The vast majority of information and quotes in this book were obtained from personal interviews with the parties involved. To simplify the references of this book, all major scientific and popular press articles from each Berlin patient are grouped together before proceeding to specific chapter references.
Christian Hahn—Berlin Patient #1
Scientific Reports
The first report that hydroxyurea could be used against HIV was shown in cell culture by Lisziewicz and Lori in Gallo’s lab: “Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication,” Science 266 (Nov 4, 1994).
An early report on the first Berlin patient by Lisziewicz, Lori, and Jessen: “HIV-1 suppression by early treatment with hydroxyurea, didanosine, and a protease inhibitor,” Lancet 352 (Jul 18, 1998).
The principal report detailing the science of the first Berlin patient can be found in “Control of HIV despite the discontinuation of antiretroviral therapy,” New England Journal of Medicine 340 (May 27, 1999).
Popular Press
The Mark Schoofs article interviewing the Berlin patient is “The Berlin Patient,” New York Times Magazine (June 21, 1998).
The article that proved so contentious among Jessen and his colleagues is “Ray of Hope in the AIDS War,” Newsweek (February 23, 1998).
The tabloid article that upset Jessen due to its bold use of the word cure is “AIDS die erste heilung?” B.Z. (June 18, 2000).
The story of the first Berlin patient was also covered in:
“HIV Suppressed Long after Treatment,” Science (September 26, 1997).
“HIV Hope in Old Cancer Drug,” The Observer (January 7, 1998).
“Der Berlin-Patient,” Rheinische Post (October 9, 2004).
“Das medizinische wunder,” Tagesspiegel (September 3, 2004).
Timothy Ray Brown—Berlin Patient #2
Scientific Reports
Gero Hütter first reported the Berlin patient in a poster session: “Treatment of HIV-1 infection by allogeneic CCR5-Δ32/Δ32 stem cell transplantation: a promising approach,” Abstract 719, 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA (2008).
Hütter first published the Berlin patient data in “Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation,” New England Journal of Medicine 360 (Feb 12, 2009).
Follow-up on the Berlin patient by Hütter was reported in “Eradication of HIV by transplantation of CCR5-deficient hematopoietic stem cells,” Scientific World Journal 11 (May 5, 2011); “Evidence for the cure of HIV infection by CCR5 Δ32/Δ32 stem cell transplantation,” Blood 117 (Mar 10, 2011); “The CCR5-delta32 polymorphism as a model to study host adaptation against infectious diseases and to develop new treatment strategies,” Experimental Biology and Medicine 236 (Aug 2011); “Transplantation of selected or transgenic blood stem cells—a future treatment for HIV/AIDS?” Journal of the International AIDS Society 12 (Jun 28, 2009); “The effect of the CCR5-delta32 deletion on global gene expression considering immune response and inflammation,” Journal of Inflammation 8 (Jan 2011); “Allogeneic transplantation of CCR5-deficient progenitor cells in a patient with HIV infection: an update after 3 years and the search for patient no. 2,” AIDS 25 (Jan 14, 2011).
Popular Press
It would be impossible to cite all popular press articles mentioning Timothy Brown. Instead, I’ve listed the key articles that influenced the research community and the public.
The Mark Schoofs article that convinced The New England Journal of Medicine to publish Gero Hütter’s paper is “A Doctor, a Mutation and a Potential Cure for AIDS,” Wall Street Journal (November 7, 2008).
Timothy was given a sizable fee for his interview in Stern, a popular German magazine. “Der Mann, der HIV besiegte,” Stern (December 8, 2010).
“The Man Who Had HIV and Now Does Not,” New York Magazine (May 29, 2011).
“The Emerging Race to Cure HIV Infections,” Science (May 13, 2011).
Chapter 1: The Good Doctor in Denial
The 1993 March on Washington for Lesbian, Gay, and Bi Equal Rights and Liberation was one of the largest civil rights demonstrations in American history. Video from the march is archived at the C-SPAN video library. http://www.c-spanvideo.org/program/40062-1.
Stages of viral disease including clinical descriptions of prodromal and incubation periods for HIV can be found in Clinical Infectious Disease, edited by David Schlossberg (Cambridge University Press, 2008).
Bob Siliciano’s first paper identifying a latent reservoir for HIV was “Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy,” Science 278 (Nov 14, 1997).
“You are stuck with the virus unless you get every last latently infected cell” was quoted from an interview with Bob Siliciano, published in “Come out, come out,” International AIDS Vaccine Initiative Report 9 (2005).
Eighty-three percent of physicians have prescribed medications for a family member was reported in “When physicians treat members of their own families,” New England Journal of Medicine 325 (1991).
A beautiful description of the fall of the Berlin Wall and its global impact can be found in 1989: The Struggle to Create Post–Cold War Europe by Mary Elise Sarotte (Princeton University Press, 2009).
Incredibly, there are still squatters from reunification in East Berlin. Their stories and many more can be found in a collection archived by National Public Radio: http://berlinstories.org.
Chapter 2: A Visit with the Family Doctor
The first report of a nucleic acid test to diagnose HIV in those with a negative antibody test, identical to the test used to diagnose Christian with HIV, was “Identification of HIV-infected seronegative individuals by a direct diagnostic test based on hybridisation to amplified viral DNA,” Lancet 2 (1988).
David Ho was named Time’s Man of the Year and featured on the cover of the magazine on December 30, 1996.
Roche discussed their new approach to targeting HIV’s protease enzyme in “Rational design of peptide-based HIV proteinase inhibitors,” Science 248 (1990).
Roche’s saquinavir was approved for use by the FDA on December 6, 1995 while Merck’s indinavir was approved roughly three months later on March 13, 1996.
Chapter 3: Death Sentence?
On page 2 of Christopher Isherwood’s memoir, Christopher and His Kind (1976), the author says, speaking of himself in the third person, “To Christopher, Berlin meant Boys.”
Further explanation of how HIV antibody tests work is available from “HIV assays: operational characteristics,” World Health Organization (2002).
Detailed description of the innate and acquired immune system can be found in Immunobiology, 5th edition, The Immune System in Health and Disease, by Charles A Janeway Jr, Paul Travers, Mark Walport, and Mark J Shlomchik (Garland, 2001).
