Creative and Novel Ideas in HIV Research (CNIHR) Program

We will study the role of integration site distribution on the establishment of a latent reservoir and ultimately aim at preventing the establishment of a latent reservoir for HIV by manipulation of the HIV-1 integrase - LEDGF/p75 interaction. Our concept is based on the retargeting of HIV integration towards regions of the human genome that are less, or even not prone to reactivation. When successful, our strategy may lead to functional eradication of HIV.

Replication competent HIV DNA that persists during antiretroviral therapy (ART) is the main impediment to HIV eradication. Levels of latent HIV DNA also predict the rate of CD4+ T-cell loss, time to AIDS, virologic failure of ART and end organ disease; therefore, reducing provial levels could have substantial clinical benefits. CMV replication in the genital tract is associated with higher levels of T-cell immune activation within both the genital compartment and peripheral blood.

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.

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.