Alonso Heredia, PhD

A. Personal Statement

A main focus of my research is on improving treatments against HIV.  Until recently, HIV resistance to ART was a main cause of treatment failure. However, the availability of ART formulations that contain potent agents and are easy to take (1 pill once a day) have dramatically decreased the frequency of HIV resistance.  Yet, drug toxicity, especially when ARTs need to be taken for life, remains a concern in treatment, particularly in older patients.  Toxicity can be worsened by comorbid medications increasingly frequent in the aging HIV population. It is estimated that by 2030, 70% of HIV patients will be older than 50, of whom 80% will have ≥ 1 age-related comorbidity. My laboratory is investigating the potential effectiveness of therapy simplification, from current 3-drug regimens to dual or even monotherapy, as an approach to maintain HIV control and reduce toxicities.  This may be possible with the recently developed second-generation integration inhibitors, which have a high genetic barrier to resistance and induce mutations that drastically impair virus fitness.

1.         Heredia, A., S. Natesan, N. M. Le, S. Medina-Moreno, J. C. Zapata, M. Reitz, J. Bryant, and R. R. Redfield. 2014. Indirubin 3’-monoxime, from a Chinese Traditional Herbal Formula, Suppresses Viremia in Humanized Mice Infected With Multidrug-resistant HIV. AIDS Res Hum Retroviruses 30(5):403-406. PMCID:PMC4010160.

2.         Heredia, A., C. E. Davis, M. S. Reitz, N. M. Le, M. A. Wainberg, J. S. Foulke, L. X. Wang, and R. R. Redfield. 2013. Targeting of the Purine Biosynthesis Host Cell Pathway Enhances the Activity of Tenofovir Against Sensitive and Drug-Resistant HIV-1. J Infect Dis 208:2085-2094. PMCID: PMC3836462.

3.         Heredia, A., C. Davis, M. N. Amin, N. M. Le, M. A. Wainberg, M. Oliveira, S. G. Deeks, L. X. Wang, and R. R. Redfield. 2014. Targeting host nucleotide biosynthesis with resveratrol inhibits emtricitabine-resistant HIV-1. Aids 28:317-323.

4.         Kawabata, S., A. Heredia, J. Gills, R. R. Redfield, P. A. Dennis, and J. Bryant. 2015. Impact of HIV on lung tumorigenesis in an animal model. Aids 13;29(5):633-635.

B.        Positions and Honors.

Positions and Employment

1995 -1997                  Postdoctoral training. Lab Molecular Virology. Food and Drug Administration. Bethesda

1997 - 2008                 Research Associate, Clinical Research Div, IHV, Univ of Maryland School of Medicine

2008 – present            Assistant Professor, Clinical Research Div, IHV, Univ of Maryland School of Medicine

Honors

2016.   Basic Science Publication of the Year Award. Department of Medicine, University of Maryland School of Medicine.

C. Contribution to Science

1.  My early publications addressed the genetic diversity of HIV. I was trained in PCR, sequencing, and tissue culture methodologies at the Laboratory of Molecular Virology, Division of Transfusion and Transmitted Diseases, FDA, NIH campus, Bethesda, Maryland.  I analyzed the genetic variability of circulating HIV-1 and HIV-2 strains in countries from Western Africa and Western Europe.  I identified several non-B HIV-1 subtypes and some of the first cases of HIV-2 circulating in Spain and Portugal.  I also showed that HIV-2 uses a broader range of coreceptors for entering cells than does HIV-1.  These studies helped me appreciate the high diversity of HIV, setting the foundation for my later research in approaches to control HIV.  This previous training on HIV sequencing will help me to interpret the genotypic data generated in the current proposal.

1.         Heredia, A., V. Soriano, S. H. Weiss, R. Bravo, A. Vallejo, T. N. Denny, J. S. Epstein, and I. K. Hewlett. 1996. Development of a multiplex PCR assay for the simultaneous detection and discrimination of HIV-1, HIV-2, HTLV-I and HTLV-II. Clinical and diagnostic virology 7: 85-92.

2.         Heredia, A., A. Vallejo, V. Soriano, J. S. Epstein, and I. K. Hewlett. 1997. Chemokine receptors and HIV-2. Aids 11: 1198-1199.

3.         Heredia, A., A. Vallejo, V. Soriano, A. Silva, K. Mansinho, S. Fevereiro, A. Mas, M. Gutierrez, J. S. Epstein, and I. K. Hewlett. 1998. Phylogenetic analysis of HIV type 2 strains from Portugal. AIDS Res Hum Retroviruses 14: 471-473.

4.         Vallejo, A., A. Heredia, A. Mas, S. F. Lee, J. S. Epstein, V. Soriano, and I. K. Hewlett. 1998. Tropism, coreceptor use, and phylogenetic analysis of both the V3 loop and the protease gene of three novel HIV-1 group O isolates. J Acquir Immune Defic Syndr 18: 417-425.

