Persistent immune activation is a strong predictor of disease progression in HIV infection and is characterized by activation of all immune cell types, increased levels of proinflammatory cytokines and activation-induced lymphocyte apoptosis. Translocation of microbial toll-like receptor (TLR) ligands from the gut to the systemic circulatio has been recognized in recent years to be a major factor in inducing immune activation. The resulting increase in inflammatory cytokines may be the fundamental cause for immune activation and determinant of disease progression. The cytokine storm, immune activation and lymphocyte apoptosis attended with microbial products in systemic circulation seen in HIV infection also characterizes natural and experimental sepsis. HMGB1 secreted from macrophages and dendritic cells acts as a master regulator of cytokine storm in sepsis. We have recently shown that silencing HMGB1 in human macrophages and dendritic cells in vivo in humanized BLT mice by targeted delivery of siRNA (via a peptide called RVG-9R) dramatically suppressed the sepsis-induced cytokine storm and mortality. Although serum level of HMGB1 as well as downstream cytokines are also elevated in HIV infected individuals, their role in chronic immune activation is not clear. In this proposal, we will test the role of HMGB1 and downstream cytokines, their relation to microbial products and the effect of suppressing these inflammatory mediators on immune activation and disease progression in vivo using the humanized mouse model for HIV infection.
In Aim 1, we will characterize the full spectrum of immune activation in HIV infected humanized mice without or with ART. In the second aim we will test if silencing HMGB1 or downstream cytokines by targeted delivery of siRNA to macrophages and dendritic cells can reduce immune activation and disease progression in infected mice.

Public Health Relevance

Although immune activation is known to exacerbate HIV disease, no specific treatment is available to reduce immune activation. Thus, we will test the effect of silencing cytokines on immune activation and disease progression in a humanized mouse model for HIV infection. The findings are likely to guide therapies directed at reducing immune activation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Stansell, Elizabeth H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Texas Tech University
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Swamy, Manjunath N; Wu, Haoquan; Shankar, Premlata (2016) Recent advances in RNAi-based strategies for therapy and prevention of HIV-1/AIDS. Adv Drug Deliv Rev 103:174-86
Abraham, Sojan; Choi, Jang-Gi; Ortega, Nora M et al. (2016) Gene therapy with plasmids encoding IFN-? or IFN-?14 confers long-term resistance to HIV-1 in humanized mice. Oncotarget 7:78412-78420
Ye, Chunting; Choi, Jang Gi; Abraham, Sojan et al. (2015) Targeting DNA vaccines to myeloid cells using a small peptide. Eur J Immunol 45:82-8
Bharaj, Preeti; Chahar, Harendra Singh; Alozie, Ogechika K et al. (2014) Characterization of programmed death-1 homologue-1 (PD-1H) expression and function in normal and HIV infected individuals. PLoS One 9:e109103
Manjunath, N; Yi, Guohua; Dang, Ying et al. (2013) Newer gene editing technologies toward HIV gene therapy. Viruses 5:2748-66