The candidate is an Assistant Professor of Medicine and Infectious Diseases at the Institute of Human Virology (IHV) at the University of Maryland School of Medicine. The candidate's long-term goal is to become an independent clinical investigator specializing in the field of humoral immunity in HIV infection. The purpose of this proposal is to provide the candidate with the appropriate tools and environment to reach this goal. The IHV was built on the premise of bringing a strong collaborative atmosphere between clinicians and laboratory researchers to promote translating basic scientific discoveries into clinically relevant applications. Through the mentorship of researchers from both the basic science (Vaccine Division) and clinical research divisions of the IHV, along with a career development program focused on Immunology, the candidate will receive a solid foundation upon which to build an independent career in academic medicine. The candidate's short-term goals are encapsulated in the research proposal, which is presented below. Vaccine efforts for HIV-1 have been hampered by the biological reality that humans can never completely clear HIV-1 once infected;consequently, finding immune correlates of humoral protection have proven to be difficult. However, within the HIV-infected population, about 1% can effectively control the replication of the virus to minimal levels without antiretrovirals. We have recently described such a cohort of HIV-1 infected individuals, Natural Viral Suppressors (NVS). The NVS and similar cohorts (Elite Controllers) represent the best available model of natural immunity to HIV-1. Much of the research focus until now has been placed on circulating antibodies in the plasma. However, as we will demonstrate, standardized plasma neutralization may not provide an accurate composite picture in these individuals. By contrast, memory B cells provide an archival record of humoral responses for the lifetime of the host. The specific hypothesis of this proposal is that effective humoral immunity (memory B cell frequency and neutralization derived from memory B cell antibodies), correlates with the HIV-1 viral suppression seen in the NVS (but not HIV-controls). We propose that detailed antibody analysis of memory B cells (which archive every antibody ever made) rather than the circulating pool (what is normally tested) in the NVS (HIV-infected persons who control the virus without medication) will reveal an association between memory B cell antibodies and being NVS. If this is correct, then NVS will be a model of antibody control for designing the antibody part of an HIV vaccine.

Public Health Relevance

We propose that detailed antibody analysis of memory B cells (which archive every antibody ever made) rather than the cirulcating pool (what is normally tested) in the NVS (HIV-infected persons who control the virus without medication) will reveal an association between memory B cell antibodies and being NVS. If this is correct, then NVS will be a model of antibody control for designing the antibody part of an HIV vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23AI084580-01A1
Application #
7931701
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Lane, Jim R
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
1
Fiscal Year
2010
Total Cost
$134,730
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Gohain, Neelakshi; Tolbert, William D; Acharya, Priyamvada et al. (2015) Cocrystal Structures of Antibody N60-i3 and Antibody JR4 in Complex with gp120 Define More Cluster A Epitopes Involved in Effective Antibody-Dependent Effector Function against HIV-1. J Virol 89:8840-54
Acharya, Priyamvada; Tolbert, William D; Gohain, Neelakshi et al. (2014) Structural definition of an antibody-dependent cellular cytotoxicity response implicated in reduced risk for HIV-1 infection. J Virol 88:12895-906
Lewis, George K; Guan, Yongjun; Kamin-Lewis, Roberta et al. (2014) Epitope target structures of Fc-mediated effector function during HIV-1 acquisition. Curr Opin HIV AIDS 9:263-70
Sajadi, Mohammad M; Redfield, Robert R; Talwani, Rohit (2013) Altered T-cell subsets in HIV-1 natural viral suppressors (elite controllers) with hepatitis C infection. AIDS 27:1989-92
Keshtkar-Jahromi, Maryam; Sajadi, Mohammad M; Ansari, Hossein et al. (2013) Crimean-Congo hemorrhagic fever in Iran. Antiviral Res 100:20-8
Eyzaguirre, Lindsay M; Charurat, Manhattan; Redfield, Robert R et al. (2013) Elevated hypermutation levels in HIV-1 natural viral suppressors. Virology 443:306-12
Guan, Yongjun; Pazgier, Marzena; Sajadi, Mohammad M et al. (2013) Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding. Proc Natl Acad Sci U S A 110:E69-78
Mojtahedzadeh, Mona; Otoukesh, Salman; Shahsafi, Mohammad R et al. (2012) Case report: portal hypertension secondary to isolated liver tuberculosis. Am J Trop Med Hyg 87:162-4
Boudová, Sarah; Li, Haishan; Sajadi, Mohammad M et al. (2012) Impact of persistent HIV replication on CD4 negative V?2V?2 T cells. J Infect Dis 205:1448-55
Sajadi, Mohammad M; Pulijala, Roopa; Redfield, Robert R et al. (2012) Chronic immune activation and decreased CD4 cell counts associated with hepatitis C infection in HIV-1 natural viral suppressors. AIDS 26:1879-84

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