Cross-protective immune responses induced in rhesus macaques by immunization with attenuated macrophage-tropic simian immunodeficiency virus

Abstract

The simian immunodeficiency virus (SIV) macaque model of AIDS has provided a valuable system with which to investigate vaccine approaches for protection against human immunodeficiency virus type 1 (HIV-1) infection. In particular, the ability of macaques persistently infected with attenuated infectious molecular clones of SIV to resist challenge with the pathogenic parental swarm has conclusively demonstrated that protective immunity can be achieved by immunization prior to exposure. The breadth of these protective responses and the immunological correlates of protection, however, have not been identified. In addition, vaccine studies have mainly employed lymphocyte-tropic strains of HIV-1 and SIV. Recent studies have implicated macrophage-tropic strains in the transmission of HIV-1 and have suggested that these virus strains should be examined in vaccine strategies. Macrophage-tropic viruses may confer additional advantages in the induction of protective immunity by replication in antigen-presenting cells. In this study, the immune response of rhesus macaques inoculated with an attenuated macrophage-tropic recombinant of SIV mac 239 (SIV/17E-Cl) was evaluated with respect to protective immunity by heterologous challenge at various times after infection. Vigorous type-specific neutralizing-antibody responses restricted to SIV/17E-Cl were evident by 2 weeks postinfection. By 7 months, however, cross-reactive neutralizing antibodies emerged which neutralized not only SIV/17E-Cl but also the heterologous primary isolate SIV/DeltaB670. Challenge of SIV/17E-Cl-infected monkeys with SIV/DeltaB670 at various times postinfection demonstrated that protective responses were associated with the appearance of cross-reactive neutralizing antibodies. Furthermore, passive transfer of sera from SIV/17E-Cl-infected animals passively protected two of four naive recipients.

Expression of IFN‐γ induced CXCR3 agonist chemokines and compartmentalization of CXCR3+ cells in the periphery and lymph nodes of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome

“…All eight inoculated animals were sacrificed within 12-14 months of challenge with SIV/DeltaB670. Procedures for inoculation and monitoring of immunologic and virologic parameters have been described previously [9]. Peripheral blood and inguinal lymph node samples were collected at necropsy.…”

Maturation of envelope‐specific antibody responses to linear determinants in monkeys inoculated with attenuated SIV

“…Recently, our laboratory has developed new serological assays (antibody avidity and conformational dependence) to provide qualitative measurements of antibody populations to complement the existing quantitative measurements of antibody titer [4,6]. The use of these new serological assays to analyze the development of antibody responses in monkeys infected with attenuated SIV revealed a remarkable departure between quantitative and qualitative measures of antibody populations.…”

Dynamic evolution of antibody populations in a rhesus macaque infected with attenuated simian immunodeficiency virus identified by surface plasmon resonance

“…This maturation process was also associated with the development of protective immunity in monkeys infected with attenuated SIV [8]. Interestingly, while neutralizing antibody titers to the homologous virus emerge rapidly after infection, it is not until this antibody maturation is achieved that emergence of neutralizing antibody responses to the heterologous challenge virus is evident [8]. Furthermore, studies in the HIV-1 [10], SHIV [10] and equine infectious anemia virus (EIAV) [24] systems suggest that this antibody maturation process is a common property of lentiviruses [36].…”

“…-Fr, and longitudinal serum samples were assayed to determine the extent of SIV envelope-specific antibody maturation using a standard panel of serological assays [11]. Similar to the maturation of antibody responses described previously in rhesus macaques infected with closely related, highly attenuated SIV/17E-CL strain [8,11], the SIV envelope-specific antibody response in these four monkeys demonstrated dramatic quantitative and qualitative changes during the first 6-8 months PI as measured by a standard panel of ELISA assays (Fig. 1).…”

“…A protective AIDS vaccine will require both enduring and broadly protective cellular and humoral immune responses to maximize the potential for protection from many HIV-1 variants by different routes of exposure. Increasing evidence for the role of antibody responses in protective immunity comes from passive serum/antibody experiments where the protective efficacy of antibodies against viral exposure in the HIV-1/ chimp [14,38], SIV/monkey [8,22,23,47,49], and simian-human immunodeficiency virus (SHIV)/monkey [3,20,28,29,32,33,45] systems has been demonstrated. In addition, neutralizing human monoclonal antibodies (MAbs) directed to conformational epitopes in the HIV-1 envelope conferred protection against both mucosal and intravenous routes of exposure to SHIV [3,32].…”