The CDC estimate that one-third of those diagnosed with HIV in the mid-1990s didn’t return for their test results was reported in Centers for Disease Control and Prevention, “Advancing HIV prevention: new strategies for a changing epidemic—United States, 2003,” Morbidity and Mortality Weekly Report 52 (2003).
More on OraQuick and other rapid HIV antibody tests is discussed in “A rapid review of rapid HIV antibody tests,” Current Infectious Disease Reports 8 (2006).
Perspective on HIV as a death sentence in the 1990s is described in “HIV: Now and Then,” Gay Times 415 (February 2013).
Chapter 4: Viral Trojan Horse
David Barry’s interest in HIV is described in “The Inside Story of the AIDS Drug,” Fortune (November 5, 1990), and in his obituary, “David Barry: Key Researcher in the Development of AZT,” Guardian (March 8, 2002).
Gallo’s report of the HTLV-III virus causing AIDS was in “A pathogenic retrovirus (HTLV-III) linked to AIDS,” New England Journal of Medicine 311 (Nov 15, 1984).
A description of retroviruses and their life cycle can be found in chapter 3 of Retroviruses: Molecular Biology, Genomics and Pathogenesis, edited by Reinhard Kurth and Norbert Bannert (Caister Academic Press, 2010).
The extraterrestrial origin of uracil was described in “The Surface Composition of Titan,” American Astronomical Society, DPS Meeting (March 2012).
Further discussion of viruses and their taxonomy can be found in A Planet of Viruses by Carl Zimmer (University of Chicago Press, 2011).
The long evolutionary history of FIV in cougars is described in “The molecular biology and evolution of feline immunodeficiency viruses of cougars,” Veterinary Immunology and Immunopathology 123 (2008).
Estimates of the long evolutionary history that African green monkeys share with their SIV can be found in “SIVagm infection in wild African green monkeys from South Africa: epidemiology, natural history, and evolutionary considerations,” PLoS Pathogens 9 (2012) and “Island biogeography reveals the deep history of SIV,” Science 329 (2010).
HIV diversity and its relationship to drug resistance is further discussed in “HIV drug resistance,” New England Journal of Medicine 350 (2004).
David Balitmore’s Nobel Prize–winning work on reverse transcriptase can be found in “Reversal of information flow in the growth of RNA tumor viruses,” New England Journal of Medicine 284 (1971).
How combination antiviral therapy (known as HAART) changed the world of HIV therapy in 1996 can be found in “The art of ‘HAART’: researchers probe the potential and limits of aggressive HIV treatments,” Journal of the American Medical Association 277 (Feb 26, 1997).
Chapter 5: A Weapon from the War on Cancer
Speculation on whether World War II delayed early investigation into the environmental factors influencing cancer is discussed in “Historical threads in the development of oncology social work,” Journal of Psychosocial Oncology 27 (2009).
Details on the early stigma of cancer and the biographical details of Mary Lasker can be found in The Mary Lasker Papers archived at the National Institutes of Health. Quotes from Mary Lasker were taken from twenty years of recordings of interviews between John T. Mason and Mary Lasker archived by Columbia University and available digitally in their notable New Yorkers section: http://www.columbia.edu/cu/lweb/digital/collections/nny/laskerm/index.html.
How Mary Lasker convinced NBC to lift the ban on cancer is described in “A Tribute to Mary Lasker,” Cancer News 48 (1994).
Jerome Horwitz’s research paper first describing AZT was “Nucleosides. IX. The formation of 2',2'-unsaturated pyrimidine nucleosides via a novel beta-elimination reaction,” Journal of Organic Chemistry 31 (1966).
The definitive book on how DNA replicates is DNA Replication, 2nd edition, by Arthur Kornberg (University Science Books, 1992).
Background information on Dr. Jerome Horwitz was obtained from the following sources as well as interviews with colleagues and family members. Sadly, Horwitz passed away on September 6, 2012.
“The Inside Story of the AIDS Drug,” Fortune (November 5, 1990).
“The Story of AZT: Partnership and Conflict,” Scribd (2006).
“We had a very interesting set of compounds waiting for the right disease” is quoted from Horwitz in “A Failure Led to Drug Against AIDS,” New York Times (September 20, 1986).
Quotes from Samuel Broder and background information obtained from the NIH online archive: “In their own words, NIH researchers recall the early years of AIDS,” http://history.nih.gov/nihinownwords/index.html and a paper he authored: “The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic,” Antiviral Research 85 (2010).
Details of Gallo’s press conference in 1984 were obtained from personal interviews and from the book Virus Hunting: Aids, Cancer, and the Human Retrovirus: A Story of Scientific Discovery by Robert Gallo (1993). Additional details were gained from an interview with Margaret Heckler included in the PBS Frontline program “The Age of AIDS” (2006).
Gallo and his team used HTLV-III as the name for what is now HIV in “Frequent detection and isolation of cytopathic references (HTLV-III) from patients with AIDS and at risk for AIDS,” Science 224 (1984).
Anthony Fauci’s quote “What lifestyle did the fetus undertake to acquire the disease?” is from the NIH online archive: “In their own words, NIH researchers recall the early years of AIDS,” http://history.nih.gov/nihinownwords/index.html.
Many sources report the discrimination that those with HIV suffered during the 1980s and 1990s. These articles document a few specific means of discrimination:
“Ban on deadly kiss of life,” Sunday Mirror (February 17, 1985).
“AIDS: prejudice and progress,” Time (September 8, 1986).
“Voices: The miracle of Ryan White,” Time (April 23, 1990).
Background on Janet Rideout and her role in AZT is discussed in “The Inside Story of the AIDS Drug,” Fortune (November 5, 1990).
Description of protests including “Trials are treatment” obtained from interviews with former and current activists.
Chapter 6: The Days of Acting Up
Seventy percent of those born after 1980 favor same-sex marriage was reported by the Pew Research Center in the report “Growing Support for Gay Marriage: Changed Minds and Changing Demographics,” (March 20, 2013).
Rent, written and composed by Jonathan Larson, became a Broadway production on April 29, 1996, at the Nederlander Theatre in NYC.
Report of the first promising signs using AZT for AIDS can be found in “AIDS therapy: first tentative signs of therapeutic promise,” Nature 323 (1986).
The first paper describing AZT as an antiviral agent for a virus that would later become known as HIV is “3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro,” Proceedings of the National Academy of Sciences of the United States of America 82 (1985).
