Research in the Kwiek Lab focuses on the biology, pharmacology, and public health impact of Human Immunodeficiency Virus (HIV-1). We are currently focusing on three projects.
The biological mechanism of HIV-1 mother-to-child transmission
Approximately 20% of all MTCT occurs in utero, and although many developing countries are testing resource-appropriate MTCT interventions, the vast majority of these strategies will not reduce the frequency of in utero HIV-1 MTCT. Our central hypothesis states that the placenta acts as a virological barrier, allowing only a subset of HIV-1 variants access to the fetus. Using both retrospective and prospective HIV-1 subtype C isolates, we are interrogating the HIV-1 genotypes and phenotypes associated with in utero MTCT. We hypothesize that HIV-1 variants successfully transmitted in utero require phenotypic characteristics that 1) enable efficient replication in the immune-privileged placental milieu, and/or 2) promote penetration/infection of cells prevalent at the maternal-fetal barrier.
The interaction of HIV-1 with host proteins during HIV-1 replication
Owing to the recent setbacks in vaccine and microbicide trails, novel strategies to slow the HIV-pandemic are desperately needed. Development of a small molecule that blocked a host process required for HIV-1 replication could provide such a strategy. Like all retroviruses, HIV-1 requires host proteins to complete its life cycle, and these intracellular host molecules represent an undeveloped pool of novel anti-HIV therapeutics. The goal of this application is to use functional proteomics to identify host proteins that are dispensable to the host but essential for viral replication. A generic proteomic screen would likely identify numerous host proteins induced by HIV-infection, most of which would be poor therapeutic candidates. A functional proteomics screen, which queries a subset of proteins with strong therapeutic potential, would greatly simplify the search for host targets; the host purinome has this potential. The purinome comprises any protein that binds purine-containing molecules (e.g. ATP, NADH), and it includes heat shock proteins, dehydrogenases, and protein kinases. Inhibition of purinome proteins forms the basis of many current therapies, including those targeting cancer, hypertension, and bacterial infections. The central hypothesis of this research states that inhibition of purinome proteins, which are induced or regulated by HIV-infection, will block HIV-1 replication.
Pediatric HIV-1 diagnostics
Despite the evidence that timely antiretroviral treatment (ART) in HIV-infected infants reduced death by approximately 75% (CHER Study, Violari et al., 2009), only 38% of the HIV-infected children in sub-Saharan Africa (SSA) are currently receiving ART (www.unaids.org). The lack of affordable, accessible and accurate HIV-1 infant diagnostic tests is one of the major bottlenecks limiting timely access to ART among children in SSA.
Several published studies have demonstrated the ability of HIV-1 p24 antigen detection assays to diagnose pediatric HIV-infection both from plasma, and dried blood spots from venous blood. Importantly, the p24 assay has been validated against HIV-1 subtype C, which comprises >95% of all HIV-infections in Malawi, and it can be easily adapted to a resource-limited setting. We hypothesize that a simplified p24 antigen assay performed on dried blood spots obtained via heel prick could serve as an accurate, inexpensive, and accessible assay to diagnose pediatric HIV-infection.
