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. 2012 Sep;86(18):9583-9.
doi: 10.1128/JVI.00996-12. Epub 2012 Jul 3.

Gag-specific cellular immunity determines in vitro viral inhibition and in vivo virologic control following simian immunodeficiency virus challenges of vaccinated rhesus monkeys

Kathryn E Stephenson  1 , Hualin Li, Bruce D Walker, Nelson L Michael, Dan H Barouch
Affiliations

Gag-specific cellular immunity determines in vitro viral inhibition and in vivo virologic control following simian immunodeficiency virus challenges of vaccinated rhesus monkeys

Kathryn E Stephenson et al. J Virol. 2012 Sep.

Abstract

A comprehensive vaccine for human immunodeficiency virus type 1 (HIV-1) would block HIV-1 acquisition as well as durably control viral replication in breakthrough infections. Recent studies have demonstrated that Env is required for a vaccine to protect against acquisition of simian immunodeficiency virus (SIV) in vaccinated rhesus monkeys, but the antigen requirements for virologic control remain unclear. Here, we investigate whether CD8(+) T lymphocytes from vaccinated rhesus monkeys mediate viral inhibition in vitro and whether these responses predict virologic control following SIV challenge. We observed that CD8(+) lymphocytes from 23 vaccinated rhesus monkeys inhibited replication of SIV in vitro. Moreover, the magnitude of inhibition prior to challenge was inversely correlated with set point SIV plasma viral loads after challenge. In addition, CD8 cell-mediated viral inhibition in vaccinated rhesus monkeys correlated significantly with Gag-specific, but not Pol- or Env-specific, CD4(+) and CD8(+) T lymphocyte responses. These findings demonstrate that in vitro viral inhibition following vaccination largely reflects Gag-specific cellular immune responses and correlates with in vivo virologic control following infection. These data suggest the importance of including Gag in an HIV-1 vaccine in which virologic control is desired.

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Figures

Fig 1
Fig 1
In vitro SIV inhibition assay results. (A) Mean SIVMAC251 log p27 levels (in pg/ml) at day 7 of culture in PBMC from SIV-infected rhesus monkeys with excellent in vivo viral control (SIV controllers; n = 3) and one naïve monkey. In vitro viral load is plotted for endogenous infection (left) and exogenous infection at a multiplicity of infection of 100 (right) in cocultures of CD8+/CD8-depleted PBMC using increasing numbers of CD8+ lymphocytes. Bars represent standard errors of the means. Bulk, unfractionated PBMC. (B) CD8+ cell-mediated viral inhibition in vaccinated rhesus monkeys is depicted for each vaccine group. *, P = 0.016, Wilcoxon signed rank test (Ad/M versus sham). The horizontal lines represent mean log inhibition levels. Ad, adenovirus serotype 26; D, DNA; M, MVA.
Fig 2
Fig 2
Correlation of prechallenge CD8+ cell-mediated viral inhibition and peak ELISPOT responses in vaccinated animals. CD8+ cell-mediated viral inhibition in vaccinated rhesus monkeys (n = 23) is plotted versus cellular immune responses to SIVMAC239 Gag, Pol, and Env as determined in gamma interferon ELISPOT assays at week 26 prechallenge. P values reflect Spearman rank correlation tests. P values of <0.017 were required for significance after multiple comparisons adjustments. SFC, spot-forming cells.
Fig 3
Fig 3
Correlation of prechallenge CD8+ cell-mediated viral inhibition and ICS responses among CD8+ T lymphocytes in vaccinated animals. CD8+ cell-mediated viral inhibition in vaccinated rhesus monkeys (n = 22) is plotted versus CD8+ total, central/transitional memory (CM; CD28+ CD95+), and effector memory (EM; CD28− CD95−) responses to Gag, Pol, and Env as determined in multiparameter gamma interferon ICS assays at week 26 prechallenge. ICS data are missing for one vaccinated animal. P values reflect Spearman rank correlation tests. P values of <0.006 were required for significance after multiple comparison adjustments.
Fig 4
Fig 4
Correlation of prechallenge CD8+ cell-mediated viral inhibition and ICS responses among CD4+ T lymphocytes in vaccinated animals. CD8+ cell-mediated viral inhibition in vaccinated rhesus monkeys (n = 22) is plotted versus CD4+ total, central/transitional memory (CM; CD28+ CD95+), and effector memory (EM; CD28− CD95−) responses to Gag, Pol, and Env as determined by multiparameter gamma interferon ICS assays at week 26 prechallenge. ICS data are missing for one vaccinated animal. P values reflect Spearman rank correlation tests. P values of <0.006 were required for significance after multiple comparison adjustments.
Fig 5
Fig 5
Correlation of prechallenge CD8+ cell-mediated viral inhibition with postchallenge in vivo set point plasma SIV RNA levels. CD8+ cell-mediated viral inhibition in vaccinated rhesus monkeys (n = 23) is plotted versus postchallenge set point plasma SIVMAC251 RNA levels (in log copies/ml). P values reflect Spearman rank correlation tests. P values of <0.05 were required for significance.
Fig 6
Fig 6
Correlation of CD8+ cell-mediated viral inhibition and concurrent ELISPOT responses in vaccinated animals postchallenge. CD8+ cell-mediated viral inhibition in vaccinated rhesus monkeys at weeks 20 to 44 postchallenge (n = 27) is plotted versus concurrent cellular immune responses to SIVMAC239 Gag, Pol, and Env as determined in gamma interferon ELISPOT assays. P values reflect Spearman rank correlation tests. P values of <0.013 were required for significance after multiple comparison adjustments. SFC, spot-forming cells.
Fig 7
Fig 7
Correlation of postchallenge CD8+ cell-mediated viral inhibition with concurrent in vivo set point plasma SIV RNA levels. CD8+ cell-mediated viral inhibition in vaccinated rhesus monkeys at weeks 20 to 44 postchallenge (n = 27) is plotted versus concurrent plasma SIVMAC251 RNA levels (in log copies/ml). P values reflect Spearman rank correlation tests. P values of <0.05 were required for significance.
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