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. 2005 Oct;79(19):12321-31.
doi: 10.1128/JVI.79.19.12321-12331.2005.

Vectored Gag and Env but not Tat show efficacy against simian-human immunodeficiency virus 89.6P challenge in Mamu-A*01-negative rhesus monkeys

Xiaoping Liang  1 , Danilo R Casimiro, William A Schleif, Fubao Wang, Mary-Ellen Davies, Zhi-Qiang Zhang, Tong-Ming Fu, Adam C Finnefrock, Larry Handt, Michael P Citron, Gwendolyn Heidecker, Aimin Tang, Minchun Chen, Keith A Wilson, Lori Gabryelski, Michael McElhaugh, Anthony Carella, Cheryl Moyer, Lingyi Huang, Salvatore Vitelli, Deepa Patel, Jing Lin, Emilio A Emini, John W Shiver
Affiliations

Vectored Gag and Env but not Tat show efficacy against simian-human immunodeficiency virus 89.6P challenge in Mamu-A*01-negative rhesus monkeys

Xiaoping Liang et al. J Virol. 2005 Oct.

Abstract

Simian-human immunodeficiency virus (SHIV) challenge studies in rhesus macaques were conducted to evaluate the efficacy of adenovirus-based vaccines in the context of different major histocompatibility complex class I genetic backgrounds and different vaccine compositions. Mamu-A*01 allele-negative rhesus monkeys were immunized with one of the following vaccine constructs: (i) replication-defective recombinant adenovirus type 5 (Ad5) expressing human immunodeficiency virus type 1 (HIV-1) Tat (Ad5/HIVTat); (ii) Ad5 vector expressing simian immunodeficiency virus (SIV) Gag (Ad5/SIVGag); (iii) Ad5 vector expressing the truncated HIV-1(jrfl) Env, gp140 (Ad5/gp140_jrfl); (iv) Ad5 vector expressing the SHIV-89.6P gp140 (Ad5/gp140_89.6P); or (v) the combination of Ad5/SIVGag and Ad5/gp140_jrfl. Following intravenous challenge with SHIV-89.6P, only those cohorts that received vaccines expressing Gag or Env exhibited an attenuation of the acute viremia and associated CD4-cell lymphopenia. While no prechallenge neutralizing antibody titers were detectable in either Ad5/gp140-vaccinated group, an accelerated neutralizing antibody response was observed in the Ad5/gp140_89.6P-vaccinated group upon viral challenge. The set-point viral loads in the Ad5/SIVGag- and Ad5/gp140_jrfl-vaccinated groups were associated with the overall strength of the induced cellular immune responses. To examine the contribution of Mamu-A*01 allele in vaccine efficacy against SHIV-89.6P challenge, Mamu-A*01-positive monkeys were immunized with Ad5/SIVGag. Vaccine-mediated protection was significantly more pronounced in the Mamu-A*01-positive monkeys than in Mamu-A*01-negative monkeys, suggesting the strong contributions of T-cell epitopes restricted by the Mamu-A*01 molecule. The implications of these results in the development of an HIV-1 vaccine will be discussed.

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Figures

FIG. 1.
FIG. 1.
Antigen-specific T-cell responses in monkeys immunized with SIV Gag and gp140 antigens delivered using Ad5 vectors (study A). The data are reported as the cohort geometric means of SFC/106 PBMC against the defined peptide pools and the associated standard errors of the geometric means. Shown are the results at 4 weeks after the second vaccine dose (week 8), 4 weeks after the third dose (week 33), around the time of challenge (week 40), and 40 days after virus challenge (day 40 PC). Postchallenge responses against the gp140_jrfl pool were not determined (ND).
FIG. 2.
FIG. 2.
Gag-specific T-cell responses in the Mamu-A*01-postive monkeys (study C). The data are reported as the cohort geometric means of the SFC/106 PBMC against the CM9 peptide (CM9) and the Gag peptide pool excluding peptides containing the CM9 epitope (Gag-CM9); also shown are the associated standard errors of the geometric means. Shown are the results at 4 weeks after the vaccine dose (week 4), at the time of challenge (week 6), and 24 days after virus challenge (day 24 PC).
FIG. 3.
FIG. 3.
Viral loads following intravenous challenge with SHIV-89.6P. The gray lines represent cohort geometric means of the viral loads up to when an animal's data point is unavailable. The animals that were humanely euthanized after exhibiting significant AIDS-like disease symptoms are marked. In study C, after day 300 the drop of baseline viral loads in the vaccine groups was due to the improved assay sensitivity to 50 viral RNA copies/ml.
FIG. 4.
FIG. 4.
Relationship between peak viral loads and postacute CD4 counts for (A) Mamu-A*01-negative and (B) Mamu-A*01-positive monkeys in all three studies.
FIG. 5.
FIG. 5.
Correlation of postacute viral loads with total ELISPOT responses (against Gag plus gp140_89.6P peptide pools) at peak anytime prior to challenge for study A vaccinees. A rank correlation analysis of the two parameters revealed a coefficient of −0.56 and one-tailed P of <0.03.
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