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, SIV239Δnef and SIVPBj6.6Δnef, 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 SIV239Δnef 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 SIVPBj6.6Δnef 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 SIV239Δnef-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 SIVPBj6.6Δnef 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.

A single vaccination with attenuated SIVmac 239 via the tonsillar route confers partial protection against challenge with SIVmac 251 at a distant mucosal site, the rectum

“…The fourth immunized monkey (11105) with a reduced capacity to control the immunizing infection with SIV∆nef showed the highest viral burden following challenge infection accompanied by declining CD4 cells in both the peripheral blood and mucosa. Likewise, Lewis and co-workers observed an accelerated course of infection with SHIV 89.6P in animals that were unable to efficiently control the immunizing SIV∆nef infection (25). In accordance with our data, i.v.…”

Effects of in Vivo Cd8+ T Cell Depletion on Virus Replication in Rhesus Macaques Immunized with a Live, Attenuated Simian Immunodeficiency Virus Vaccine

“…In most cases, virus replication is well controlled and infected animals remain clinically healthy. However, in some instances, infection with live, attenuated SIV leads to high levels of viremia and disease progression in both infant and adult macaques 1234, raising questions as to the safety of these candidate vaccines. Although vigorous immune responses are induced after immunization with live, attenuated SIV (for a review, see reference 5), the mechanisms involved in controlling virus replication in the host are unknown.…”

Protection by Live, Attenuated Simian Immunodeficiency Virus against Heterologous Challenge

“…While the most solid protection has been observed in monkeys with apparent sterilizing immunity, some animals have exhibited longterm protective effects despite a transient take of the challenge virus (18,36), again apparently more consistent with immunemediated protection than with viral interference. Monkeys that control replication of SIVmac239⌬nef least effectively are the least protected upon subsequent challenge (23). Finally, CD4 ϩ cells in peripheral blood mononuclear cells (PBMC) of vaccinated animals are perfectly capable of supporting the replication of SIV in culture (11).…”