Day 1 :
Founder and CEO
University of Rochester School of Medicine
Keynote: Chemically Modified Camptothecin with Low Cytotoxicity is Broadly Neutralizing of HIV-1 as an Inhibitor of Vif-Dependent, APOBEC3G Degradation
Time : 10:00-10:40
Harold C. Smith is a tenured full professor of Biochemistry and Biophysics at the University of Rochester School of Medicine and Dentistry and Founder and CEO of OyaGen, Inc. His expertise is as a cell and molecular biologist with a focus in his research on the structure, function and regulation of nucleic acid protein interactions. He is an opinion leader on the viral restriction factors known as APOBEC. OyaGen is a drug discovery and drug development company focused on eradication of HIV/AIDS and other viral diseases through the identification of novel drug targets and small molecules that interact with these targets.
Camptothecin (CPT) is a natural product discovered to be active against various cancers through its ability to inhibit Topoisomerase 1 (TOP1). CPT analogs also have anti-HIV-1 (HIV) activity that has been previously shown not to depend on inhibition of TOP1. We show that anti-cancer inactive CPT analogs inhibit HIV infection by disrupting homo-oligomerization of an HIV auxiliary protein known as viral infectivity factor (Vif). Antiviral activity depended on the expression of the cellular viral restriction factor known as APOBEC3G (A3G) that, in the absence of functional Vif, has the ability to hypermutate HIV proviral DNA during reverse transcription. Our studies demonstrate that a non-toxic CPT analog (i) prevented Vif multimerization and Vif-dependent A3G degradation, (ii) increased A3G in pseudotyped HIV viral particles along with A3G signature hypermutations in viral genomes, and (iii) possessed an A3G-dependent and broadly neutralizing antiviral activity against seventeen HIV clinical isolates from Groups M (subtypes A-G), N, and O as well as seven single and multi-drug resistant strains of HIV. Medicinal chemistry and structure activity relationship (SAR) efforts further identified a more potent analog that reached a therapeutic index of greater than 1,000 against live HIV subtype A following a single dose in 7-day spreading infections. We propose that CPT analogs not active against TOP1 have an antiviral mechanism through Vif antagonism that enables A3G-dependent hypermutation of HIV.
Professor of Medicine
Senior Investigator of the Oswaldo Cruz Foundation
Time : 10:40 - 11:20
Edgar M. Carvalho is Professor of Medicine of the Federal University of Bahia Medical School and Senior Investigator of the Oswaldo Cruz Foundation. He is a clinic immunologist with expertise in the pathogenesis, Immunology and therapy of tropical diseases. Regarding HTLV-1 he follows in the HTLV-1 out clinic of the Federal University of Bahia Hospital a cohort of 495 infected subjects. He has documented that more 51% of HTLV-1 infected subjects have clinical manifestations related to HTLV-1 such as overactive bladder, erectile dysfunction and others inflammatory diseases. He has also performed clinical trials in patients with different clinical manifestations related to HTLV-1.
The HTLV-1 infection has been neglected mainly due to the misconception it is a low morbidity virus infection, as HTLV-1 associated myelopathy (HAM) and adult T cell leukemia, occurs in less than 5% of infected patients. In a cohort of 495 HTLV-1 infected individuals followed for up to 18 years we have determined the frequency and pathogenesis of diseases associated to HTLV-1. Patients were classified in 4 groups: 1) HTLV-1 carriers; 2) Neurogenic bladder and/or erectile dysfunction; 3) Definitive HAM/TSP; 4) Other inflammatory diseases. The diagnosis was performed by detection of anti HTLV-1 antibodies by ELISA and confirmed by Western blot. The pro-viral load was measured by RT-PCR and cytokine levels in supernatants of unstimulated lymphocyte cultures by ELISA. While there was an association between increase in pro-inflammatory cytokines and pro-viral load (PVL) with HAM, and at lesser extension with neurogenic bladder, these variables were not correlated with other inflammatory diseases related to the virus. The sicca syndrome was associated with high PVL in saliva and gland atrophy. The patients with chronic periodontitis had HTLV-1 in the periodont, increased expression of pro-inflammatory cytokines in this tissue and down modulation of anti-inflammatory cytokines. HTLV-1 associated arthropathy was characterized by pain in large joints, absence or little synovitis, entesitis detected by X-ray and no association with PVL or pro-inflammatory cytokines levels.
More than 95% of these patients who present neurogenic bladder or erectile dysfunction did not progress to HAM/TSP. Morbidly related to HTLV-1 is observed in more than 50% of infected subjects and is related to virus migration to specific tissues associated with a systemic or local exaggerated inflammatory response.