ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency - PubMed (original) (raw)

. 2002 Jan;76(1):292-302.

doi: 10.1128/jvi.76.1.292-302.2002.

D Venzon, N L Letvin, S Santra, D C Montefiori, N R Miller, E Tryniszewska, M G Lewis, T C VanCott, V Hirsch, R Woodward, A Gibson, M Grace, E Dobratz, P D Markham, Z Hel, J Nacsa, M Klein, J Tartaglia, G Franchini

Affiliations

ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency

R Pal et al. J Virol. 2002 Jan.

Abstract

T-cell-mediated immune effector mechanisms play an important role in the containment of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication after infection. Both vaccination- and infection-induced T-cell responses are dependent on the host major histocompatibility complex classes I and II (MHC-I and MHC-II) antigens. Here we report that both inherent, host-dependent immune responses to SIVmac251 infection and vaccination-induced immune responses to viral antigens were able to reduce virus replication and/or CD4+ T-cell loss. Both the presence of the MHC-I Mamu-A*01 genotype and vaccination of rhesus macaques with ALVAC-SIV-gag-pol-env (ALVAC-SIV-gpe) contributed to the restriction of SIVmac251 replication during primary infection, preservation of CD4+ T cells, and delayed disease progression following intrarectal challenge exposure of the animals to SIV(mac251 (561)). ALVAC-SIV-gpe immunization induced cytotoxic T-lymphocyte (CTL) responses cumulatively in 67% of the immunized animals. Following viral challenge, a significant secondary virus-specific CD8+ T-cell response was observed in the vaccinated macaques. In the same immunized macaques, a decrease in virus load during primary infection (P = 0.0078) and protection from CD4 loss during both acute and chronic phases of infection (P = 0.0099 and P = 0.03, respectively) were observed. A trend for enhanced survival of the vaccinated macaques was also observed. Neither boosting the ALVAC-SIV-gpe with gp120 immunizations nor administering the vaccine by the combination of mucosal and systemic immunization routes increased significantly the protective effect of the ALVAC-SIV-gpe vaccine. While assessing the role of MHC-I Mamu-A*01 alone in the restriction of viremia following challenge of nonvaccinated animals with other SIV isolates, we observed that the virus load was not significantly lower in Mamu-A*01-positive macaques following intravenous challenge with either SIV(mac251 (561)) or SIV(SME660). However, a significant delay in CD4+ T-cell loss was observed in Mamu-A*01-positive macaques in each group. Of interest, in the case of intravenous or intrarectal challenge with the chimeric SIV/HIV strains SHIV(89.6P) or SHIV(KU2), respectively, MHC-I Mamu-A*01-positive macaques did not significantly restrict primary viremia. The finding of the protective effect of the Mamu-A*01 molecule parallels the protective effect of the B*5701 HLA allele in HIV-1-infected humans and needs to be accounted for in the evaluation of vaccine efficacy against SIV challenge models.

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Figures

FIG. 1.

FIG. 1.

Schematic representation of the immunization regimen. IM, intramuscular route; IR, intrarectal route; IN, intranasal route; V, vcp180 (ALVAC-SIV-gpe), 108 PFU; vcp, empty vector control (ALVAC), 108 PFU; •, gp120 (300 μg) in QS-21 (100 μg). The numbers on the right indicate the number of Mamu-A*01-positive and Mamu-A*01-negative macaques in each group. The long black arrow signifies the time (week 117 or 147) of intrarectal challenge with SIVmac251 stock 561.

FIG. 2.

FIG. 2.

Humoral response in immunized animals. (A) Median titer values of Ab in prechallenge sera of the immunized macaques. ELISA Ab titers were obtained using a total lysate of SIVmac251 spiked with purified native gp120. (B) Neutralization Ab titers in sera of ALVAC-SIV-_gpe_-vaccinated macaques. The median neutralizing Ab titer of immunized animals from groups A through D to the laboratory-adapted SIVmac251 was assessed on CEMx174 cells using sera collected at month 12 (clear bar) and 2 weeks after the final boost (filled bar), whereas for group G animals the assay was conducted using sera collected at 2 weeks after the final boost (filled bar).

