Broad neutralization and complement-mediated lysis of HIV-1 by PEHRG214, a novel caprine anti-HIV-1 polyclonal antibody.

OBJECTIVES: To assess the potency, breadth of action, and mechanism of action of the polyclonal goat anti-HIV antibody, PEHRG214. DESIGN: Typical human antibody responses to HIV-1 infection are unable to neutralize virus efficiently, clear the infection, or prevent disease progression. However, more potent neutralizing antibodies may be capable of playing a pivotal role in controlling HIV replication in vivo. PEHRG214 is a polyclonal caprine antibody raised against purified HIV-associated proteins, such that epitopes that are immunologically silent in humans may potentially be recognized in another species. It has been administered safely to HIV-infected individuals in Phase I clinical trials. METHODS: The anti-HIV activity of PEHRG214 was assessed using neutralization and virion lysis assays. The target proteins for PEHRG214 activity were investigated using flow cytometry and by adsorption of anti-cell antibodies from the antibody cocktail. RESULTS: PEHRG214 strongly neutralized a diverse range of primary HIV-1 isolates, encompassing subtypes A to E and both CCR5 and CXCR4 phenotypes. Neutralization was enhanced by the presence of complement. PEHRG214 also induced complement-mediated lysis of all HIV-1 isolates tested, and recognized or cross-reacted with a number of host cell proteins. Lysis was abrogated by adsorption with T and/or B cells expressing GPI-linked proteins, but not by GPI-deficient B cells or red blood cells. CONCLUSIONS: PEHRG214 was found to potently neutralize and lyse HIV-1 particles. By targeting host cell proteins present in the viral envelope, which are conserved among all strains tested, PEHRG214 potentially opens up a highly novel means of eliminating circulating virus in infected individuals.

Viral reservoirs an impediment to HAART: new strategies to eliminate HIV-1.

The introduction of potent drug combinations comprising reverse transcriptase and protease inhibitors has dramatically altered the natural history of HIV disease, at least in the short term. Unfortunately, poor penetrability into different anatomic compartments, toxicity and drug resistance, are some of the problems related to their prolonged use. HIV's ability to mutate and become resistant along with the ongoing viral replication during HAART, which may lead to the emergence of independently evolving viral strains in different anatomic compartments and establishment of latent viral reservoirs also remain critical for the success and failure of antiretroviral therapy. Current drug therapies do not eliminate these viral reservoirs, nor do they discourage their formation. New strategies are needed for flushing hidden pockets of HIV in vivo. This review will focus mainly on novel strategies in the pipeline, along with the recent developments in the field.

Comprehensive analyses of a unique HIV-1-infected nonprogressor reveal a complex association of immunobiological mechanisms in the context of replication-incompetent infection.

We recently demonstrated that a unique HIV-1-infected nonprogressor was infected with a nonevolving replication-incompetent HIV-1 strain, showing a total absence of viral evolution in vivo. Potent immune responses against HIV-1 were observed in his PBMC, despite an apparent lack of viral replication for at least 8 years. His PBMC resisted superinfection with CCR5, CXCR4, and dual-tropic HIV-1 strains, although highly purified CD4+ T cells supported infection, but without any visible cytopathic effect. Potent noncytolytic CD8+ T cell antiviral activity was shown to protect his PBMC from productive infection. This activity was not mediated by several known chemokines or IFN-gamma, which were produced at high levels after PHA activation of his CD8+ T cells, indicating the action of other CAF-like CD8 factors. This antiviral activity was a memory response, induced by HIV-specific stimulation to similar levels observed by PHA stimulation, but absent in ex vivo resting T cells. Immunological mechanisms associated with this antiviral suppressive activity included vigorous Gag-specific helper T cell proliferative responses and high-level IFN-gamma release by both CD4 and CD8 T cells. These responses were broadly directed against multiple Gag epitopes, both previously reported and some novel epitopes. Strong HIV-specific helper T cell function was also associated with strong neutralizing antibodies. Understanding how to induce these protective immune responses in other individuals could provide a major step forward in the design of effective immunotherapies or vaccines against HIV infection.