Our research is focused on developing novel strategies to cure HIV infection. This involves finding ways to significantly reduce the pool of cells with latent HIV-infection that can reactivate and induce recrudescent viremia following ART cessation or enhancing immunity against HIV such that after ART cessation any residual viral reactivation can be eliminated or stringently controlled over a lifetime. While the challenge of finding a cure for HIV infection cannot be underestimated, if successful, this work could significantly contribute towards the global fight against one of the deadliest infectious diseases of the 21st century.

Understanding mechanisms of HIV persistence

ART does not cure HIV infection due to the ability for the virus to integrate its genetic material into the host genome and remain dormant (i.e., latent). These latently-infected cells are long-lived and can carry an integrated, fully replication-competent form of the HIV genome. As such, if ART is stopped the virus can reactivate from this pool of latently-infected cells and resume replication and disease progression. This pool of latently-infected cells is commonly referred to as the “HIV reservoir”. We believe identifying where these latently-infected cells are located and understanding the mechanisms that allow them to persist during long-term ART will allow us to develop strategies to limit viral persistence in people living with HIV.

HIV reservoir depletion

We are evaluating several reservoir depletion strategies, including the use of latency-reversing agents (LRA) that can induce HIV gene expression in the presence of ART. Upon viral reactivation, infected cells can then be eliminated through viral cytopathic effects or following recognition and elimination by immune mechanisms.  We are currently assessing the safety and efficacy of multiple LRAs to determine their potential to disrupt HIV latency in vivo. As new LRAs become available, we are addressing important questions regarding their clinical application, such as; 1) When are LRAs most effective, i.e., at the time of ART initiation or during full ART suppression? 2) How long should LRAs be administered in order to achieve clinically-relevant reservoir reduction? 3) What dose and/or route of administration is optimal for targeting both circulating and tissue-resident HIV reservoirs? 

Enhancing immunity against HIV

Another potential route to a HIV cure is to enhance the immune system in people living with HIV such that after ART is stopped, reactivating HIV reservoirs can be eliminated or stringently controlled over a lifetime, thus eliminating the need for ART. Crucial to this approach, are CD8+ T cell responses which constitute important components of the adaptive immune response against intracellular pathogens such as HIV. However, in the vast majority of people living with HIV, CD8+ T cell responses are often suboptimal and ineffective at suppressing HIV replication after ART is withdrawn. We are working to develop therapeutic vaccination protocols that can generate high frequencies of potent, systemically distributed, HIV-specific CD8+ T cell responses with optimized magnitude, breadth, and function at the time of ART release to ensure immediate interception of rebounding HIV reservoirs.

Aging and immune function

A hallmark of aging is the gradual decline in the immune system’s ability to mount an effective cell-mediated and/or humoral response against novel antigenic challenge. The consequences of this can be severe, as aging is often associated with increased susceptibility to infectious diseases, malignancies and reduced responses to vaccination. We are interested in understanding how aging impact immune function with the goal of developing interventions to rejuvenate immunity in the elderly.