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Pathogenesis and Immunity

Protection of Macaques against Intrarectal Infection by a Combination Immunization Regimen with Recombinant Simian Immunodeficiency Virus SIVmne gp160 Vaccines

Patricia Polacino, Virginia Stallard, David C. Montefiori, Charles R. Brown, Barbra A. Richardson, William R. Morton, Raoul E. Benveniste, Shiu-Lok Hu
Patricia Polacino
Regional Primate Research Center and
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Virginia Stallard
Regional Primate Research Center and
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David C. Montefiori
Duke University Medical Center, Durham, North Carolina; and
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Charles R. Brown
Henry M. Jackson Foundation, Rockville, and
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Barbra A. Richardson
Department of Biostatistics, University of Washington, and
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William R. Morton
Regional Primate Research Center and
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Raoul E. Benveniste
National Cancer Institute, Frederick, Maryland
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Shiu-Lok Hu
Regional Primate Research Center and
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington;
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DOI: 10.1128/JVI.73.4.3134-3146.1999
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  • Fig. 1.
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    Fig. 1.

    Viral load in macaques challenged intrarectally with E11S clone (a and b) or uncloned SIVmne (c to f). The proviral load in PBMC was determined by PCR analysis by using radiolabeled primer incorporation (a to d). Values are expressed as copies of proviral genome per 106 PBMC. Quantification of proviral DNA was determined by using an external standard containing a known copy number of SIVmne E11S proviral DNA. Plasma viral load was determined by RT-QC-PCR (e and f) with an internally controlled template as described in Materials and Methods.

  • Fig. 2.
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    Fig. 2.

    SIV-specific antibody responses in immunized and control macaques after challenge. Dilutions of macaque sera collected at the indicated times were incubated with disrupted, gradient-purified SIVmne virion proteins immobilized on microtiter plates. Endpoint titers were defined as the reciprocal of the highest dilution that gave an optical absorbance value at least threefold higher than the average values obtained with SIV-negative macaque sera. Panels (a) and (b), immunized and control animals challenged with SIVmne E11S; panels (c) and (d), immunized and control animals challenged with uncloned SIVmne. Arrows indicate the time of challenge.

  • Fig. 3.
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    Fig. 3.

    Immunoblot analysis of SIV-specific antibody responses in macaques challenged with SIVmne clone E11S (A) or uncloned SIVmne (B). Macaque plasma (diluted 100-fold) was reacted with SDS-PAGE-separated proteins from disrupted, sucrose gradient-purified SIVmne clone E11S as described earlier (5). At various times after SIV challenge, antibodies were detected in infected animals to envelope surface (gp120) and transmembrane (gp32) proteins; to the Gag proteins p28, p16, and p6; and to the Vpx protein p14. Antibodies to gp120 and gp32 were evident in all immunized macaques on the day of challenge (week 0). A weak antibody that cross-reacts with p28 was also present in one control animal at week 0 (animal 92169 [panel A]). This has occasionally been observed in naive M. fascicularis. The source of this cross-reactive antibody is unknown.

  • Fig. 4.
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    Fig. 4.

    In situ hybridization analysis of lymph nodes from macaques challenged intrarectally with uncloned SIVmne. Peripheral lymph node samples from control (a to f) and immunized (g to i) animals were collected on day 14 (a to c) or day 26 or 27 (d to i) after challenge. Samples were examined with SIV-specific digoxigenin-labeled riboprobes as described in Materials and Methods. Panels: a and b, macaque 93191; c, macaque 93080; d, macaque 93204; e, macaque 93205; f, macaque 93206; g, macaque 90099; h, macaque 90108; and i, macaque 91074. Magnifications in panels a to i are, respectively, ×25, ×25, ×31.2, ×10, ×15, ×31.2, ×31.2, ×12.5, and ×12.5. The sample in panel a was hybridized with a “sense” probe as a control. All other samples shown were hybridized with “anti-sense” probes.

  • Fig. 5.
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    Fig. 5.

    SIV-specific antibody responses in immunized macaques. Sera collected on the day of challenge were analyzed for neutralizing activities against the homologous challenge virus (E11S or uncloned SIVmne). Neutralizing titers are expressed as the reciprocal serum dilutions that resulted in >50% cytopathicity of E11S or uncloned SIVmne infection in CEMx174 cells (a and c). Serum reactivity with disrupted SIVmne E11S virion proteins was analyzed by ELISA, and the results are expressed as endpoint titers (b and d). Top panels (a and b), animals challenged with SIVmne E11S; bottom panels (c and d), animals challenged with uncloned SIVmne. Solid symbols denote persistently infected animals; open symbols show the protected animals. The shaded areas denote the 95% confidence interval for the mean titer of the protected animals. The upper and lower dotted lines represent, respectively, the titers of positive and negative control serum samples in each assay.

  • Fig. 6.
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    Fig. 6.

    Analysis of env V1 sequences recovered from the PBMC of macaques infected intrarectally with uncloned SIVmne. (A) Percentages of E11S-like (solid area) and variant-like (stippled area) V1 sequences in each of the six intrarectally infected control macaques are represented in individual pie charts. For comparison, the composition of the uncloned challenge virus and the results of a similar analysis (31) of intravenously infected animals are included. Analyses of PBMC were done on samples collected 2 weeks after infection. (B) Change of V1 genotype in the PBMC of animals 93204 and 93205 during the acute phase of infection. Percentages of E11S-like (solid bar) and variant-like (stippled bar) V1 sequences are as indicated.