Toxicity problems with AZT in AIDS patients was first reported in “The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex,” New England Journal of Medicine 317 (1987). This paper lists the red blood cell transfusion rates for those taking AZT as 31 percent while those on a placebo had an 11 percent transfusion rate. This study also lists adverse reactions to AZT; 84 percent of those taking AZT reported an adverse reaction.
Results of the first AZT clinical trial were reported in “The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex, a double-blind, placebo-controlled trial,” New England Journal of Medicine 317 (1987).
Effects of AZT in the bone marrow was discussed in Pluda JM, Mitsuya H, Yarchoan R, “Hematologic effects of AIDS therapies,” Hematology Oncology Clinics of North America 5 (1991), and “Zidovudine pharmacokinetics in zidovudine-induced bone marrow toxicity,” British Journal of Clinical Pharmacology 37 (1994).
Background on AZT development can be found in the author’s Introduction to North Carolina and the Problem of AIDS: Advocacy, Politics, and Race in the South by Stephen Inrig (University of North Carolina Press, 2011).
“The debate over AZT clinical trials,” Harvard University, John F. Kennedy School of Government, Case program (1999).
The Ethics and the Business of Bioscience by Margaret L. Eaton (Stanford Business Books, 2004).
Cost of AZT was reported in “AZT’s Inhuman Cost,” New York Times (August 28, 1989).
The $400 million in profits garnered by Burroughs Wellcome in 1992 was reported in “Market Place: Burroughs Wellcome, Analysts Say, Is More Than Just AZT,” New York Times (June 10, 1993).
The cultural phenomena of AZT and AIDS activism is documented in The ACT UP Oral History Project, http://www.actuporalhistory.org/interviews/index.html.
Before the patent to AZT ended, in 2002 Jerome Horwitz joined a lawsuit against GlaxoSmithKline, formerly Burroughs Wellcome, for patent rights to AZT. Details about AZT development can be found in documentation from this lawsuit against GlaxoSmithKline in the United States Federal Court for Central District of California (Western Division, Case No. 02-5223 TJH Ex) by AIDS Healthcare Foundation.
Samuel Broder discussed how new drugs coming from the NCI were “an antidote to the sense of therapeutic nihilism” in an interview recorded in “In their own words, NIH researchers recall the early years of AIDS,” http://history.nih.gov/nihinownwords/index.html.
“The perfect is the enemy of the good” is translated from the French in Voltaire’s poem “La Bégueule.”
Chapter 7: Recognizing a Global Pandemic
David Ho’s history was obtained from personal interviews.
The first reported cases of an unknown disease that would later be identified as HIV were 5 homosexual men with biopsy-confirmed Pneumocystis carinii pneumonia from three hospitals in Los Angeles. This first report was “Pneumocystis pneumonia—Los Angeles,” Morbidity and Mortality Weekly Report 30 (1981).
More details on smallpox can be found in Smallpox: The Death of a Disease: The Inside Story of Eradicating a Worldwide Killer by D. A. Henderson and Richard Preston (Prometheus, 2009).
David Ho’s paper “Time to hit HIV, early and hard,” New England Journal of Medicine 333 (1995), would have an enormous influence on the HIV community and inspire part of Heiko Jessen’s therapy for Christian.
David Ho was named Time’s Man of the Year and featured on the cover of the magazine on December 30, 1996.
Ho’s work on combination therapy was featured in the cover story “The End of AIDS?” Newsweek (December 1, 1996).
GRID, or gay-related immune deficiency, was a term coined by the media. The term was both inaccurate and offensive since there is no link between homosexuality and the disease. In 1982, the CDC established the term acquired immune deficiency, or AIDS. This is detailed in “What to call the AIDS virus?” Nature 321 (1986).
More detail about the human leukocyte antigen and its role in the immune system can be found in Immunobiology, 5th edition, The Immune System in Health and Disease, by Charles A Janeway Jr, Paul Travers, Mark Walport, and Mark J Shlomchik (Garland, 2001).
Bruce Walker’s personal history was obtained by personal interviews.
Walker’s first paper was “HIV-specific cytotoxic T lymphocytes in seropositive individuals,” Nature 328 (1987).
Chapter 8: From the One Percent
Notes from the 1993 International Conference on AIDS can be found in “We are all Berliners: notes from the Ninth International Conference on AIDS,” American Journal of Public Health 83 (1993).
A nice review of CD4 T cells and their role in the immune system can be found in “CD4 T cells: fates, functions, and faults,” Blood 112 (2008).
Perspective on the CONCORDE trial can be found in “After Concorde,” British Medical Journal 306 (1993).
“How much is Roche paying you to say this?” is attributed to Margaret Fischl in “Once We Were Warriors: Activist Corpses Borne in Protest, Furtive Legislative Coups and the Devastation That Was Berlin,” Treatment Action Group (2002). This article also describes the 1993 conference as the “most depressing AIDS conference ever.”
Abstracts and data presented at the Ninth International AIDS Conference in Berlin in 1993 can be found on the AIDS Education Global Information System website: http://www.aegis.org/DisaplayConf/directory.aspx? Conf=The%20International%20AIDS%20Society-IAS.
Saquinavir was first described by Roche in “Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase,” Antiviral Research 16 (1991).
Details of saquinavir development at Roche can be found in Ethics and the Business of Bioscience by Margaret L. Eaton (Stanford University Press, 2004).
Merck’s early (and incorrect) structure of protease was reported in “Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1,” Nature 337 (1989).
The effectiveness of HAART was reported in “Long term effectiveness of potent antiretroviral therapy in preventing AIDS and death: A prospective cohort study,”Lancet 366 (2005).
Two papers reported that HAART reduces death by 60–80 percent: “A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less,” New England Journal of Medicine 337 (1997), and “Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy,” New England Journal of Medicine 337 (1997).
Chapter 9: But, Doctor, I Don’t Feel Sick
Descriptions of HIV-positive patients at St. Clare’s hospital were made from personal observations.
An overview of the controversy of when to begin antiviral therapy for HIV can be found in “When to start antiretroviral therapy—ready when you are?” New England Journal of Medicine 360 (2009).
The finding that HIV infects as a single “founder virus” was surprising in the field. Some believe characterization of this founder virus may lead to new vaccine strategies. This was first reported in “Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection,” Proceedings of the National Academy of Sciences 105 (2008).
