Previously, the lab has shown that there is a genetic bottleneck in the viruses that are transmitted between heterosexual partners, leading to selection of just one or a few HIV variants in the new host. Members of the lab have also found similar evidence of a bottleneck in the context of mother-infant transmission, where the infant is infected in the presence of maternal HIV-specific antibodies.
We have found that infants develop broad antibody responses to HIV. We have isolated antibodies from infants, including the first HIV-specific broadly neutralizing antibody. The infant antibodies are remarkable because they have very limited somatic hypermutation. We have ongoing studies to isolate and characterize additional infant antibodies. We collaborate with the lab of Kelly Lee on structural studies of these antibodies. We collaborate with the lab of Jesse Bloom to identify the specific amino acids that define the epitope using mutational antigenic profiling with deep mutational scanning.
We are studying how these antibodies arose by deep sequencing the antibody repertoire and using computational methods to reconstruct the antibody linage pathway. This work is in collaboration with Erick Matsen’s group.
We are also very interested in antibodies that mediate ADCC because we found that they are associated with better infected infant outcomes.
We have isolated ADCC antibodies, including antibodies that target the gp120 surface protein and the gp41 transmembrane protein. We are currently developing new methods to define the epitope of ADCC and binding antibodies.
The Zika epidemic in South America inspired us to try to understand why Zika was causing disease in that setting while Zika-associated disease has not been described in East Africa, where the virus was first identified. We are developing better methods to detect Zika infections and are screening banked samples from regions of Kenya where the relevant mosquitoes are present for evidence of Zika infections. We are also examining the innate immune response to Zika viruses from Africa compared to the Americas to determine if this could explain differences in disease.
We are performing large scale CRISPR screens for IFN-induced factors that inhibit HIV-1 in either macaque or human cells.
Ongoing studies are focused on defining the virus-host interactions that limit replication of circulating HIV variants and that may contribute to the selection for viruses during transmission and adaptation in the host. We are interest in innate immune factors that inhibit HIV in both human and macaque CD4 T lymphocytes.
Superinfection increases the breadth of the HIV-specific Nab response (Cortez et al PLoS Pathogens 2012. Cortez et al PLoS Pathogens 2015.)
Another main focus of the lab is on HIV-1 superinfection, an occurrence where people already infected with HIV become re-infected with HIV from a different source partner. The lab has shown that superinfection is common in high-risk groups although the risk of superinfection is lower than the risk of initial HIV infection. Ongoing efforts are focused on whether there is any immune response from a first HIV infection that provides protection against reinfection. An additional avenue of research in the lab aims to characterize the kinetics and epitope targets of the broad antibody response that developed post-superinfection in a subset of “elite neutralizers”. We have begun to isolate antibodies from superinfected individuals with the purpose of understanding the mechanisms that lead to a broad antibody response.