Jesse Kwiek's Curriculum Vitae [pdf]
Member, Center for Microbial Interface Biology
Member, Center for Retrovirus Research
Member, Medical Scientist Training Program
- Keim SA, Hogan JS, McNamara KA, Gudimetla V, Dillon CE, Kwiek JJ & Geraghty SR. “Microbial Contamination of Human Milk Purchased Via the Internet.” Pediatrics, 2013 Nov; 132(5):e1227-35. PMID: 24144714
- Norris Turner A, Tabbah S, Mwapasa V, Rogerson SJ, Meshnick SR, Ackerman WE IV & Kwiek JJ. Severity of maternal HIV-1 disease is associated with adverse birth outcomes in Malawian women: a cohort study. JAIDS, 2013, Dec; 64(4):392-9. PMID: 23846560
- Mates JM, Kumar SB, Bazan J, Voronkin I, Handelman SK, Janies DJ & Kwiek JJ. “Genotypic and phenotypic heterogeneity in the U3R region of HIV-1 subtype C.” AIDS Research and Human Retroviruses, 2014 Jan.;30(1):102-12. PMID: 23826737
- Keim SA, Kulkarni M, Billock RM, Hogan JS, McNamara KA, Dillon CE, Geraghty SR & Kwiek JJ. “Cow’s Milk Contamination of Human Milk Purchased Via the Internet.” Pediatrics, 2015, May 135(5):e1157-62. PMID: 25847797
- Mates JM, de Silva S, Lustberg M, Van Deusen K, Baiocchi RA, Wu, L. (co-senior author) & Kwiek JJ. (co-senior author). “A Novel Histone Deacetylase Inhibitor, AR-42, 1 Reactivates HIV-1 from Chronically and Latently Infected CD4+ T-Cells. Retrovirology (Auckl). 2015; 7:1-5. Epub 2015 Oct 15. PMID: 26855567
- Geraghty SR, McNamara KA, Kwiek JJ, Rogers L, Klebanoff MA, Augustine M & Keim SA. “Tobacco metabolites and caffeine in human milk purchased via the Internet.” Breastfeeding Medicine, 2015, Breastfeed Med. 2015 Nov; 10(9):419-24. PMID: 26394021
- Keim SA, McNamara KA, Kwiek JJ & Geraghty SR. “Drugs of abuse in human milk purchased via the Internet” Breastfeeding Medicine, 2015, Breastfeed Med. 2015 Nov; 10(9):416-8. PMID: 26460596
- Yazan Alwarawrah, Philip Hughes, David Loiselle, David A. Carlson, David B. Darr, Jamie L. Jordan, Jessie Xiong Lucas M. Hunter, Laura G. Dubois, J. Will Thompson, Manjusha M. Kulkarni, Annette N. Ratcliff, Jesse J. Kwiek†, Timothy A. J. Haystead†. “Fasnall, a selective FASN inhibitor shows potent anti-tumor activity in the MMTV Neu model of HER2+ breast cancer.” † = Co-corresponding authors. In Press, Cell Chemical Biology, May 2016.
- Abigail Norris Turner, Nicholas T. Funderburg, Brandon Snyder, Kristi Small, Jan Clark, Jose A. Bazan, Nicole C. Kwiek, Jesse J. Kwiek. “High levels of self-reported prescription opioid use by HIV-positive individuals attending an infectious disease clinic.” In press, AIDS Care, June 2016.
- Fouda GG, Mahlokozera T, Salazar-Gonzalez J, Salazar M, Learn G, Barotra S,Sekaran M, Russell ES, RizzoloK, Jaeger F, Cai F, Gao F, Hahn B, Swanstrom RI, Meshnick SR, Mwapasa V, Kalilani L, Fiscus SA, Montefiori D, Haynes B, Kwiek JJ, Alam M & Permar SM. (2013). “Postnatally-transmitted HIV-1 Envelope variants are efficient at dendritic cell trans-infection and are sensitive to neutralization by autologous and broadly-neutralizing antibodies.” Retrovirology;10(3).
- Ackerman WE 4th & Kwiek JJ. (2013) "Role of the placenta in adverse perinatal outcomes among HIV-1 seropositive women." J Nippon Med Sch, 80: 90-94.
- Geraghty SR, McNamara KA, DillonCE, Hogan JS, Kwiek JJ & Keim SA. (2013) “Buying Human Milk Via the Internet: Just a Click Away.” Breastfeeding Medicine. Accepted.
Norris Turner A, Tabbah S, Mwapasa V, Rogerson SJ, Meshnick SR, Ackerman WE IV, Kwiek JJ. (2013). Placental HIV and Adverse Birth Outcomes. JAIDS, Accepted.
- Kumar SB, Rice CE, Milner DA Jr, Ramirez NC, Ackerman WE 4th, Mwapasa V, Turner AN & Kwiek JJ. (2012) "Elevated cytokine and chemokine levels in the placenta are associated with in-utero HIV-1 mother-to-child transmission" AIDS. 2012 Mar 27;26(6):685-94.
- Russell ES, Kwiek JJ, Keys J, Barton K, Montefiori D, Mwapasa V, Meshnick S, & Swanstrom R. (2011) “The Genetic Bottleneck in Vertical Transmission of Subtype C HIV-1 Is Not Driven by Selection of Especially Neutralization Resistant Virus from the Maternal Viral Population” J Virol. 2011 Aug;85(16):8253-62.
