My laboratory at the Ragon Institute of MGH, MIT and Harvard focuses on understanding the genetic adaptations of HIV in response to host immune pressures and leveraging these discoveries to develop novel immunotherapies and vaccines. HIV can rapidly adapt to evade host immune responses through sequence evolution, which provides insight to identify immune responses critical to the control of this pathogen. My laboratory has 4 major areas of interest designed to aid in the development of more effective vaccines against HIV:
HIV evolution: A critical issue to HIV vaccine design is determining which cellular immune responses are influencing immune control. Longitudinal assessment of viral evolution following acute HIV infection enables us to pinpoint immune responses exerting the greatest selective pressure on HIV. Here we use next-generation deep sequencing technologies to characterize the specific evolutionary pathways by which HIV escapes these responses. These data are then linked to the impact these mutations have on the replicative capacity (or fitness) of HIV, and thus the ability of the selected mutation to cripple its ability to replicate effectively. Collectively these data are then used to inform the development of novel HIV vaccines capable of focusing the host immune response against the most vulnerable regions of the virus.
HIV transmission: Despite the diverse circulating viral quasi-species during infection, HIV transmission typically occurs through transmission of a single viral variant, termed the transmitted/founder (TF) virus. Identification of the genotypic or phenotypic properties of the TF could lead to novel immunotherapies or vaccine candidates. Utilizing a large library of patient-derived TF and non-transmitted (NT) variants we recently demonstrated the ability of our humanized mouse model to recapitulate the preferential transmission of TF viruses in vivo. This provides a powerful model to identify the viral and/or host factors governing the preferential transmission of TF viruses, which may include enhanced in vivo replicative fitness, CD4+ T cell activation and recruitment, or differential induction of host innate transcripts.
HIV cure: The case of the “Berlin Patient” has opened the door to the possibility of an HIV treatment intervention that will engender long-term protection against viral rebound (a functional cure), if not complete eradication of the virus. Utilizing the CRISPR/Cas system and humanized mouse models we are engineering human hematopoietic stem cells (HSC) to modify critical host genes (i.e. CCR5 receptor) to explore the feasibility of protecting the human immune system from HIV infection. In parallel, we are exploring the efficacy of HIV-specific chimeric antigen receptor (CAR) immunotherapies to enhance the ability of autologous T cells to target and eradicate HIV infected reservoir cells. CAR-T cellular immunotherapies have exhibited unique success against human cancers and could facilitate boosting of patient immune responses to target the latent HIV reservoir.
Broadly neutralizing antibodies: HIV-specific broadly neutralizing antibodies (bNAbs) represent the holy grail of HIV vaccine design given their ability to recognize upwards of 90% of circulating HIV strains. However, these antibodies are highly affinity matured due to their ongoing recognition of highly mutating regions of the HIV envelope protein. As such, a deeper understanding of the viral mutations giving rise to such bNAbs is required to engineer Env immunogens capable of recapitulating the critical step-wise mutations giving rise to the bNAb. Here we are using longitudinal deep sequencing to identify the critical Env mutations required to induce bNAbs in HIV acutely infected individuals. In parallel, we are sequencing the B cell receptor (BCR) repertoire to reveal the viral and host co-evolutionary pathways giving rise to the unique bNAb response. These data will facilitate the development of HIV immunogens capable of recapitulating the development of a broadly neutralizing antibody response.
400 Technology Square
Cambridge, MA 02139