Studies on a Potential Vaccine for the Treatment of HIV Infection and Sensitive Immunoassays to Simultaneously Detect Multiple Infections and Monitor Post-vaccination Safety
Principal Investigator: Subhash Dhawan, PhD
Office / Division / Lab: OBRR / DETTD / LMV
Serious challenges are posed in managing the medical consequences when the immune system fails to defend itself against an invading HIV and other blood-borne pathogens, or when there are limited options for effective diagnosis or treatment of existing and emerging infections. In addition, multidrug resistance in pathogens and infection by mutated or recombinant pathogens can further complicate these limitations.
Frequent travels to endemic disease areas and changing climate conditions continue to offer significant opportunities for the spread of deadly infections. The global prevalence of HIV-1 and emerging infections with dengue virus, West Nile virus (WNV) and Zika virus has greatly increased in recent decades. The spread of many of these infections has been reported in many countries. We believe that evaluation and scientific advancement of novel effective tools for in vitro diagnostics should rank among the highest public health priority.
Aligning with the above serious global health concerns, therapeutic activation of a safe and effective host innate response with an understanding of subsequent steps in host defense against pathogenic infections leading to a favorable medical and regulatory outcome in these difficult situations should also rank among the top priorities. These considerations are extremely important, especially when there is no vaccine or drugs available to prevent or treat notorious blood-borne infections.
Our research program addresses: (a) evaluation and scientific advancement of effective tools for quantitative measurement of blood-borne transfusion-transmitted pathogens such as HIV, dengue, WNV, mycoplasma and Zika virus as well as co-infections with these pathogens; (b) understanding virus-host interactions in cells infected with these individual and multiple pathogens; (c) evaluation of innate host protective potential of the inducible endogenous host defense factor heme oxygenase-1 (HO-1) against HIV, dengue, WNV, Ebola, Zika and mycoplasma infections and co-infections with these deadly pathogens.
The major objective of our studies is directly translation of the research findings into practical correlates of in vitro diagnostics and monitoring drug therapies. Specifically, our studies focus on developing technologically advanced systems for the evaluation of efficient quantitative in vitro diagnostics coordinating with developing novel therapeutic strategies to help reduce the progression of the existing and emerging blood-borne infections. Our studies will provide directions for a potentially useful clinical outcome, especially when conventional treatments fail to stimulate an effective immune response to the viruses. This immune system failure can occur when pathogens are resistant to treatment or when mutations in the genetic makeup of these pathogens cause sensitive varieties to mutate and become resistant to drugs.
FDA regulates in vitro diagnostics, designing and manufacturing of blood products, and other biologics to ensure that these products are safe and effective. Our regulatory-oriented research is important because it will aid in FDA regulatory strategies particularly in terms of evaluation of the performance of in vitro diagnostic tests for existing and emerging pathogens and monitoring how patients respond to drug therapy. Therefore, these studies are of significant potential for improving the public health.
Emerging infectious diseases pose great threat to public health, including recipients of blood transfusions. Among many blood-borne infections transmitted through transfusion of infected blood donated by apparently healthy and asymptomatic blood donors are dengue, malaria, Ebola, West Nile viruses (WNV), and Zika. Dengue virus, WNV and Zika belong to the family of flaviviruses that can be transmitted to humans by mosquitoes and other non-human carriers, as well as by transfusion of blood or blood products, bone marrow, organ transplant, hemodialysis, and exposure to infected mucous membranes. The presence of these infectious agents in the blood supply can significantly impact the safety of blood and blood-derived biologics.
We have successfully developed novel assay controls and standards for quantification of Zika virus. We are further expanding our experimental approach to develop new strategies for assay controls and standards for quantifying HIV, dengue, WNV, and potential co-infections.
Our laboratory is the first to establish a pivotal role of an inducible endogenous cytoprotective enzyme, heme oxygenase-1 (HO-1), against blood-borne infections. We have confirmed that HO-1 induction substantially inhibits infection of cells with HIV and other pathogens. While the mechanism of action of HO-1 induction as a host defense factor remains unclear; nonetheless, the findings from our studies are highly encouraging, since they demonstrate activation of a natural host defense mechanism against these individual pathogens as well as against co-infections. We are focusing our efforts on understanding the HO-1-dependent and HO-1-independent innate host protection mechanisms against HIV, WNV, dengue, mycoplasma and Zika infections.
Our studies may provide new directions in identifying new target molecules and safe methods for inducing innate host defense responses against pathogenic infections. Our studies may lead to the development a novel strategy for the treatment of HIV and possibly other deadly infections for which no treatment is currently available, given that hemin administration in humans has previously met required FDA safety standards and is FDA approved. Therefore, our comprehensive, systematic, yet unconventional approach to addressing new emerging regulatory pathways relates to important public health issues.