- Kumar SB, Handelman SK, Voronkin I, Mwapasa V, Janies D, Rogerson SJ, Meshnick SR, & Kwiek JJ (2011) “Different Regions of HIV-1 Subtype C env are Associated with Placental Localization and In Utero Mother-to-Child Transmission” J Virol. 2011 Jul;85(14):7142-52.
- Garnsey MR, Matous JA, Kwiek JJ & Coltart DM. (2011) “Asymmetric Total Synthesis of (+)- and (–)-Clusianone and (+)- and (–)- Clusianone Methyl Enol Ether via ACC Alkylation and Evaluation of their Anti- HIV Activity.” Bioorganic & Medicinal Chemistry Letters, 2011, 21(8):2406-9.
- Mwapasa V, Cachafeiro A, Makhuta Y, Beckstead DJ, Pennell ML, Chilima B, Mwagomba B, Fiscus SA, & Kwiek JJ. (2010) “Using a Simplified Human Immunodeficiency Virus Type I p24 Antigen Assay to Diagnose Pediatric HIV-Infections in Malawi.” Journal of Clinical Virology, 2010, 49, 299-302.
- Gay CL, Mwapasa V, Murdoch DM, Kwiek JJ, Fiscus SA, Meshnick SR & Cohen MS.(2010) Acute HIV infection among pregnant women in Malawi. Diagn Microbiol Infect Dis. 66, 356-60.
- Kwiek JJ, Alker AP, Wenink EC, Chaponda M, Kalilani LV & Meshnick SR. (2008) Estimating true antimalarial efficacy by heteroduplex tracking assay in patients with complex Plasmodium falciparum infections. Antimicrob Agents Chemother. 51, 521-7.
- Kwiek JJ, Russell ES, Dang KK, Burch CL, Mwapasa V, Meshnick SR & Swanstrom R. (2008) The molecular epidemiology of HIV-1 envelope diversity during HIV-1 subtype C vertical transmission in Malawian mother-infant pairs. AIDS. 22, 863-71.
- Kwiek JJ, Arney LA, Harawa V, Pedersen B, Mwapasa V, Rogerson SJ & Meshnick SR. (2008) Maternal-fetal DNA admixture is associated with intrapartum mother-to-child transmission of HIV-1 in Blantyre, Malawi. J Infect Dis. 197, 1378-81.
- Kwiek JJ, Mwapasa V, Alker AP, Muula AS, Misiri HE, Molyneux ME, Rogerson SJ, Behets FM & Meshnick SR. (2008) Socio-demographic characteristics associated with HIV and syphilis seroreactivity among pregnant women in Blantyre, Malawi, 2000-2004. Malawi Med J. 20, 80-5.
- Mwapasa V, Rogerson SJ, Kwiek JJ, Wilson PE, Milner D, Molyneux ME, Kamwendo DD, Tadesse E, Chaluluka E & Meshnick SR. (2006). Maternal syphilis infection is associated with increased risk of mother-to-child transmission of HIV in Malawi. AIDS. 20, 1869-77.
- Kwiek JJ, Mwapasa V, Milner DA Jr, Alker AP, Miller WC, Tadesse E, Molyneux ME, Rogerson SJ & Meshnick SR.(2006) Maternal-fetal microtransfusions and HIV-1 mother-to-child transmission in Malawi. PLoS Med. 3, e10.
- Ngrenngarmlert W, Kwiek JJ, Kamwendo DD, Ritola K, Swanstrom R, Wongsrichanalai C, Miller RS, Ittarat W & Meshnick SR. (2005) Measuring allelic heterogeneity in Plasmodium falciparum by a heteroduplex tracking assay. Am J Trop Med Hyg. 72, 694-701
- Kwiek JJ, Haystead TA & Rudolph J. (2004) Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines. Biochemistry. 43, 4538-47.
- Graves PR, Kwiek JJ, Fadden P, Ray R, Hardeman K, Coley AM, Foley M & Haystead TA. (2003) Discovery of novel targets of quinoline drugs in the human purine binding proteome. Mol Pharmacol. 62, 1364-72.
- Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, White FM, Christian RE, Settlage RE, Shabanowitz J, Hunt DF, Weber MJ. (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem. 277, 29304-14.
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