About Us
About Us
  • Board Of Directors
  • Collaborators
  • Staff Directory
  • Job Openings
Our Legacy
Our Legacy
  • Achievements
  • History
  • Irene Diamond
  • Photo Gallery
Current Research
Current Research
  • Our Scientists and Labs
    • David D. Ho
    • Yaoxing Huang
    • Martin Markowitz
    • Moriya Tsuji
    • Xueling Wu
    • Masahiro Yamashita
  • Core Facilities
    • Personnel
    • Flow Cytometry
    • Microscope Imaging Facility
Clinical Trials
Clinical Trials
  • HIV+
    • Newly Infected With HIV
    • Living With HIV
    • Physicians
    • FAQ's
  • HIV.
    • Healthy Volunteer
    • FAQ's
Focus On HIV
Focus On HIV
  • Facts About HIV and AIDS
  • HIV Biology
    • The HIV Virus Particle
    • The HIV Replication Cycle
Giving Center
Giving Center
  • Online Giving
  • Other Giving Opportunities
  • Financial Summary
News Center
News Center
  • ADARC In The News
  • Seminars
  • Newsletters and Brochures
  • For Journalists
China Aids Initiative
China Aids Initiative
Multimedia Library
Multimedia Library
Talks at ADARC
Talks at ADARC
ADARC Gala
ADARC Gala
  • Gala video
  • Gala photo
  • leadership committee
  • Online Giving
Register for Updates
Register for Updates
Current Research

Scientific Overview


XLW
CHOOSE ANOTHER SCHOLAR Drop Down Menu

Xueling Wu, Ph.D.
Assistant Professor

Our overall research interest is to elucidate the mechanisms by which the HIV-1 envelope glycoprotein (Env) elicits broadly neutralizing antibody (bnAb) responses in humans and rhesus macaques, with an ultimate goal to guide HIV-1 vaccine development.

1. Isolate and characterize HIV-1 bnAbs. We have a NIH funded R01 to develop HIV-1 Env probes by VSV-surface display to efficiently isolate bnAbs from a large number (n>50) of clade-B and non-B clade infected individuals. We have properly constructed and applied an HIV-1 Env.VSV to two clade-B infected donor samples and successfully isolated three bnAbs from each donor. Epitope mapping indicated that: #1 targets the entire V3 loop of gp120 and is independent of glycans; #2 is trimer-dependent; #3 and #4 are glycan-dependent, with #3 targeting both N301 and N332, and #4 targeting N332 only. Based on the antibody sequences and genetic compositions, the six bnAbs are unique antibody clones and different from currently known bnAbs in the field. We are currently testing the reproducibility of HIV-1 Env.VSV probes. Once the probes are highly reproducible, we will apply them to more human and macaque samples for bnAb isolation.

2. Determine bnAb precursors. To understand how bnAbs are developed, we face two fundamental immunological questions: 1) what are the naïve or founder B cells selected to generate HIV-1 bnAbs? 2) how do these selected founder B cells react with HIV-1 Env? Funded by a NIH R01, we proposed to identify founder B cells by longitudinal analysis. For this study we have obtained longitudinal plasma and PBMC samples from SHIV-infected rhesus macaques and HIV-1 infected individuals. We have established the Illumina 2x300bp pair-end MiSeq sequencing platform to sequence longitudinally collected samples from time points prior to bnAb isolation. As we examine earlier samples, we expect to find less mutated antibody sequences and eventually the heavy and light chain progenitor sequences for expression and functional tests.

3. Determine how neutralization breadth is developed. While only a fraction of infected individuals mount bnAb responses and such responses typically do not appear until 2-3 years after infection, almost all infected individuals develop nAbs against autologous viral strains during the first year of infection. Currently we do not understand how the early narrow autologous nAbs develop into bnAbs in some individuals. We hypothesize that bnAbs arise through two mechanisms that are not mutually exclusive. First, through founder B cells that precisely target a conserved neutralizing epitope. In this case, once the antibody obtains sufficient somatic hypermutation to neutralize autologous strains, it simultaneously acquires neutralization breadth against heterologous strains. Second, through epitope shifting. In this case, the founder B cells that originally target suboptimal epitopes with narrow autologous neutralizing activity shift to optimal epitopes (by additional somatic mutations) in response to autologous viral escape, thus acquiring neutralization breadth. For these studies, we will test longitudinal plasmas to determine the time period at which antibodies transition from autologous to heterologous neutralization and gain breadth. We will then isolate mAbs and perform antibody deep sequencing before and after the transition time. We will compare the isolated mAbs with and without neutralization breadth to determine key changes.

4. Develop SHIV models that consistently produce HIV-1 bnAbs. From two SHIV-infected macaques GB40 and FF69 (Jia et al, Journal of Virology 2016), we have isolated sequential Env sequences and identified a total of FOUR sequential autologous nAb waves prior to the rise of heterologous nAbs. We hypothesize that the sensitive Env clones provide necessary sequential Env antigens to stimulate and guide the broadening of nAbs. Collaborating with Dr. Theodora Hatziioannou at the Rockefeller University, we have generated replication-competent SHIV molecular clones bearing Env of interest from GB40 and FF69. Collaborating with Dr. Huanbin Xu at the Tulane Nationals Primate Center, we are currently inoculating naïve rhesus macaques with these SHIV molecular clones to replicate the broadening processes of nAbs observed in these animals.

In summary, our research will fill in knowledge gaps in understanding the processes of effective B cell response. It is our view that this knowledge is required to induce HIV-1 bnAbs through vaccination. Having access to precious samples from longitudinally followed SHIV-infected rhesus macaques and HIV-1 infected humans, we have the opportunity to address two critical steps during these processes: the initial activation of rare B cell precursors and the later antibody somatic hypermutation and affinity maturation to gain neutralization breadth function. Results from these studies will lead towards our ultimate goal of developing an effective HIV-1 vaccine.