DARE: Delaney AIDS Research Enterprise to find a cure

Our research group is a part of an ongoing international initiative concerned with HIV eradication strategies funded by the US NIH.

Characterising Latent HIV-1 Reservoirs

Our research group is conducting an in-depth analysis of peripheral blood and tissue samples from patients to provide an unprecedented systematic survey of three important factors which influence the magnitude and nature of the HIV reservoir in patients on effective therapy: treatment initiation (during acute versus chronic infection); the pool of follicular dendritic cell-associated virions in lymphoid follicles; and host genetics (CCR-5 Δ32 heterozygosity).

Genetic analysis of unspliced HIV RNA produced during HDAC inhibitor therapy

Despite advances in the treatment of HIV-infected patients, including the complete or near-complete inhibition of viral replication with standard therapies, replication-competent HIV persists indefinitely in all infected individuals. This latent form persists even in persons under effective therapy and can actively and life-threateningly rebound if therapy stops or is taken incorrectly. One promising approach to eradicate HIV and cure infected individuals is to reactivate and target this latent HIV for elimination.

During recent clinical trials, latent HIV was reactivated in patients who while on effective therapy were also treated with compounds called histone deacetylaseinhibitors. In this study we are investigating the genetic composition of this reactivated HIV to determine which cells and tissue compartments are producing this HIV.

We anticipate this study will reveal which cells are most prone to HIV reactivation by histone deacetylaseinhibitor therapy. In addition, this study will provide evidence that this reactivated HIV is an important prognostic marker for the latent form of HIV found in cells, an important step in current treatment strategies aimed at eradicating and curing HIV infection.

Longitudinal assessment of the relationship between immune activation and HIV persistence

T cell proliferation, differentiation and activation have poorly defined effects on the latent HIV reservoir during antiretroviral therapy (ART). We recently found that the most consistent association correlate of reservoir size is the frequency of memory CD4+ T cells expressing HLA-DR, which is upregulated upon activation.

In conducting this project we are measuring the levels of cellular activation markers over time in subjects who have been on ART for 15 years, and determining how these markers predict changes of infection frequency, genetic composition, and replication competency of HIV in memory T cells. Specifically, we will determine if the inducible reservoir is enriched in cells expressing markers of activation.