Reduction of simian-human immunodeficiency virus 89.6P viremia in rhesus monkeys by recombinant modified vaccinia virus Ankara vaccination

Abstract

Since cytotoxic T lymphocytes (CTLs) are critical for controlling human immunodeficiency virus type 1 (HIV-1) replication in infected individuals, candidate HIV-1 vaccines should elicit virus-specific CTL responses. In this report, we study the immune responses elicited in rhesus monkeys by a recombinant poxvirus vaccine and the degree of protection afforded against a pathogenic simian-human immunodeficiency virus SHIV-89.6P challenge. Immunization with recombinant modified vaccinia virus Ankara (MVA) vectors expressing SIVmac239 gag-pol and HIV-1 89.6 env elicited potent Gag-specific CTL responses but no detectable SHIV-specific neutralizing antibody (NAb) responses. Following intravenous SHIV-89.6P challenge, sham-vaccinated monkeys developed low-frequency CTL responses, low-titer NAb responses, rapid loss of CD4+ T lymphocytes, high-setpoint viral RNA levels, and significant clinical disease progression and death in half of the animals by day 168 postchallenge. In contrast, the recombinant MVA-vaccinated monkeys demonstrated high-frequency secondary CTL responses, high-titer secondary SHIV-89.6-specific NAb responses, rapid emergence of SHIV-89.6P-specific NAb responses, partial preservation of CD4+ T lymphocytes, reduced setpoint viral RNA levels, and no evidence of clinical disease or mortality by day 168 postchallenge. There was a statistically significant correlation between levels of vaccine-elicited CTL responses prior to challenge and the control of viremia following challenge. These results demonstrate that immune responses elicited by live recombinant vectors, although unable to provide sterilizing immunity, can control viremia and prevent disease progression following a highly pathogenic AIDS virus challenge.

FIG. 1

Vaccine-elicited CTL responses. Mamu-A*01-positive monkeys were immunized at weeks 0, 4, and 21 with recombinant MVA constructs expressing SIV gag-pol and HIV-1 89.6 env. Vaccine-elicited CD8⁺ T-cell responses specific for the immunodominant SIV Gag p11C (CTPYDINQM) epitope (1, 24) were measured by tetramer staining of freshly isolated PBMC (3, 21). The percent CD3⁺ CD8⁺ T cells that bound the Mamu-A*01/p11C tetramer is shown. Arrows indicate times of immunization.

FIG. 2

Secondary CTL responses following challenge. Monkeys were challenged with SHIV-89.6P by the i.v. route on day 0. CD8⁺ T-cell responses specific for the SIV Gag p11C epitope were determined by tetramer staining of freshly isolated PBMC at multiple time points (3, 21). The percent CD3⁺ CD8⁺ T cells that bound the Mamu-A*01/p11C tetramer is shown.

FIG. 3

NAb responses following challenge. Plasma antibody titers capable of neutralizing SHIV-89.6 (A) and SHIV-89.6P (B) were measured by MT-2 cell-killing assays at multiple time points (9).

FIG. 4

CD4⁺ T-lymphocyte counts following challenge. CD4⁺ T-lymphocyte counts in peripheral blood were determined by multiplying the total lymphocyte count by the percentage of CD3⁺ CD4⁺ lymphocytes at multiple time points.

FIG. 5

Viral RNA levels following challenge. Plasma viral RNA levels were determined at multiple time points by a real-time amplification assay with a detection limit of 500 copies/ml (17, 39). †, death of the animal.

FIG. 6

Correlation of prechallenge vaccine-elicited plateau-phase p11C-specific CTL responses as determined by tetramer staining and day 70 postchallenge setpoint viral RNA levels (P = 0.03).