How T cells are infected by HIV and the mechanism of their destruction is described in “HIV preferentially infects HIV-specific CD4+ T cells,” Nature 417 (2002).
Most HIV replication occurs in the intestines. This is discussed in “Getting to the guts of HIV pathogenesis,” Journal of Experimental Medicine 200 (2004).
Numerous studies have examined the dense network of lymphocytes in the intestines and other mucosal tissue, including “Overview of the mucosal immune system,” Current Topics in Microbiology and Immunology 146 (1989).
A discussion of the importance of mucosal lymphocytes in HIV infection can be found in “HIV pathogenesis: the first cut is the deepest,” Nature Immunology 6 (2005).
Surprisingly, the kinetics of T cell depletion remains the same whether infection occurs through the mucosal route (rectal or vaginal) or intravenously. This was described in “Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection,” Science 280 (1998).
Numerous papers have described the destruction of T lymphocytes in the gut following HIV. One of the first is “Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy,” Journal of Virology 77 (2003).
The first report of the importance of CCR5 in HIV entry is “Identification of a major co-receptor for primary isolates of HIV-1,” Nature 381 (1996).
How the HIV envelope protein fuses with the human cell is described in detail in “The HIV Env-mediated fusion reaction,” Biomembranes 1614 (2003).
The number of CD4 T cells in the blood of an average person varies quite a bit, accounting for the range in values cited. This variation with average numbers controlled for sex and age is reported in “Laboratory control values for CD4 and CD8 T lymphocytes: implications for HIV-1 diagnosis,” Clinical Experimental Immunology 88 (1992).
HIV makes on average 10 billion copies of itself a day as reported in “HIV-1 dynamics in vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time,” Science 271 (1996).
HIV is able to inflict massive cell death by direct cell killing and other indirect mechanisms. This cell death is discussed in detail in Cell Death during HIV Infection, edited by Andrew D. Badley (CRC Press, 2006).
Stopping antiviral therapy leads to mutation of the virus and development of drug resistance as reported in “Basic science kinetics of HIV-1 RNA and resistance-associated mutations after cessation of antiretroviral combination therapy,” AIDS 15 (2001).
Chapter 10: The Delta 32 Mutation
The first paper detailing HIV resistance in individuals with a defect in their CCR5 gene was “Homozygous defect in HIV-1 co-receptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection,” Cell 86 (1996).
While most people with the Δ32 mutation lead healthy lives, a few studies have found that those without a working CCR5 gene are at higher risk for West Nile virus. These studies are controversial. We can’t be certain of all the potential consequences of CCR5 deficiency. Of interest, other studies have pointed to protection conferred by the Δ32 in other disease, such as cerebral malaria, from the mutation. Both sides can be found in “CCR5 deficiency increases risk of symptomatic West Nile virus infection,” Journal of Experimental Medicine 203 (2006); “CCR5 deficiency is a risk factor for early clinical manifestations of West Nile virus infection but not for viral transmission,” Journal of Infectious Diseases 201 (2010); “Role of chemokines polymorphisms in diseases,” Immunology Letters 145 (2012).
The vast majority of transmitted viruses use the CCR5 receptor to enter cells, as reported in David Ho’s paper “Genotypic and phenotypic characterization of HIV-1 patients with primary infection,” Science 261 (1993).
Viruses use CCR5 no matter how they were originally transmitted, by sex, intravenously, or passed from mother to child: “Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission,” Journal of Clinical Investigation 94 (1994).
The CCR5 Δ32 mutation is commonly found in Western European populations as reported in “Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene,” Nature 382 (1996); “The geographic spread of the CCR5 Delta32 HIV-resistance allele,” PLoS Biology 3 (2005).
The paper that Hütter read in his medical school library and the first paper to describe the Δ32 mutation and its link to HIV was “Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene,” Nature 382 (1996).
Chapter 11: Calling All Elite Controllers
A Song in the Night: A Memoir of Resilience by Bob Massie (Doubleday, 2012).
Details on Bruce Walker’s relationship with Bob Massie and the development of a cohort of elite controllers were obtained by personal interviews. Additional details and the quote “I must have audibly gasped” obtained from “Secrets of the HIV controllers,” Scientific American 307 (2012).
Gene therapy for cystic fibrosis was described in “Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis,” Current Opinion in Pulmonary Medicine 16 (2010).
Gene therapy for Parkinson’s disease was described in “Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial,” Lancet 369 (2007).
Gene therapy for Beta-thalassemia was described in “Beta-thalassemia treatment succeeds, with a caveat,” Science 326 (2009).
Gene therapy for inherited blindness was described in Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, Mingozzi F, Bennicelli JL, Ying GS, Rossi S, et al., “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial,” Lancet 374 (9701):1597-1605; 2009.
Details on Jesse Gelsinger’s death after receiving an experimental gene therapy in 1999 and its impact on research is discussed in “Gene therapy death prompts review of adenovirus vector,” Science 286 (1999).
Epidemiology and description of HIV controllers can be found in “Prevalence and comparative characteristics of long-term nonprogressors and HIV controller patients in the French Hospital Database on HIV,” AIDS 23 (2009).
The high expression of CCR5 in tissue lymphocytes is described in “Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes,” American Journal of Pathology 160 (2002).
The importance of the gut in acute HIV is discussed in “Immunopathogenesis of acute AIDS virus infection,” Current Opinion in Immunology 18 (2006).
An overview of HLA and HIV written by Walker is described in “HIV and HLA class I: an evolving relationship,” Immunity 37 (2012).
The HLA alleles B*27 and B*57 are found frequently in HIV controllers as described in “HLA alleles associated with delayed progression to AIDS contribute strongly to the initial CD8+ T-cell response against HIV-1,” PLoS Medicine 3 (2006).
The monkey version of elite HIV control, the Mamu-A*01 allele, was shown to protect primates from SIV in “Mamu-A*01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection,” Journal of Virology 76 (2002).
Specific amino acids in the groove of the HLA-B gene that confer HIV control was described in “The major genetic determinants of HIV-1 control affect HLA class I peptide presentation,” Science 330 (2010).
The association of HLA-B*57 and psoriasis was reported in “HLA-B57 is significantly associated with psoriasis in Northeast Romania,” Roumanian Archives of Microbiology and Immunology 61 (2002).
