Limited protection from a pathogenic chimeric simian-human immunodeficiency virus challenge following immunization with attenuated simian immunodeficiency virus

Abstract

Two live attenuated single-deletion mutant simian immunodeficiency virus (SIV) constructs, SIV239Deltanef and SIVPBj6.6Deltanef, were tested for their abilities to stimulate protective immunity in macaques. During the immunization period the animals were examined for specific immune responses and virus growth. Each construct generated high levels of specific immunity in all of the immunized animals. The SIV239Deltanef construct was found to grow to high levels in all immunized animals, with some animals remaining positive for virus isolation and plasma RNA throughout the immunization period. The SIVPBj6.6Deltanef was effectively controlled by all of the immunized animals, with virus mostly isolated only during the first few months following immunization and plasma RNA never detected. Following an extended period of immunization of over 80 weeks, the animals were challenged with a pathogenic simian-human immunodeficiency virus (SHIV) isolate, SIV89. 6PD, by intravenous injection. All of the SIV239Deltanef-immunized animals became infected with the SHIV isolate; two of five animals eventually controlled the challenge and three of five animals, which failed to check the immunizing virus, progressed to disease state before the unvaccinated controls. One of five animals immunized with SIVPBj6.6Deltanef totally resisted infection by the challenge virus, while three others limited its growth and the remaining animal became persistently infected and eventually died of a pulmonary thrombus. These data indicate that vaccination with attenuated SIV can protect macaques from disease and in some cases from infection by a divergent SHIV. However, if animals are unable to control the immunizing virus, potential damage that can accelerate the disease course of a pathogenic challenge virus may occur.

FIG. 1

Plasma RNA levels following immunization with SIV_239Δnef. The lower limit of detection for the assay was 200 copies/ml. The values on the y axis are expressed as log¹⁰. Rhesus macaques infected with the pathogenic molecular clone SIV₂₃₉ produce 10⁵ to 10⁷ RNA copies/ml within 3 weeks of intravenous challenge.

FIG. 2

Antibody responses following immunization with attenuated virus and after challenge with SHIV_89.6PD. Levels of antibody are expressed as kinetic units (10⁻³ OD units/min) on the y axis for each individual animal. Solid symbols are data for animals immunized with attenuated virus. A, responses of animals immunized with the SIV_PBj6.6Δnef isolate; B, responses of animals immunized with SIV_239Δnef. Open symbols are data for control animals. The break in the x axis demarcates the period prior to challenge (to the left) and that following challenge (to the right), at week 92 p.i. for panel A and at week 86 for panel B.

FIG. 3

Immunoblot analysis of serum collected from attenuated-virus-immunized animals on the day of challenge. Reactivities to SIV_mne/e11s-derived antigens (A) and HIV-1_IIIB-derived antigens (B) are shown.

FIG. 4

Levels of circulating CD4⁺ lymphocytes in peripheral blood during the first 40 weeks following SHIV challenge. Solid symbols are data for vaccinated animals, and open symbols are data for control animals. A, levels for animals immunized with the SIV_PBj6.6Δnef isolate; B, levels for animals immunized with SIV_239Δnef.

FIG. 5

Early plasma virus RNA levels following challenge with SHIV_89.6PD. The lower limit of detection for the assay was 200 copies/ml. Solid symbols are data for vaccinated animals, and open symbols are data for control animals. A, levels for animals immunized with the SIV_PBj6.6Δnef isolate; B, levels for animals immunized with SIV_239Δnef. The values on the y axis are expressed as log¹⁰.