Currently, there are no vaccines for the prevention of WNV, dengue or Zika virus infections and no effective drugs to treat these blood-borne diseases. Therefore, we strongly believe that HO-1 induction might provide a useful strategy for minimizing emerging public health crises and maximizing economical therapeutic interventions. In view of the continual challenges due to emergence of drug-resistant mutants, our approach of identifying HO-1 and HO-1-related genomic and proteomic pathways mediating host protection mechanisms may offer novel biomarkers and therapeutic targets for treating infections and disease conditions. The FDA regulates applications for diagnostics, drugs, and other products related to many of these disease conditions. Our studies strongly support the public health mission of facilitating the application of new tools for qualitative and quantitative in vitro diagnostics as well as for the development of new biologic and drug products by stimulating a potent endogenous host defense mechanism.
Virology 2017 Mar;503:1-5
Nrf2-dependent induction of innate host defense via heme oxygenase-1 inhibits Zika virus replication.
Huang H, Falgout B, Takeda K, Yamada KM, Dhawan S
Curr Trends Immunol 2016;17:117-23
Therapeutic potential of the heme oxygenase-1 inducer hemin against Ebola virus infection.
Huang H, Konduru K, Solovena V, Zhou ZH, Kumari N, Takeda K, Nekhai S, Bavari S, Kaplan GG, Yamada KM, Dhawan S
Blood Adv 2016 Dec 27;1(3):170-83
Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease.
Kumari N, Ammosova T, Diaz S, Lin X, Niu X, Ivanov A, Jerebtsova M, Dhawan S, Oneal P, Nekhai S
Biochem Biophys Res Commun 2015 Aug 14;464(1):7-12
Hemin activation of innate cellular response blocks human immunodeficiency virus type-1-induced osteoclastogenesis.
Takeda K, Adhikari R, Yamada KM, Dhawan S
Virology 2015 Feb;476:372-6
Pathogenic prion protein fragment (PrP106-126) promotes human immunodeficiency virus type-1 infection in peripheral blood monocyte-derived macrophages.
Bacot SM, Feldman GM, Yamada KM, Dhawan S
Antimicrob Agents Chemother 2014 Nov;58(11):6558-71
Phenyl-1-Pyridin-2yl-ethanone-based iron chelators increase IkappaB-alpha expression, modulate CDK2 and CDK9 activities, and inhibit HIV-1 transcription.
Kumari N, Iordanskiy S, Kovalskyy D, Breuer D, Niu X, Lin X, Xu M, Gavrilenko K, Kashanchi F, Dhawan S, Nekhai S
Biochem Biophys Res Commun 2014 Oct 18;454(1):84-8
Non-coding RNAs and heme oxygenase-1 in vaccinia virus infection.
Meseda CA, Srinivasan K, Wise J, Catalano J, Yamada KM, Dhawan S
PLoS One 2014 Apr 9;9(4):e94402
Oversulfated chondroitin sulfate binds to chemokines and inhibits stromal cell-derived factor-1 mediated signaling in activated T cells.
Zhou ZH, Karnaukhova E, Rajabi M, Reeder K, Chen T, Dhawan S, Kozlowski S
Biochem Biophys Res Commun 2013 Jun 7;435(3):373-7
Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages.
Zhou ZH, Kumari N, Nekhai S, Clouse KA, Wahl LM, Yamada KM, Dhawan S
Future Virol 2013 Mar;8(3):301-11
Role of cellular iron and oxygen in the regulation of HIV-1 infection
Nekhai S, Kumari N, Dhawan S
J Leukoc Biol 2010 May;87(5):915-24
Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction.
Devadas K, Hewlett IK, Dhawan S
Peptides 2007 Mar;28(3):496-504
Antibodies against a multiple-peptide conjugate comprising chemically modified human immunodeficiency virus type-1 functional Tat peptides inhibit infection.
Devadas K, Boykins RA, Hewlett IK, Wood OL, Clouse KA, Yamada KM, Dhawan S
Expert Rev Mol Diagn 2006 Sep;6(5):749-760
Signal amplification systems in immunoassays: implications for clinical diagnostics.
Peptides 2006 Apr;27(4):611-21
Selective side-chain modification of cysteine and arginine residues blocks pathogenic activity of HIV-1-Tat functional peptides.
Devadas K, Boykins RA, Hardegen NJ, Philp D, Kleinman HK, Osa EO, Wang J, Clouse KA, Wahl LM, Hewlett IK, Rappaport J, Yamada KM, Dhawan S
J Immunol 2006 Apr 1;176(7):4252-7
Hemin Activation Ameliorates HIV-1 Infection via Heme Oxygenase-1 Induction.
Devadas K, Dhawan S