Chapter 12: Treatment in Hiding
Percent of medical school graduates entering family medicine residencies was reported in “Entry of US medical school graduates into family medicine residencies,” Family Medicine 44 (2012).
Development of hydroxyurea for clinical use was first published in “Hydroxyurea. A new type of potential antitumor agent,” Journal of Medicinal Chemistry 6 (1963).
Basic mechanism of action, and diseases hydroxyurea is FDA-approved for, can be found in the product insert for Hydrea, hydroxyurea capsules, USP, from Bristol-Myers Squibb.
Chapter 13: The Second Diagnosis
The 25 percent 5-year survival rate for adult patients in the US from 2006 to 2010 diagnosed with AML and 11 percent 5-year survival rate for those patients experiencing a relapse is reported by the National Cancer Institute in the SEER cancer statistics review, 1975–2010 (2012).
A review of AML, how it invades tissue and its clinical ramifications can be found in “Acute myeloid leukaemia in adults,” Lancet 381 (2013).
Discussion of the role immune suppression might play in AML can be found in “Commentary: does immune suppression increase risk of developing acute myeloid leukemia?” Leukemia 26 (2012).
More detail on hematopoietic stem cells can be found in Hematopoietic Stem Cell Biology, edited by Motonari Kondo (Humana Press, 2010).
Allogeneic stem cell transplantation is described in “Allogeneic hematopoietic cell transplantation for acute myeloid leukemia when a matched related donor is not available,” Hematology (2008).
CXCR4 isolates of HIV are expressed later in infection as described in “The HIV co-receptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes,” Proceedings of the National Academy of Sciences of the United States of America 94 (1997).
The pathogenic nature of the CXCR4 virus was described in “Phenotypic and genotypic comparisons of CCR5- and CXCR4-tropic human immunodeficiency virus type 1 biological clones isolated from subtype C-infected individuals,” Journal of Virology 78 (2004).
Murine fetuses that lack CXCR4 are lethal, as reported in “Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. The role of SDF-1/CXCR4 interactions,” Annals of the New York Academy of Sciences 938 (2001), whereas mice that lack CCR5 survive, as reported in “Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine,” Journal of Immunology 164 (2000).
A review of graft-versus-host disease can be found in “Concise review: acute graft-versus-host disease: immunobiology, prevention, and treatment,” Stem Cells Translational Medicine 2 (2013).
More information about the ZKRD and rates of stem cell transplants in Germany can be found at the website http://www.zkrd.de/en/index.php
Likelihood of bone marrow match success in the United States calculated from data and analysis by the national marrow donor program and can be obtained from the website http://marrow.org/Home.aspx.
Age of the Δ32 mutation and postulation that its high frequency in Western European populations is linked to the bubonic plague was first proposed in the paper “Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes,” American Journal of Human Genetics 62 (1998). This theory is controversial, and other studies attempting to replicate this selective pressure in CCR5-deficient mice have been conflicting. See “Evolutionary genetics: CCR5 mutation and plague protection,” Nature 427 (2004); “Evolutionary genetics: ambiguous role of CCR5 in Y. pestis infection,” Nature 430 (2004); “The evolutionary history of the CCR5-Delta32 HIV-resistance mutation,” Microbes and Infection 7 (2005); “The Black Death and AIDS: CCR5 Δ32 in genetics and history,” Quarterly Journal of Medicine 99 (2006).
Description of one of the oldest mutations in humans can be found in “Adaptive Evolution of the FADS Gene Cluster within Africa,” PLoS One 9 (2012).
Chapter 14: The Compassionate Use Exception
The compassionate use exception is described in congressional testimony from the U.S. Food and Drug Administration’s statement Availability of Investigational Drugs for Compassionate Use by Robert Temple (June 20, 2001).
The statistic, 44 percent of HIV-positive gay men in the United States don’t know they are infected, comes from a CDC survey: “Prevalence and awareness of HIV infection among men who have sex with men—21 cities, United States, 2008,” Morbidity and Mortality Weekly Report 59 (2010).
Chapter 15: Three Deadly Diseases Move In
A hilarious description of the difficulty of taking the antiviral drug DDI (didanosine) can be found in Queer and Loathing: Rants and Raves of a Raging AIDS Clone by David B. Feinberg (Penguin Books, 1995).
Bioavailability data for didanosine, brand-name Videx, can be found in Table 10 of the package insert from Bristol-Myers Squibb.
Chapter 16: The Comfort of Family and Strangers
Studies examining the benefits of supportive family on the health of lesbian, gay, and bisexual individuals include: “The health of people classified as lesbian, gay and bisexual attending family practitioners in London: a controlled study,” BMC Public Health 6 (2006); “Family rejection as a predictor of negative health outcomes in white and Latino lesbian, gay, and bisexual young adults,” Pediatrics 123 (2009); “Parents’ supportive reactions to sexual orientation disclosure associated with better health: results from a population-based survey of LGB adults in Massachusetts,” Journal of Homosexuality 59 (2012); “A qualitative exploration of sexual risk and HIV testing behaviors among men who have sex with men in Beirut, Lebanon,” PLoS ONE 7 (2012).
HIV and cachexia are further discussed in “HIV-related cachexia: potential mechanisms and treatment,” Oncology 49 (1992).
The links between mitochondria, antiretroviral therapy and lipoatrophy are reported in “Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection,” Antiviral Therapy 13 (2008).
Chapter 17: Timing
All quotes and background information from Dr. Julianna Lisziewicz obtained by personal interview.
A description of how mRNA is translated can be found in The Cell: A Molecular Approach, 2nd edition, by Geoffrey Cooper (Sinauer Associates, 2000).
The gene therapy approaches pioneered by Julianna Lisziewicz can be found in her paper “Gene therapy approaches to HIV infection,” American Journal of Pharmacogenomics 2 (2002).
More information on the research institute founded by Lisziewicz and Lori can be found at the RIGHT website: http://www.rightinstitute.net.
Chapter 18: Transplanting
A review of who should get stem cell transplants for AML, and why, can be found in “Who should be transplanted for AML?” Leukemia 15 (2001).
Data for the low survival rate after a second transplant for AML can be found in “Prognosis of patients with a second relapse of acute myeloid leukemia,” Leukemia 14 (2000). The 11 percent 5-year survival rate in adults with a relapse of AML is reported in “Prognostic index for adult patients with acute myeloid leukemia in first relapse,” American Society of Clinical Oncology 23 (2005).