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    Fig. 7.

    Peripheral blood CD4+ T-lymphocyte numbers in immunized and control macaques after intrarectal challenge with SIVmne E11S (a and b, respectively) or uncloned SIVmne (c and d, respectively). Animals euthanatized because of AIDS are labeled A; animals sacrificed at the end of the experimentation period are labeled E; and animals that died of causes unrelated to AIDS are labeled U. The last datum point for each animal represents the time of death or the termination of the experiment (euthanatized, alive, or rechallenged [Rech]).

Tables

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  • Table 1.

    Virus isolation and nested PCR analysis of PBMC and lymph node cells from macaques after intrarectal challenge with E11S clone or with uncloned SIVmne

    Challenge virus and macaque no.Results of analysis at (wks postchallenge)a:
    248121620344275829098112171210
    E11S clone
     Control
      92169+/++/++/++/+−/+−/+−/+−/++/+−/++/++/++/++/NTE
      92172+/++/++/++/++/+−/+NT/NT+/++/++/++/++/+U
      93023+/++/++/++/++/++/+−/++/++/++/++/++/++/+E
     Immunized
      86171−/−+/+−/+−/+−/+−/+−/+−/+−/−−/+−/−−/−−/−−/NTE
      90071−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−R
      90077−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−R
      90099−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−R
    24612203240557092109124133141180
    Uncloned SIVmne
     Control
      93204+/+/++/+/++/++/++/++/++/++/++/++/++/++/++/++/+A
      93205+/+/++/+/++/++/++/++/++/+A
      93191+/+/++/+/++/++/++/++/++/++/++/++/++/++/++/++/+A
      93206+/+/++/+/+−/+−/+−/+−/+−/−−/−−/−−/−−/−−/−NT/−NT/−NT
      93080+/+/++/+/++/+−/+−/+−/+−/+−/+−/+−/+−/−−/−NT/−NT/−NT
      92175+/+/++/+/++/+−/−−/−−/+−/−−/+−/−−/−−/−−/NTNT/−NT/−NT
     Immunizedb
      90071−/−/NT−/−/NT−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−NT
      90077−/−/−−/−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−NT
      90099−/−/−−/+/−−/+−/−−/−−/−−/−−/−−/?−/?−/−−/−−/−−/−NT
      90090+/+/++/+/++/++/++/++/++/++/+A
      91074−/−/−−/−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−NT
      90108−/−/−−/−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−NT
    • ↵a Symbols within each column denote positive (+) or negative (−) results in the following assays: virus isolation from PBMC, PCR analysis of PBMC DNA, and PCR analysis of lymph node DNA. When only two data are indicated, they refer to results from the first two assays. R, reassigned to be rechallenged with uncloned SIVmne. Animals 93204, 93205, and 93191 were euthanatized due to AIDS at, respectively, 160, 55, and 178 weeks after challenge. Letters within the column denote the cause of death as follows: A, AIDS-related euthanasia; E, elective euthanasia; U, unrelated death. NT, not tested; ?, results inconclusive.

    • ↵b Macaques 90071, 90077, and 90099 were previously challenged intrarectally with SIVmne E11S (produced from a HuT 78 single-cell clone). Macaques 90090, 91074, and 90108 were challenged intravenously at the same time with the same virus grown on macaque PBMC (31). All six animals were protected from the first challenge and were consistently found to be virus negative by PBMC coculture and nested PCR for >2 years before rechallenge with uncloned SIVmne.

  • Table 2.

    Summary of results from challenge studies

    Challenge routeNo. of uninfected macaques/total no. of macaques challenged (% protection) with:
    E11S cloneUncloned SIVmne
    ImmunizedControlPImmunizedControlP
    Intravenousa 14/16 (88)1/15 (7)<0.0013/10 (30)0/10 (0)0.2
    Intrarectal3/4 (75)0/3 (0)0.1435/6 (83)0/6 (0)0.015
    • ↵a Results of previous intravenous challenge studies (31) are included here for comparison.

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Protection of Macaques against Intrarectal Infection by a Combination Immunization Regimen with Recombinant Simian Immunodeficiency Virus SIVmne gp160 Vaccines
Patricia Polacino, Virginia Stallard, David C. Montefiori, Charles R. Brown, Barbra A. Richardson, William R. Morton, Raoul E. Benveniste, Shiu-Lok Hu
Journal of Virology Apr 1999, 73 (4) 3134-3146; DOI: 10.1128/JVI.73.4.3134-3146.1999

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Protection of Macaques against Intrarectal Infection by a Combination Immunization Regimen with Recombinant Simian Immunodeficiency Virus SIVmne gp160 Vaccines
Patricia Polacino, Virginia Stallard, David C. Montefiori, Charles R. Brown, Barbra A. Richardson, William R. Morton, Raoul E. Benveniste, Shiu-Lok Hu
Journal of Virology Apr 1999, 73 (4) 3134-3146; DOI: 10.1128/JVI.73.4.3134-3146.1999
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KEYWORDS

Gene Products, env
Simian Acquired Immunodeficiency Syndrome
simian immunodeficiency virus
Vaccines, Synthetic
Viral Vaccines

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