Creative and Novel Ideas in HIV Research (CNIHR) Program

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.

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.

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.

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.

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.

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.