How conditioning regimens dampen the immune system in AML transplants can be found in “Myeloablative conditioning regimens for AML allografts: 30 years later,” Bone Marrow Transplantation 32 (2003).
Chapter 19: “Perhaps We Have Eradicated HIV”
Details on how CD4:CD8 ratios are used by clinicians can be found in “CD4 percentage, CD4 number, and CD4:CD8 ratio in HIV infection: which to choose and how to use,” Journal of Acquired Immune Deficiency Syndromes 2 (1989).
Siliciano’s highly influential paper is “Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy,” Science 278 (1997).
Percentage of resting T cells in the blood and relationship to HIV is described in “Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells,” Nature 435 (2005).
Lymph nodes are a favorite target for HIV. This is described in “Lymph node pathology of acquired immunodeficiency syndrome (AIDS),” Annals of Clinical and Laboratory Science 20 (1990).
Cecil Fox’s paper that influenced his involvement in both Berlin patients is “HIV in infected lymph nodes,” Nature 370 (1994).
Destruction of lymph node architecture is discussed in “Human immunodeficiency virus pathogenesis: insights from studies of lymphoid cells and tissues,” Clinical Infectious Disease 33 (2001).
Walker’s influential papers discussed from 1996 include “Recognition of the highly conserved YMDD region in the human immunodeficiency virus type 1 reverse transcriptase by HLA-A2-restricted cytotoxic T lymphocytes from an asymptomatic long-term nonprogressor,” Journal of Infectious Diseases 173 (1996); “T cell receptor usage and fine specificity of human immunodeficiency virus 1-specific cytotoxic T lymphocyte clones: analysis of quasispecies recognition reveals a dominant response directed against a minor in vivo variant,” Journal of Experimental Medicine 183 (1996); “Strong cytotoxic T cell and weak neutralizing antibody responses in a subset of persons with stable nonprogressing HIV type 1 infection,” AIDS Research and Human Retroviruses 12 (1996); “Cytotoxic T lymphocytes in asymptomatic long-term nonprogressing HIV-1 infection. Breadth and specificity of the response and relation to in vivo viral quasispecies in a person with prolonged infection and low viral load,” Journal of Immunology 156 (1996); “Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes,” Journal of Virology 70 (1996).
The interaction of HIV and IFN-γ in the ELISPOT assay is described in “The role of IFN-[gamma] Elispot assay in HIV vaccine research,” Nature 4 (2009).
The debate over problems with the use of ELISPOT in HIV is described in “The role of IFN-g Elispot assay in HIV research,” Nature Protocols 4 (2009).
Chapter 20: An Unexciting Recovery
Percent GDP which fuels welfare in Germany compared to the United States was obtained from “What the European and American welfare states have in common and where they differ: facts and fiction in comparisons of the European Social Model and the United States,” Journal of European Social Policy 20 (2010).
The CROI talk in 2008 that released results from MOTIVATE on the drug maraviroc was “Efficacy and safety of maraviroc plus optimized background therapy in treatment-experienced patients infected with CCR5-tropic HIV-1: 48-week combined analysis of the MOTIVATE studies,” Abstract #792, 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA (2008).
Chapter 21: Trials
Walker’s early paper looking at immune responses in acute HIV is “Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia,” Science 278 (1997).
The ACTG 5025 trial was also known as “A study of the safety and effectiveness of hydroxyurea in patients on potent antiretroviral therapy and who have less than 200 copies/ml of HIV RNA in their blood.” Details on the investigators, drugs given, and number of patients recruited can be found, like all clinical trials in the United States, through clinicaltrials.gov.
The saga of ACTG 5025 is covered in “Pancreatitis Deaths Shut Down ACTG 5025,” HIV Plus Magazine (February/March 2000).
Differing perspective on hydroxyurea and clinical trials from Julianna Lisziewicz and Franco Lori can be found in this review written by them: “Hydroxyurea in the treatment of HIV infection: clinical efficacy and safety concerns,” Drug Safety 26 (2003).
The warning letter sent by the FDA to Bristol-Myers Squibb on the marketing of hydroxyurea and false claims of ACTG 5025 was sent on October 27, 1999, and can be found on the FDA website at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166219.pdf.
Jerome Horwitz’s paper on discovering d4T is “Nucleosides. X. The action of sodium ethoxide on 3'-0-tosyl-2'-deoxyadenosine,” Tetrahedron Letters 7 (13) (1966).
History of d4T and Yale University can be found in “Yale Pressed to Help Cut Drug Costs in Africa,” New York Times (March 12, 2001).
The incidence of neuropathy in patients on d4T is discussed in “Human immunodeficiency virus-neuropathy with special reference to distal sensory polyneuropathy and toxic neuropathies,” Annals of Tropical Medicine and Public Health 1 (2008).
Deborah Cotton was quoted as saying, “I’m not sure how good our advice was today,” in “F.D.A. Panel Recommends AIDS Drug Despite Incomplete Data,” New York Times (May 21, 1994).
Walker’s results using treatment interruptions at first seemed promising as reported in “Immune control of HIV-1 after early treatment of acute infection,” Nature 407 (2000).
Fauci was quoted as saying, “The strategy needs to be tested. The stop-and-go game can lead to drug resistance even if it looks so far like the wild type strain remains” in “Absence Makes the HAART Grow Fonder,” The Body (February 1999).
The SMART study that changed the prevailing view on treatment interruptions was “CD4+ count–guided interruption of antiretroviral treatment: the strategies for management of antiretroviral therapy (SMART) study group,” New England Journal of Medicine 355 (2006).
Results from Lori and Lisziewicz’s study of hydroxyurea were published in “Lowering the dose of hydroxyurea minimizes toxicity and maximizes anti-HIV potency,” AIDS Research and Human Retroviruses 21 (2005).
Chapter 22: Proof of Principle
Jeffrey Laurence was quoted as saying, “I thought it was the most exciting thing I’d heard about since the discovery of the virus. I couldn’t believe people didn’t take notice,” in “The Man Who Had HIV and Now Does Not,” New York Magazine (May 29, 2011).
