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.

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.

Despite the remarkable success of ART, HIV patients still experience excess mortality and morbidities. Persistent inflammation strongly predicts these complications and is likely an important mediator of disease hampering efforts towards a functional cure. While the etiology of persistent immune activation is incompletely understood, compromised mucosal barrier function and increased translocation of immunostimulatory microbial products from the gut lumen into the systemic circulation have been implicated.

Antiretroviral therapy (ART) has been effective in the suppression of HIV-1 viremia, but does not eliminate the reservoir of cells with latent HIV-1 infection, obligating lifelong therapy. Recent work has identified mechanisms for activating HIV-1 transcription in latently infected cells without inducing cellular activation, including the use of histone deacetylase (HDAC) inhibitors. This offers a pathway towards potential eradication of the viral reservoir and cure of the infection.

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.

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.

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.

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.

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 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.