Research Overview

Our studies focus primarily on high risk cohorts including HIV exposed women and infants

Our early studies focused on characterizing the viruses present during early/acute infection, which provides a window into the nature of transmitted viruses that could inform vaccine and other prevention approaches

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.

  • HIV infection is typically with one or a few variants (Poss et al. J Virol 1995; Long et al. Nat Med 2000)
  • Infants are typically infected with a single variant that has escaped neutralizing antibody pressure in the mother (Wu, 2006).
  • Infection with multiple HIV-1 variants in women is associated with other  STDs and hormonal contraceptive use (Sagar, JV 2003)
  • After infection, the virus diversifies  by 0.3-0.6 % per year  (Piantadosi, JV 2009)
Transmission bottleneck graphic

The HIV-1 specific Nab response in infants has unique features that suggest infants elicit different responses than adults

  • Infants develop HIV-1 broadly neutralizing antibodies with more rapid kinetics than adults
  • The epitopes that are targeted on HIV-1 envelope appear to be different from those of adults. Goo, Nature Medicine, 2014
Graphic of the first infant derived HIV-specific broadly neutralizing antibody.
BF520.1: the first infant derived HIV-specific broadly neutralizing antibody. Simonich, Cell 166, 2016.
Graphic of structural studies in collaboration with the lab of Kelly Lee
Structural studies in collaboration with the lab of Kelly Lee.
Graphic of mutational antigenic profiling
Mutational antigenic profiling. (Dingens, Cell Host and Microbe, 2017. Dingens, Immunity, 2019).

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 defining the affinity maturation pathway of antibodies we isolated from infants and from cases of superinfection as this can provide a template for how to elicit these responses with a vaccine

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.

Graphic of deep sequence Abs from different times and reconstruct the likely evolutionary pathway
Simonich and Doepker et al, Nature Communications, 2019

~60% of infants born to HIV+ women do not get infected despite exposure. Do ADCC antibodies play a role?

ADCC: Antibody-dependent cell cytotoxicity leads to elimination of infected cells

Graphic of percentage of infants infected over years
Nduati et al. JAMA 2000
Graphic of infected and effector cells
Graphic of percentage of survival over months after estimated infection
Passively transferred antibodies that mediate ADCC are associated with better clinical outcomes in infants (Milligan Cell Host and Microbe 2015).

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 HIV- specific antibodies that mediate ADCC and developed new ways to map their epitopes

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.

Graphic of ADCC antibodies
Williams, EBioMed 2015; Williams et al PLoS Pathogens, 2019 High-res version

Is Zika circulating in East Africa?

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.

Map of East Africa and Zika locations

Studies to define the restrictions to HIV-1 infection of macaque

We are performing large scale CRISPR screens for IFN-induced factors that inhibit HIV-1 in either macaque or human cells.

HIV-1 and the macaque CD4 receptor for entry
HIV-1 can not use the macaque CD4 receptor for entry. This is due to a single SNP at position 39. Humes JV 2011 and 2012.
HIV-1 is inhibited by an IFN-induced factor expressed in macaque lymphocytes
HIV-1 is inhibited by an IFN-induced factor expressed in macaque lymphocytes. Boyd, PLoS Pathogens July 2016.

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.

Studies of HIV-1 superinfection: reinfection by a second source partner

Superinfection increases the breadth of the HIV-specific Nab response (Cortez et al PLoS Pathogens 2012. Cortez et al PLoS Pathogens 2015.)

Graph should Nab breadth over years post-infection
Superinfection drives HIV neutralizing antibody responses from several B cell lineages that contribute to a polyclonal response
Superinfection drives HIV neutralizing antibody responses from several B cell lineages that contribute to a polyclonal response. One of the dominant antibodies was directed to the N332 amino acid and it drives virus escape. High-res version

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.