The Boston Think Tank that Gero Hütter attended in 2008 was written up by researchers Rowena Johnston and Jeffrey Laurence in “amFAR Think Tanks: A Blueprint for Action Against HIV/AIDS,” amFAR, The Foundation for AIDS Research Newsletter (September 16, 2008).
John Zaia’s three-pronged attack to HIV is described in “Safety and efficacy of a lentiviral vector containing three anti-HIV genes—CCR5 ribozyme, tat-rev siRNA, and TAR decoy—in SCID-hu mouse-derived T cells,” Molecular Therapy 15 (2007).
Gene therapy in AIDS lymphoma patients at City of Hope by Zaia is described in “RNA-based therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma,” Science Translational Medicine 2 (2010).
Chapter 23: The Good Doctor in Court
Up until 1991, methadone could be administered in Germany only to drug users with highly specific criteria (which included AIDS). Numerous family doctors ignored these regulations, prescribing the drug to opiate addicts. Germany prosecuted the doctors, taking away many licenses. The narcotics act in 1992, called Betäubungsmittelgesetz, legalized methadone. However, a special license is still required to distribute it. A longer discussion of the history of methadone in Germany can be found in “Substitution treatment for opiod addicts in Germany,” Harm Reduction Journal 4 (2007).
Chapter 24: Not Even Surprising
The abstract book and meeting report for the Fourth International Workshop on HIV Persistence during Therapy, which includes details on Robert Gallo’s opening talk and Gero Hütter’s presentation, are available from the global antiviral journal at: http://www.ihlpress.com/gaj_persistence2009.html.
Information from Anthony Fauci concerning his opinions on the Berlin patients was obtained from a personal interview.
Fauci was quoted as saying, “It’s very nice, and it’s not even surprising, but it’s just off the table of practicality,” in “Rare Treatment Is Reported to Cure AIDS Patient,” New York Times (November 13, 2008).
The average lifetime cost of antiviral drugs is reported as $709,731 for undiscounted therapy and $425,440 with discounts in “Newer drugs and earlier treatment: impact on lifetime cost of care for HIV-infected adults,” AIDS 26 (2012).
The 2011 Milliman Medical Index estimated the cost of an allogeneic bone marrow transplant like Timothy received to be $805,400 USD: http://publications.milliman.com/research/health-rr/pdfs/2011-us-organ-tissue.pdf.
Cost of Atripla is discussed in “Generic HIV drugs will widen US treatment net,” Nature (August 15, 2012).
Neurophysiology of HIV and aging is reported in “Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity,” Neurology (2013); “Where does HIV hide? A focus on the central nervous system,” Current opinion in HIV and AIDS (2013).
The pervasiveness of neurological conditions in HIV is reported in “HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities,” Journal of Neuroimmune Pharmacology 5 (2010).
Life expectancy for HIV-positive individuals in developed countries has leaped in recent years. These gains have been reported in “Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies,” Lancet 372 (2008); “Potential gains in life expectancy from reducing heart disease, cancer, Alzheimer’s disease, kidney disease or HIV/AIDS as major causes of death in the USA,” Public Health (2013).
Rise of life expectancy for those beginning early antiretroviral therapy was reported in “Projected life expectancy of people with HIV according to timing of diagnosis,” AIDS 26 (2012).
Chapter 25: The Promise Kept
Fire with Fire is a short film directed by Ross Kauffman © Red Light Films (2013). It can be found online at http://focusforwardfilms.com/films/72/fire-with-fire.
More information on the CART-19 trial at Children’s Hospital of Philadelphia can be found at their websites: http://www.chop.edu/service/oncology/pediatric-cancer-research/t-cell-therapy.html; http://www.chop.edu/system/galleries/download/pdfs/articles/oncology/summit-grupp-cart19.pdf.
More information on Emma Whitehead’s story can be found on her website, where her mother, Kari Whitehead, has chronicled their experiences: http://emilywhitehead.com, and in “In Girl’s Last Hope, Altered Immune Cells Beat Leukemia,” New York Times (December 9, 2012).
All background information on Carl June obtained from a personal interview.
Information on bone marrow transplants and the Cold War obtained from “Atomic Medicine: the Cold War Origins of Biological Research,” History Today 59 (2009).
All background information on Bruce Levine obtained from a personal interview.
Written by June and Levine, this article discusses their approaches to CCR5 gene therapy: “Blocking HIV’s attack,” Scientific American 306 (2012).
The paper in which Levine and June looked at dendritic cells was published in 1996: “Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients as a result of CD28 co-stimulation,” Science 272 (1996).
Background information on Edward Lanphier was obtained from a personal interview.
Percent homology between HIV and SIV is reported in “Comparison of SIV and HIV-1 genomic RNA structures reveals impacct of sequence evolution on conserved and non-conserved structural motifs,” PLoS Pathogens 9 (2012).
Further reading on the development and application of ZFNs can be found in “Zinc finger nucleases: custom-designed molecular scissors for genome engineering of plant and mammalian cells,” Nucleic Acids Research 33 (2005).
Further reading on SIV and HIV can be found in “Where the wild things are: pathogenesis of SIV infection in African nonhuman primate hosts,” HIV/AIDS Reports 7 (2010), and “Natural SIV hosts: showing AIDS the door,” Science 335 (2012).
Evidence that SIV has evolved over 32,000 years was published in “Island biogeography reveals the deep history of SIV,” Science 329 (2010).
Comparison of pathogenic and nonpathogenic monkey models of SIV can be found in “AIDS pathogenesis: a tale of two monkeys,” Journal of Medical Primatology 37 (2008).
Genetic similarities between “Black 6” mice and humans is reported in “Of Mice and Men: Striking Similarities at the DNA Level Could Aid Research,” San Francisco Chronicle (December 5, 2002).
Comparison of mouse and human gene expression was published in “Genomic responses in mouse models poorly mimic human inflammatory diseases,” Proceedings of the National Academy of Sciences of the United States of America 110 (2013).
A review of humanized mice in HIV infection can be found in “Humanized mouse models of HIV infection,“ AIDS Reviews 13 (3):135-148 (2011).
Some researchers don’t believe that humanized mice represent a viable model for HIV therapies. This perspective is presented in “The mouse is out of the bag: insights and perspectives on HIV-1-infected humanized mouse models,” Experimental Biology and Medicine 236 (2011).
