Creative and Novel Ideas in HIV Research (CNIHR) Program

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.

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.