Creative and Novel Ideas in HIV Research (CNIHR) Program

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.

A major contributor to HIV persistence despite antiretroviral therapy (ART) is latent infection in long-lived CD4+ cell populations. Subsets of these cells have been shown to harbor virus and activate to re-establish infection when ART is stopped. Classification of discreet cell types and the mechanism by which reservoirs are maintained has been limited by lack of access to these cells, which are found in very small numbers in circulating 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.

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.

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).