FIG. 3.

FIG. 3.

Levels of viremia in control macaques following SIV251 challenge. (A) Viral RNA copies/milliliter of plasma over time in each animal from groups E, F, and G (Fig. 1). (B) Mean levels of viral load at each time point in Mamu-A*01-positive and -negative control macaques.

FIG. 4.

FIG. 4.

Viral load and anamnestic response in Mamu-A*01-positive control and ALVAC-SIV-_gpe_-vaccinated macaques. (A) Average viral load in the mock-vaccinated (•) and ALVAC-SIV-_gpe_-vaccinated (▪) Mamu-A*01-positive macaques. (B) Mean values of the frequency of SIV Gag p11C-tetramer-binding CD8+ lymphocytes in the whole blood of the control and ALVAC-SIV-_gpe_-immunized Mamu-A*01-positive rhesus monkeys after challenge with SIVmac251. The percent p11C tetramer represents p11C-tetramer-binding CD8αβ+ T cells in unstimulated whole blood at each time point tested. Open circles represent the means and standard errors of means (SEMs) of percent p11C-tetramer-binding CD8αβ+ T cells of five monkeys that received the control vaccine, and filled squares represent the means and SEMs of percentages of p11C-tetramer-binding CD8αβ+ T cells of six monkeys that received the ALVAC-SIV-gpe vaccine.

FIG. 5.

FIG. 5.

Virus load, CD4+ T cell counts, and survival in vaccinated and control Mamu-A*01-negative macaques. (A) Mean virus load in Mamu-A*01-negative vaccinated (•), control (•), and all vaccinated and nonvaccinated Mamu-A*01-positive animals (▪). In this analysis, only animals that were monitored for 1 year are included. Therefore, the group of Mamu-A*01-positive animals included 8 macaques (6 vaccinees and 2 controls), the group of Mamu-A*01-negative vaccinees included 18 macaques, and the group of Mamu-A*01-negative control animals included 6 macaques. Peak viral loads during primary infection differed significantly between vaccinated and mock-vaccinated Mamu-A*01-negative macaques (P = 0.011) when analyzed using the Wilcoxon rank sum test. Because of the frequency of left censoring, the Wilcoxon-Gehan test was applied to the median viral load over later intervals. However, in these intervals no significant difference in virus load was observed (P = 0.37 at set point and P = 0.97 thereafter). (B) Mean CD4+ T-cell count in the animal groups described in the legend to panel A. The same symbols are used as for panel A, and the same animals per group were analyzed. CD4+ T-cell counts were tested by repeated-measures analysis of variance of the square-root-transformed raw data, and during primary infection a significant difference was observed between vaccinated and control animals (P = 0.013). (C) Number of deaths for SIVmac251-related disease within 1 year of viral challenge. The animals per group are the same as for panel A. Survival probabilities were estimated by the Kaplan-Meier method and demonstrated a trend of higher survival in vaccinated macaques than in control macaques.

FIG. 6.

FIG. 6.

Analysis of the mean CD4+ T-cell value in Mamu-A*01-positive and Mamu-A*01-negative macaques after intravenous SIV challenge. (Top) Data from five Mamu-A*01-positive and 12 Mamu-A*01-negative macaques challenged intravenously with SIVmac251 (stock 561). (Bottom) Data from five Mamu-A*01-positive and six Mamu-A*01-negative macaques challenged intravenously with SIVSME660.

FIG. 7.

FIG. 7.

Virus load and CD4+ T-cell counts in macaques infected with the SHIV89.6P and SHIVKU2 strains. Shown are viremia and CD4+ T-cell data obtained from four Mamu-A*01-positive and four Mamu-A*01-negative macaques infected intravenously with SHIV89.6P (top panels) and viremia and CD4+ T-cell counts obtained from five Mamu-A*01-positive and six Mamu-A*01-negative macaques infected intrarectally with SHIVKU2 (bottom panels).

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