The study of HIV has yielded both effective antiretroviral medications, and a wealth of fundamental biological insights. Our lab is striving to build upon both aspects of this legacy through the study of HIV persistence on antiretroviral therapy. We approach this by structuring our lab into the following 5 areas of current focus, which are intended to reinforce each other. Each area is represented by a subgroup of lab members, led by a rotating ‘Czar’, which meets biweekly to brainstorm, troubleshoot, and identify areas for synergy.
Three elements are thought to be required for the elimination of persistent HIV reservoirs: i) expression of HIV antigens from reservoir-harboring cells – requiring latency reversal ii) functional immune effectors, such as HIV-specific cytotoxic T-lymphocytes (CTL) or natural killer (NK cells) iii) co-localization of these target and effector cell populations. Our recent work has built evidence, rationale, and mechanistic insights supporting the existence of a fourth element, arising from differences in the intrinsic sensitivities of target cells to CTL- or NK-cell mediated elimination.
The Resistance ‘Omics Subgroup aims to develop comprehensive profiles and broad understanding of the signatures of infected cells that survive CTL- or NK-cell killing assays, for example, using bulk or single cell transcriptomics or CRISPR screens. The Resistance Mechanisms Subgroup focuses in on validating and describing individual putative mechanisms of resistance, with an eye towards therapeutic strategies to enhance CTL killing. A recent example of the combined output of these subgroups is our demonstration of a role for BCL-2 over-expression in the ability of the HIV reservoir to resist CTL (Ren & Huang et al, JCI, 2020). We are currently exploring a wealth of other diverse putative mechanisms towards the dual goals of generating novel immunological insights and identifying novel therapeutic targets.
An important component of the translational nature of our research program is the ability to bridge results from our in vitro experiments with clinical studies. To this end, we work extensively with a novel type of humanized mouse model which we have developed to be uniquely well suited to testing T- and NK-cell based immunotherapies. In recent work, we have demonstrated the utility of this model for testing the in vivo antiviral activity of clinically relevant T-cell therapy products, as well as, innovative drug-delivery approaches designed to enhance these therapies https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3596601. An exciting aspect of this model is that it robustly recapitulates CTL escape mutation profiles known to occur in humans, allowing us to also explore approaches for overcoming this critical limitation of CTL activity.
In addition to serving as a preclinical model for evaluating therapies, we are exploring the potential of this model to address fundamental questions, such as the roles of CTL in shaping the landscape of proviral reservoirs.
A particularly exciting and rewarding aspect of our research program is the ability to partner with collaborators and clinical trial networks to test whether therapeutic strategies showing promise in our research program will have benefit in people living with HIV. We currently have a leading role in the ACTG Study A5386, which will test the safety, tolerability, and efficacy of a combination of HIV-specific broadly neutralizing antibodies with the IL-15 superagonist ‘N-803’. Based on preclinical results from us and others, we hope that this combination may ultimately enable durable immune control of virema –https://www.clinicaltrials.gov/ct2/show/NCT04340596?term=n803&cond=hiv&draw=2&rank=1.
We are also playing key roles in two other clinical trials testing the abilities of T-cell and DC therapies to enhance immune responses to HIV. The former approach has shown antiviral activity in vivo in our humanized mouse model. The clinical samples derived from these studies, as well as our non-interventional clinical activities (ex. leukapheresis sample collection), are also key in assessing in vivo relevance of insights that we gain from the other subgroups. An example, is our confirmation that BCL-2 is over-expressed in bonafide HIV reservoir cells ex vivo (Ren & Huang et al, JCI, 2020).
A key driver in the study of HIV persistence is the ongoing development of novel assays for measuring and characterizing the HIV reservoir. We aim to be at the forefront of this both through the rapid integration of novel assays into our workflows, and through direct innovation of novel approaches. An example of the former is our recent adoption of the ‘Intact Proviral DNA assay’ (IPDA), along with the identification of HIV sequence diversity as a limitation of this approach – and initial steps to overcome this https://www.biorxiv.org/content/10.1101/2020.05.26.115006v1.article-metrics. We continue to build upon and improve a suite of in-house assays that enable characterization of proviral landscapes along with integration sites, and to leverage these approaches to the benefit of every other subgroup.
Through the subgroup structure, we aim to foster a lab environment where – although each lab member has individual projects – these synergize with each other in a way that makes us more than the sum of our parts. Similarly, the Czar/subgroup model helps us be accountable for and take satisfaction from not only our individual successes, but those of the lab as a whole.
Please click on the link below to learn more about our current research projects!