2.  The variability of HIV strains led me to focus my research on approaches that inhibit HIV by circumventing virus variability.  In particular, I became interested in cellular proteins that HIV needs for its replication because cellular proteins have lower mutation rates than do viral proteins.  We demonstrated that targeting of cellular Ribonucleotide reductase with Resveratrol inhibited HIV, including drug resistant strains, and synergized with some of the available NRTIs at the time (e.g, DDI).  We were the first to demonstrate that targeting of cellular Inosine Monophosphate Dehydrogenase (IMPDH) with Mycophenolic acid had anti-HIV synergy with several of the available NRTIs, especially with Abacavir.  Our initial studies with Mycophenolic acid prompted several studies by other groups evaluating the therapeutic potential of Mycophenolic acid against HIV.  We have also successfully targeted the cellular CCR5 coreceptor by approaches that upregulate CCR5 ligands and/or lower coreceptor density (molecules/cell) and thereby blocking virus entry, providing the first demonstration that CCR5 levels can be reduced in ways other than the use of antagonists.  Together, these studies provided proof-of-concept for targeting cellular proteins as an approach to inhibit HIV, particularly HIV strains resistant to antiretrovirals.

1.         Heredia, A., D. Margolis, D. Oldach, R. Hazen, N. Le, and R. Redfield. 1999. Abacavir in combination with the inosine monophosphate dehydrogenase (IMPDH)-inhibitor mycophenolic acid is active against multidrug-resistant HIV-1. J Acquir Immune Defic Syndr 22: 406-407.

2.         Heredia, A., C. Davis, and R. Redfield. 2000. Synergistic inhibition of HIV-1 in activated and resting peripheral blood mononuclear cells, monocyte-derived macrophages, and selected drug-resistant isolates with nucleoside analogues combined with a natural product, resveratrol. J Acquir Immune Defic Syndr 25: 246-255.

3.         Latinovic, O., N. Le, M. Reitz, R. Pal, A. Devico, J. S. Foulke, R. R. Redfield, and A. Heredia. 2011. Synergistic inhibition of R5 HIV-1 by maraviroc and CCR5 antibody HGS004 in primary cells: implications for treatment and prevention. Aids 25:1232-1235. PMCID: PMC3748726.

4.         Latinovic, O., M. Reitz, N. M. Le, J. S. Foulke, G. Fatkenheuer, C. Lehmann, R. R. Redfield, and A. Heredia. 2011. CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells. Virology 411:32-40. PMCID: PMC3039059

Complete List of Published Work in MyBibliography:

http://www.ncbi.nlm.nih.gov/sites/myncbi/alonso.heredia.1/bibliography/40739751/public/?sort=date&direction=ascending

D. Research Support.

Ongoing Research Support

1R21AI114288 (Heredia)                                                                                            05/08/2014 - 04/30/2017                    

NIH/NIAID

Long-term Inhibition of HIV transcription by targeting cellular CDK9 in vivo.

The goal is to evaluate targeting of CDK9 in a humanized mouse model infected with HIV as a means to control virus replication and to overcome drug resistance.

Role: PI.

Completed Research Support

1R03AI084417-01 (Heredia)                                                                          07/22/2009-06/30/2011

NIH/NIAID

Control of HIV drug resistance in older patients

The goal of this grant was to determine the mechanism by which R5 HIV resistant to CCR5 antagonist regains sensitivity at reduced CCR5 density.

Role: PI.

HIV, drug resistance, host pathways, CCR5, CDK9

1.         Heredia, A., S. Natesan, N. M. Le, S. Medina-Moreno, J. C. Zapata, M. Reitz, J. Bryant, and R. R. Redfield. 2014. Indirubin 3’-monoxime, from a Chinese Traditional Herbal Formula, Suppresses Viremia in Humanized Mice Infected With Multidrug-resistant HIV. AIDS Res Hum Retroviruses 30(5):403-406. PMCID:PMC4010160.

2.         Heredia, A., C. E. Davis, M. S. Reitz, N. M. Le, M. A. Wainberg, J. S. Foulke, L. X. Wang, and R. R. Redfield. 2013. Targeting of the Purine Biosynthesis Host Cell Pathway Enhances the Activity of Tenofovir Against Sensitive and Drug-Resistant HIV-1. J Infect Dis 208:2085-2094. PMCID: PMC3836462.

3.         Heredia, A., C. Davis, M. N. Amin, N. M. Le, M. A. Wainberg, M. Oliveira, S. G. Deeks, L. X. Wang, and R. R. Redfield. 2014. Targeting host nucleotide biosynthesis with resveratrol inhibits emtricitabine-resistant HIV-1. Aids 28:317-323.

4.         Kawabata, S., A. Heredia, J. Gills, R. R. Redfield, P. A. Dennis, and J. Bryant. 2015. Impact of HIV on lung tumorigenesis in an animal model. Aids 13;29(5):633-635.