Creative and Novel Ideas in HIV Research (CNIHR) Program

We have identified a super-agonist monoclonal antibody (mAb) to human IL-21 (hIL-21) by screening homemade libraries. The mAb (clone 2P2) enhances the hIL-21 bioactivity at a level ~10 fold in vitro. The anti-hIL-21 super-agonist mAb represents a novel class of immunostimulating therapeutics to boost IL-21-mediated immune enhancement to eliminate activated latently infected cells for HIV cure. We hypothesize: 1. The super-agonist mAb 2P2 boosts hIL-21 bioactivity to enhance the cytotoxicity of CD8+ T cells and NK cells to eliminate activated latently infected CD4+ T cells. 2.

Current methodologies to quantify latent HIV-1 infection demand high cell numbers, require repeated leukapheresis of subjects and highly expert molecular biology techniques. For HIV cure regimens to reach the clinic, efficient and high-throughput diagnostic assays will be needed to confirm disruption of latent HIV-1 infection, preferably while patients continue antiretroviral therapy (ART).

We have identified a super-agonist monoclonal antibody (mAb) to human IL-21 (hIL-21) by screening homemade libraries. The mAb (clone 2P2) enhances the hIL-21 bioactivity at a level ~10 fold in vitro. The anti-hIL-21 super-agonist mAb represents a novel class of immunostimulating therapeutics to boost IL-21-mediated immune enhancement to eliminate activated latently infected cells for HIV cure. We hypothesize: 1. The super-agonist mAb 2P2 boosts hIL-21 bioactivity to enhance the cytotoxicity of CD8+ T cells and NK cells to eliminate activated latently infected CD4+ T cells. 2.

Human immunodeficiency virus (HIV) infection creates a long-lived latent reservoir that is maintained during antiretroviral therapy (ART). With a half-life of approximately ~44 months, these latently-infected CD4 T cells threaten recrudescence even after prolonged treatment and are a major impediment to the eradication of virus reservoirs. Our long-term goals are to discover the mechanisms responsible for conveying the very long half-life of latent CD4 T cells and develop strategies to shorten the half-life to allow their elimination during a relevant time interval.

Human immunodeficiency virus (HIV) infection creates a long-lived latent reservoir that is maintained during antiretroviral therapy (ART). With a half-life of approximately ~44 months, these latently-infected CD4 T cells threaten recrudescence even after prolonged treatment and are a major impediment to the eradication of virus reservoirs. Our long-term goals are to discover the mechanisms responsible for conveying the very long half-life of latent CD4 T cells and develop strategies to shorten the half-life to allow their elimination during a relevant time interval.

The human genome is not a linear sequence, but rather a contorted knot of chromosomes in the three-dimensional space of the nucleus. The transcription community is now starting to realize that chromosomes do not work in isolation. Interchromosomal associations regulate gene expression. This innovation, however, has not been applied to retroviral infections. We still talk of host and pathogen genomes as if they only interact locally.

The human genome is not a linear sequence, but rather a contorted knot of chromosomes in the three-dimensional space of the nucleus. The transcription community is now starting to realize that chromosomes do not work in isolation. Interchromosomal associations regulate gene expression. This innovation, however, has not been applied to retroviral infections. We still talk of host and pathogen genomes as if they only interact locally.

This study is aimed at determining whether targeting a novel immune-inhibitory pathway can deplete latently HIV infected CD4 memory T cells in HIV virally suppressed patients. Although antiretroviral therapy (ART) can suppress HIV replication and significantly improve the long-term health of the patient, it is unable to permanently remove latent reservoirs of virus. Therefore, novel strategies are needed to specifically target and destroy latently infected cells.

This study is aimed at determining whether targeting a novel immune-inhibitory pathway can deplete latently HIV infected CD4 memory T cells in HIV virally suppressed patients. Although antiretroviral therapy (ART) can suppress HIV replication and significantly improve the long-term health of the patient, it is unable to permanently remove latent reservoirs of virus. Therefore, novel strategies are needed to specifically target and destroy latently infected cells.

With 34 million people currently living with HIV, stopping the HIV epidemic remains imperative. Highly active antiretroviral therapy (HAART) limits viral replication, but is not curative. Thus, there is an urgent need to define and eliminate the viral reservoir. While the role of resting memory CD4+ T cells is well established, little is known about other cells as reservoirs. Macrophages are a major target of both HIV and SIV infection.