The HIV-1 envelope glycoprotein, Env, facilitates the translocation of the viral capsid across the cellular membrane. Env is a trimer of hetero-dimers composed of a gp120 subunit and gp41 transmembrane protein. The gp120 subunit binds the primary receptor, CD4, leading to conformational changes of Env that then promote binding to the coreceptor, principally CCR5 or CXCR4. As the sole protein on the surface of the virion, Env is under continuous pressure from the host's antibody response. Two classes of antibodies target the highly conserved receptor-binding sites of gp120: CD4-binding site (CD4bs) and CD4-induced (CD4i) antibodies.

Animal models have greatly contributed to the understanding of different aspects of human biology, as well as a variety of human-related pathogens and diseases. In order to study them, humanized mice susceptible to pathogens that replicate in human immune cells have been developed (e.g., humanized Rag2-/-γc-/- mice). These animals are engrafted with human hematopoietic stem cells (HSCs), resulting in the de novo development and maturation of the major functional components of the human adaptive immune system and the production of a variety of human cell types. Primary and secondary lymphoid organs in the mouse are populated with human cells, and animals have long term engraftment. These features make humanized mice an excellent in vivo model to study pathogenesis of human-specific viruses in the context of a human antiviral immune response. In addition, humanized mice have been shown to be useful preclinical models for the development and validation of antiviral therapeutics. In the present study, we aimed to successfully re-establish the humanized Rag2-/-γc-/- mouse model using cord blood-derived HSCs in our laboratory. We have shown that these mice sustain long term engraftment and systemic expansion of human cells, including the major targets of Kaposi's sarcoma Herpesvirus (KSHV) and Human immunodeficiency virus type 1 (HIV-1), in peripheral blood and different lymphoid organs. Further, we have begun to evaluate the susceptibility of the humanized Rag2-/-γc-/- mouse model to infection with KSHV. We demonstrate that human lymphocytes differentiated in reconstituted Rag2-/-γc-/- mice are permissive to KSHV infection ex vivo. This finding was corroborated by detection of KSHV mRNA expression in the spleen of a humanized mouse at 6 months post infection. In a different study, we tested the in vivo antiviral efficacy of a novel HIV-1 fusion inhibitor (PIE-12-trimer) in humanized Rag2-/-γc-/- mice. We have determined the half life of PIE-12-trimer in mouse plasma. Furthermore, the administration of PIE-12-trimer to HIV-1 infected humanized Rag2-/-γc-/- mice prevents depletion of CD4+ T cells in blood, thus it may be useful to prevent AIDS in human patients.

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Viruses cause human diseases by entering in to human cells. Many drugs have been developed that act at various stages of viral infection, but they fail due to their toxic side effects and high mutation rates of viruses. Recently, a new class of drugs called entry inhibitors has been developed which acts on the early stages of viral infection. These drugs have been developed by studying the entry process of viruses in to host cells. The success of these drugs, however, is still limited and research is being done to quantify the optimum dosage of these drugs and find new drugs targets. We developed a mathematical model based on chemical reaction kinetics to estimate the threshold number of complexes between viral and target cell surface proteins necessary for HIV-1 entry into target cells. Our model quantitatively describes data of HIV entry in the presence of several entry inhibitors and presents an avenue for identifying optimal drug levels for restricting HIV entry. Majority of viruses enter into host cells by either endocytosis of fusion. But when virus enters through endocytosis and when through fusion is still not clear. We developed a theory that predicts the virus entry pathway based on the underlying biophysical properties like membrane bending modulus, viral and cellular receptor concentration and the energy released by the formation of protein complexes. Through this theory of viruses we presented the entry of viruses through fusion or endocytosis on a phase diagram. We validated the phase diagram by comparing it with known pathways of existing viruses. This study may aid in unraveling the entry pathways of new viruses and may also help in identifying new drug targets.