Kristina Rodriguez, Agegnehu Gettie, Kasi Russell-Lodrigue, James Blanchard, Susan Ford, Hiroshi Mohri, Cecilia Cheng-Mayer, Zhi Hong, David D. Ho, Martin Markowitz*

      *Corresponding author. E-mail: mmarkowitz{at}adarc.org

      Published 14 January 2015, Sci. Transl. Med. 7, 270ra4 (2015)
      DOI: 10.1126/scitranslmed.3010298

      This PDF file includes:

      • Fig. S1. Plasma PK of individual GSK744 LA–treated rhesus macaques throughout the PK study.
      • Fig. S2. Correlation of rectal tissue GSK744 concentrations by processing method before freezing.
      • Fig. S3. Correlation of cervical tissue GSK744 concentrations from individual samples.
      • Fig. S4. GSK744 plasma concentrations from Depo-Provera–treated rhesus macaques compared with humans.
      • Fig. S5. Consensus sequence analysis of SHIV integrase-coding regions from plasma of infected GSK744 LA–treated macaques.
      • Fig. S6. Minimum number of T/F variants was estimated from plasma collected within 1 week of detection of viremia.
      • Table S1. Summary of time of detection for plasma vRNA, proviral DNA, and anti-SHIV antibodies (Ab).
      • Table S2. Susceptibility of single-cycle recombinant viruses with the integrase-coding regions of SHIV162P3 viral stock, FM26, FG95, and mutants to GSK744.
      • Table S3. Env single-genome analysis summary.

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