HIV/AIDS vaccine development: Defending the frontline Ruth M Ruprecht Texas Biomedical Research Institute/Southwest National Primate Research Center, San Antonio, Texas, USA Abstract Although 90% of all new HIV transmission events occur through mucosal contact, AIDS vaccine development has not focused strongly on inducing mucosal immune defenses. Almost all mucosal transmissions involve CCR5-tropic HIV. The genetic subtype C is the most prevalent HIV clade worldwide. We have generated nonhuman primate models with simian–human immunodeficiency virus strains that carry HIV clade C envelopes (SHIV-Cs). These viruses are R5-tropic and pathogenic. We have generated proof-of-concept data with human monoclonal antibodies (mAbs) that target the conserved V3 loop crown of HIV gp120. We used dimeric IgA (dIgA) isotypes alone or in combination with the IgG version of the same mAb. We found a surprising synergy between the intravenously administered IgG1 and intra-rectally administered dIgA2 mAb forms; this synergy was highly reproducible in SHIV-C-challenged macaques. Active vaccination with gp41-displaying virosomes has also induced protection against mucosal SHIV transmission (Bomsel et al. Immunity 2011). New data and potential mechanisms of protection by IgG + mucosal dIgA will be discussed. Potential development of inactivated HIV-1 transmitted/ founder virus (T/F) vaccine Adan Rios1,4*, Ethan C. Pottet2, Edward B. Siwak3, Dallas W. Anderson1, Qizhi C.Yao2 1PhotoImmune Biotechnology Inc. Houston, Texas, USA 2Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA 3Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA 4The University of Texas McGovern Medical School at Houston. Background: Nearly 80% of sexually transmitted HIV infections are established by one transmitted/founder virus (T/F). Highly mutated bNAbs resulting from chronic infection will not be needed if the initial T/F virus infection is prevented. Our method inactivate HIV by a targeted photo-inactivation of HIV reverse transcriptase (RT). We propose its use to develop a T/F virus polyvalent inactivated whole-virus vaccine with the most frequent subtypes of T/F viruses to prevent initial T/F virus infections. Methods: An azido (-N3) group introduced into a diarylpyrimidine (DAPY) creates a photo active DAPY analog (PADAPYa). When incubated with HIV-1 particles and exposed to non-microbicidal UV light, there is irreversible cross-link of the PA-DAPYa to the HIV-1 RT. To confirm inactivation, control and test suspensions of SF162 HIV were used to infect PBMCs and incubated up to 21 days. Results: With UV light alone as control HIV virus replicated after 40 minutes. Control-DAPY inhibited replication at 100 nM with variable inactivation effectiveness even at 500 nM. In contrast, at all UV exposure times, 500 nM of PA-DAPYa totally inactivated HIV. HIV p24 was not detected in the supernatant of inactivated HIV cultured in PBMCs. This experiment was repeated with different viral stocks and PBMC donor pools. Conclusion: Incubating a suspension of HIV SF162 with PA-DAPYa followed by UV light exposure completely and irreversibly inactivates HIV-1. We foresee using this inactivation methodology to inactivate T/F viruses to lead to a polyvalent preventive HIV vaccine capable of neutralizing the most common T/F virus strains.
The Human Immune Response to HIV and Its Impact in the Potential Development of an Inactivated HIV Vaccine
1 PhotoImmune Biotechnology Inc., Houston, TX, USA. 2 University of Texas Medical School at Houston. Houston, TX, USA. 3 Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA. 4 Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA. 5 Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX, USA.
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