β-Chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques

Abstract

One of the obstacles to AIDS vaccine development is the variability of HIV-1 within individuals and within infected populations, enabling viral escape from highly specific vaccine induced immune responses. An understanding of the different immune mechanisms capable of inhibiting HIV infection may be of benefit in the eventual design of vaccines effective against HIV-1 variants. To study this we first compared the immune responses induced in Rhesus monkeys by using two different immunization strategies based on the same vaccine strain of HIV-1. We then utilized a chimeric simian͞HIV that expressed the envelope of a dual tropic HIV-1 escape variant isolated from a later time point from the same patient from which the vaccine strain was isolated. Upon challenge, one vaccine group was completely protected from infection, whereas all of the other vaccinees and controls became infected. Protected macaques developed highest titers of heterologous neutralizing antibodies, and consistently elevated HIV-1-specific T helper responses. Furthermore, only protected animals had markedly increased concentrations of RANTES, macrophage inf lammatory proteins 1␣ and 1␤ produced by circulating CD8 ؉ T cells. These results suggest that vaccine strategies that induce multiple effector mechanisms in concert with ␤-chemokines may be desired in the generation of protective immune responses by HIV-1 vaccines.

Protection of Rhesus Monkeys against Infection with Minimally Pathogenic Simian-Human Immunodeficiency Virus: Correlations with Neutralizing Antibodies and Cytotoxic T Cells

“…The previous study that demonstrated the efficacy of neutralizing antibodies induced by active immunization involved an immunogen that is expected to induce a narrowly specific immune response. That study demonstrated cross-neutralization only against a strain of HIV-1 derived from the same donor as the vaccine and protection against a strain of SHIV constructed from the same late isolate from that donor (28). We were able to induce neutralizing antibodies in rhesus monkeys with broad cross-reactivity against heterologous strains of HIV-1 and with neutralizing activity against a heterologous strain of SHIV.…”

“…The strongest protection that has been observed to date in vaccine studies in animal models has involved either passive immunization with IgG and/or MAbs that neutralize HIV-1 or active immunization to induce neutralizing antibodies (28,44,45,60). The previous study that demonstrated the efficacy of neutralizing antibodies induced by active immunization involved an immunogen that is expected to induce a narrowly specific immune response.…”

Chemokine immunobiology in HIV-1 pathogenesis

“…However, despite the discrepancies in the literature as cited above, it is our opinion that the preponderance of the more recent evidence indicates that decreasing levels of chemokine secretion are correlated with the severity of disease progression [100,112,113]. Particularly convincing are data from animal models showing an association between high circulating CC chemokine levels with sterilizing immunity in HIV-1-vaccinated macaques [114,115]. Nevertheless, given the intrinsic difficulty in accurately measuring serum or plasma levels of chemokines, developing methods to quantify the level of intracellular chemokines in specific immune subsets may offer a way around this difficulty.…”

Ebola virus-like particles protect from lethal Ebola virus infection

“…Presently, we cannot rule out the possibility that particular types or specificities of anti-EBOV antibodies are most responsible for protection from challenge, as suggested by studies with monoclonal antibodies against EBOV that protected mice from lethal Ebola infection (52). Additionally, it is feasible that antibody is required for protection and that onboard antibody may be an effective host response that delays viral takeover but alone may not be sufficient (53).…”