A refined understanding of virus/host relationships that promote transmission and those that contribute to the rate of disease progression following infection is critical for the design of effective vaccines against HIV-1. One parameter that is increasingly recognized as being critical and understudied is the role of viral env glycosylation not only in preferential transmission but also in the ability of the virus to select receptors for entry and for its susceptibility to neutralizing antibodies. In addition, data is now accumulating o show that a variety of cell surface molecules that serve as ligands/receptors for the glycosylated env proteins and those that are influenced by glycosylated versus de-glycosylated viruses, could contribute to the quality of immune response the virus engenders. These issues can only be objectively addressed using appropriate nonhuman primate models such as macaques infected with SHIVs that contain the env from primary HIV-1 isolates, particularly from transmitted/founder viruses to study the roles of env glycosylation in preferential transmission. Therefore, we plan to explore the role of env glycans using sets of HIV molecular clones obtained from transmitted/founder (T/F) viruses from a Zambian cohort-where clade C viruses predominate. We have generated several unique tools/reagents and assembled a highly talented team of Investigators and a series of systematic logically designed studies are outlined which will first focus on the composition and arrangement of glycans in paired clones from T/F circulating HIV strains including N-and O-glycans as outlined in aim 1. Based on glycan profiles, we proposed to select a) a highly glycosylated, b) low level of env glycosylated viruses from transmitter and c) as control, a founder virus to prepare corresponding replication competent Simian Human Immunodeficiency viruses (SHIV) for further advanced studies, which include detailed in vitro characterization of replication kinetics in primary cells and cell lines, glycan content, particle envelope glycoprotein content, dendritic cell (DC) capture, DC-T cell trans-infection, sensitivity to IFN-?, anti-?4?7 and blocking mAbs against select lectin-like molecules (Galectin-9, SIGLECs, MINCLE, and CD200/200R). Then we will select the viruses to test in vivo for transmission efficiency studies in rhesus macaques based primarily on comparable in vitro replication but differing glycan content (aim 2).
Under specific aim 3, we will define whethe it is the signature site(s) of Env glycosylation that facilitates transmission, using isogenic SHIV based on the backbone of the """"""""poor"""""""" transmitter and mutating only those select residues corresponding to the founder virus from aim 2b, using a repeated multiple-low-dose Intra-Vaginal (IVAG) challenge model. Results of these studies will provide a strong foundation for future rational HIV vaccine design.

Public Health Relevance

The envelope of HIV is known to be heavily glycosylated (contains proteins that have sugar molecules) and it has been shown previously that these sugars form a shield that protects the virus from being neutralized by antibodies made by the host. In addition, there are also studies that appear to show that HIV whose envelopes are less glycosylated gets preferentially transmitted over viruses that are heavily glycosylated. Thus it is important to identify the role of these glycans in viral transmission and therefore, studies outlined in the present proposal are directed to systematically address this important issue that may have important implications for the formulation of effective vaccines against HIV-1.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1)
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Onami, Thandi M
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Emory University
Schools of Medicine
United States
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Routhu, Nanda Kishore; Byrareddy, Siddappa N (2017) Host-Virus Interaction of ZIKA Virus in Modulating Disease Pathogenesis. J Neuroimmune Pharmacol 12:219-232
Ortiz, Kristina; Sampathkumar, Rebecca S; Ansari, Aftab A et al. (2017) Preliminary studies on the use of pertussis toxin for the modulation of intravaginal SIV transmission in rhesus macaques. J Med Primatol 46:327-331
Basiri, Alireza; Xiao, Michelle; McCarthy, Alec et al. (2017) Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors. Bioorg Med Chem Lett 27:228-231
Dave, Rajnish S; Sharma, Ravi K; Muir, Roshell R et al. (2017) FDC:TFH Interactions within Cervical Lymph Nodes of SIV-Infected Rhesus Macaques. J Neuroimmune Pharmacol :
Silveira, Eduardo L V; Rogers, Kenneth A; Gumber, Sanjeev et al. (2017) Immune Cell Dynamics in Rhesus Macaques Infected with a Brazilian Strain of Zika Virus. J Immunol 199:1003-1011
Ansari, Aftab A; Byrareddy, Siddappa N (2016) The Role of Integrin Expressing Cells in Modulating Disease Susceptibility and Progression (January 2016). Int Trends Immun 4:11-27
Byrareddy, Siddappa N; Little, Dawn; Mayne, Ann E et al. (2015) Phenotypic and Functional Characterization of Monoclonal Antibodies with Specificity for Rhesus Macaque CD200, CD200R and Mincle. PLoS One 10:e0140689
Tieu, Roger; Amancha, Praveen Kumar; Villinger, Fran├žois et al. (2014) TIM-3, a Possible Target for Immunotherapy in Cancer and Chronic Viral Infections. Austin Virol Retro Virol 1:
Singh, Shailbala; Yang, Guojun; Byrareddy, Siddappa N et al. (2014) Natural killer T cell and TLR9 agonists as mucosal adjuvants for sublingual vaccination with clade C HIV-1 envelope protein. Vaccine 32:6934-6940