Carl June’s test of CCR5 ZFNs in humanized mice challenged with HIV was published in “Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases,” Nature Biotechnology 26 (2008).
Results from Carl June’s CCR5 ZFN clinical trial in HIV-positive volunteers was presented at “HAART treatment interruption following adoptive transfer of zinc finger nuclease (ZFN) modified autologous CD4+ T-cells (SB-728-T) to HIV-infected subjects demonstrates durable engraftment and suppression of viral load,” Abstract #165, 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA (2011); “Induction of acquired CCR5 deficiency with zinc finger nuclease-modified autologous CD4 T cells (SB-728-T) correlates with increases in CD4 count and effects on viral load in HIV-infected subjects,” Abstract #155, 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA (2012).
The 2011 Milliman Medical Index estimates the cost of an autologous transplant as performed by Carl June’s team using CCR5 ZFNs to be $363,800. Therefore, the cost of an autologous transplant is approximately $300,000 less than that of lifetime antiviral therapy. http://publications.milliman.com/research/health-rr/pdfs/2011-us-organ-tissue.pdf.
Chapter 26: A Child Cured—So What?
Report of an HIV cure in a toddler was made in “Functional HIV cure after very early ART of an infected infant,” Abstract #48LB, 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, GA (2013).
Details on Eric and John Wagner’s quote reported in “Revolutionary treatment begins,” University of Minnestota News (April 24, 2013).
Timothy Brown’s phone call to Eric Blue was reported in “Babies could be key to HIV cure,” Washington Blade (Aplril 26, 2013).
Background information on David Margolis was obtained by personal interview.
History of HDACi in cancer as well as the approval of vorinostat as the first HDACi by the FDA are discussed in “Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy,” Clinical Epigenetics 1 (Dec 2010).
Investigation of the HDACi, valproic acid, by David Margolis can be found in “Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression,” AIDS 18 (May 21, 2004); “Depletion of latent HIV-1 infection in vivo: a proof-of-concept study,” Lancet 366 (Aug 13, 2005).
David Margolis’s data on vorinostat can be found in “Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid,” AIDS Research and Human Retroviruses 25 (Feb 2009).
A nice review on HDACi from David Margolis can be found in “Histone deacetylase inhibitors and HIV latency,” Current Opinion in HIV and AIDS 6 (2011).
David Margolis’s presentation to an overflowing crowd: “Administration of vorinostat disrupts HIV-1 latency in patients on ART,” Abstract #157LB, 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA (2012).
Sharon Lewin shared her data and perspective on vorinostat in “HIV latency and eradication: clinical perspectives,” Abstract #106, 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA (2012).
David Margolis was quoted as saying, “This proves for the first time that there are ways to specifically treat viral latency, the first step towards curing HIV infection,” in a press release, “Drug helps purge hidden HIV virus, UNC study shows” from the University of North Carolina School of Medicine (March 8, 2012).
Chapter 27: Zinc Finger Snap
The paper from my dissertation research that Paula Cannon and I wrote is “Zinc finger nuclease-mediated CCR5 knockout hematopoietic stem cell transplantation controls HIV-1 in vivo,” Nature Biotechnology 28 (Aug 2010).
Background information on Paula Cannon obtained from personal interviews.
CIRM funding for the “dream team” is reported online by CIRM at http://www.cirm.ca.gov/our-funding/awards/ziinc-finger-nuclease-based-stem-cell-therapy-aids.
Paula Cannon’s quote “The fact that it worked, it was like the ‘Duh!’ moment. It was the most unremarkable thing. I wasn’t quite prepared for how exciting people thought the results were” is from “Locking Out HIV,” CIRM Annual Report (2011).
Background information on Timothy Henrich and Dan Kuritzkes obtained from personal interviews.
Tim Henrich first presented results from the Boston patients in “Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation in two HIV-positive individuals,” Abstract THAA0101, Ninteenth International AIDS Conference, Washington, DC (2012).
The Boston patients received wide coverage in the press, including “Two More Nearing AIDS ‘Cure’ after Bone Marrow Transplants, Doctors Say,” National Public Radio, Shots health blog (July 26, 2012).
Results from the VISCONTI cohort are published in “Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI study,” PLoS Pathogens (Mar 24, 2013).
Background information on David Baltimore was obtained from a personal interview.
David Baltimore and Irvin Chen’s first paper on siRNA is “Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5,” Proceedings of the National Academy of Sciences of the USA 100 (Jan 7, 2003).
“amFAR’s interest in exploring the role of gene therapy in the eradication of HIV infection stems from a February 2009 report in the New England Journal of Medicine of a patient in Berlin” is from “Manipulating the Smallest Building Blocks of Life to Defeat the World’s Biggest Infectious Disease Killer,” amFAR, The Foundation for AIDS Research press release (February 18, 2010).
Irvin Chen and David Baltimore’s $20 million grant from CIRM, “HPSC based therapy for HIV disease using RNAi to CCR5,” was reported in “Researchers knock down gene to stop HIV in its tracks,” Nature Medicine 16 (2010).
Chapter 28: The Abused, the Respected, the Relentless
Steve Yukl’s talk on Timothy’s remnant virus was “Increased risk of virologic rebound in patients on antiviral therapy with isolated detectable viral loads <48 copies/ml by Taqman PCR RT-PCR Assay,” International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies, Sitges, Spain (2012).
“If you do enough cycles of PCR, you can get a signal in water for pink elephants” was quoted in “Evidence That Man Cured of HIV Harbors Viral Remnants Triggers Confusion,” Science Insider (June 11, 2012).
The press release by Alain Lafeuillade is “The So Called HIV Cured ‘Berlin’ Patient Still Has Detectable HIV in His Body,” PRWeb UK (June 11, 2012).
“Despite the possibility of intermittently detectable, very low levels of HIV, the Berlin patient has remained off of ART for 5 years, has no detectable viremia using standard assays, has waning HIV antibody levels, has limited to undetectable HIV-specific T cell responses, and has no evidence of HIV-related immunologic progression. The patient certainly meets any clinical definition for having achieved a long-term remission, and may even have had a sterilizing cure. Even the most extraordinary ‘elite’ controllers described in the literature have more robust evidence for persistent infection.” This is quoted from “Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient,” PLoS Pathogens (May 9, 2013). This paper also contains the virus data analyzed by two labs from Timothy’s samples taken five years after he stopped therapy.