A recent Opinion article by Dr. Goodson (1) expresses pseudoscientific views typical of HIV/AIDS denialism (2–13) and ignores the overwhelming evidence that HIV is a causative agent of AIDS, the evidence accumulated during more than 30 years of research.
Fulfilling the Koch’s Postulate 1: HIV is Invariably Epidemiologically Associated with AIDS
Dr. Goodson ignores the fact that Koch’s postulates for viruses have been completely fulfilled in the case of HIV (9, 14, 15).
The overwhelming evidence suggests an invariable epidemiological association of HIV with AIDS. AIDS occurs exclusively in HIV-infected people (16). HIV can be detected in all AIDS patients (17). High levels of HIV in the organism predict progression to AIDS (18–23). Many children born to HIV-infected mothers have developed AIDS and died (24). AIDS-related conditions, such as Pneumocystis pneumonia and disseminated Mycobacterium avium complex disease, have become much more common after the start of the HIV epidemic (25). Death rates are much higher in HIV-seropositive treatment-naïve than in seronegative individuals (26–34).
An HIV-triggered decrease in CD4+ T-lymphocyte count is a specific feature of HIV infection, and is extraordinarily rare in the absence of HIV (16, 35–37). The HIV-caused CD4+ T-lymphocyte depletion occurs through at least two mechanisms. (1) Direct killing of infected CD4+ T-lymphocytes. Dr. Goodson seems unfamiliar with the fact that HIV-1, HIV-2, and other representatives of the genus Lentivirus (e.g., Simian immunodeficiency virus), as well as some other retroviruses (e.g., Feline leukemia virus and members of the Avian leukosis virus group), exert a cytopathic effect in infected cells (38). (2) HIV directly kills Th17 CD4+ T-lymphocytes in the intestinal submucosa, triggering the damage of the mucosal integrity, translocation of microbial products from the intestine to the blood and chronic immune activation, resulting in further massive loss of CD4+ T-lymphocytes (39, 40).
Dr. Goodson claims that recreational drug use, clotting factor VIII, or receptive anal intercourse, but not HIV, are causes of AIDS. However, all of these claims have long ago been rejected by overwhelming scientific evidence (16, 35–37, 41–45).
Fulfilling the Koch’s Postulate 2: HIV has been Isolated from Patients at all Stages of the Infection
Contrary to Dr. Goodson’s claims, HIV has been isolated from patients at all stages of HIV infection, including AIDS, and propagated in cell culture (17, 46–54). Various protocols for HIV-1 isolation (without “contaminants” claimed by Dr. Goodson) have been developed, and each of these protocols can be considered “standard” (55–62). Detailed images of HIV-1 virions, revealing morphology typical of the genus Lentivirus, have been obtained using transmission electron microscopy (46–48, 53, 63) and electron cryotomography (64, 65). A combination of immunofluorescent and electron microscopy has allowed visualization of intracellular trafficking of individual HIV-1 particles toward the nucleus of the infected cell (66). The process of cell-to-cell transfer of HIV-1 between T-lymphocytes has been visualized using high-speed three-dimensional video microscopy (67).
Fulfilling the Koch’s Postulate 3: Accidental HIV Transmission in Humans
Dr. Goodson ignores several tragic cases of accidental HIV transmission to laboratory workers who worked with purified HIV-1, became infected after a needle-stick or mucosal exposure and developed AIDS-like symptoms. HIV has been isolated from their blood, and DNA sequencing confirmed that the HIV variant isolated was identical to the one they were working with (15, 68–70). Other well-documented cases include HIV transmission from a dentist in the USA to several patients (15, 71), and HIV transmission through blood transfusion to 11 children in the USA (72) and 75 children in the former Soviet Union (73).
In addition, the Koch’s postulates for HIV and another lentivirus, Simian immunodeficiency virus, have been fulfilled in experiments with animal models (15, 74).
HIV Laboratory Testing
Three types of assays are used for HIV detection: (1) ELISA – specificity 98.5–99.9% (75–77), (2) Western blot (77), and (3) PCR – specificity 98.3–100% (78–80). The probability that both ELISA and Western blot would give false-positive results is extremely low (<1/140,000) (77). Thus, contrary to Dr. Goodson’s claims, these tests are highly specific for HIV-1. Since the diagnosis is based on the combination of the three tests (77), HIV testing will produce similar conclusions irrespective of the country.
Dr. Goodson misrepresents the study by Rodriguez et al. (81), which has never stated that PCR “is not sufficiently accurate” (1).
Antiretroviral Therapy
Contrary to Dr. Goodson’s claims, antiretroviral therapy (ART) has profoundly improved the prognosis for HIV-1-infected patients, suppressing their viral load, restoring CD4+ T-lymphocyte count, and reducing the risk of developing AIDS or dying (Figure 1A) (82–104). The success of ART has been determined by its high specificity for HIV-1-encoded proteins (105, 106). Along with therapeutic agents for many other diseases, ART does have side effects, but these are far outweighed by its benefits (106). New anti-HIV agents should help to mitigate side effects, overcome drug resistance, and ultimately cure HIV infection, e.g., through excising HIV proviral DNA from the chromosome (107–109).
Dr. Goodson misrepresents the study by the ART Cohort Collaboration, which showed that ART is extremely beneficial for HIV-infected patients, but better clinical outcomes are observed when CD4+ T-lymphocyte counts at the start of ART are higher than 200 cells/μl (110). These conclusions have been corroborated by many other studies (111–117) and serve as a background to recommend starting ART early, when the HIV-triggered damage of the immune system is easier to restore (106).
Detrimental Impact of HIV/AIDS Denialism on Public Health
P. Duesberg, D. Rasnick, and some other HIV/AIDS denialists served on a controversial advisory panel of the South African president Thabo Mbeki. The policy of the South African government over HIV/AIDS during the period 2000–2005 is considered by a majority of scientists to have resulted in the death of at least 330,000 HIV-infected people (Figure 1B) (9, 12, 118). The Opinion article by Dr. Goodson (1) [as well as earlier published or publicly expressed opinions of P. Duesberg, K. Mullis, and other denialists, none of whom has ever worked with HIV/AIDS (2–5, 7–12)] is similarly harmful for public health, as it disseminates dangerous misinformation about HIV/AIDS that can affect prevention decisions made by uninfected people and treatment decisions made by HIV-infected people. Therefore, the following recommendations should be given to public health workers: (1) to learn and disseminate up-to-date knowledge on HIV/AIDS based on the most recent scientific literature, and (2) to be aware of HIV/AIDS denialism and be able to effectively counteract its detrimental impact on public health.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
I would like to thank Dr. Nicoli Nattrass for providing an electronic file for Figure 1B, Raymond W. Wong for providing PDF files, and Andrew Reddin for critical reading of the manuscript.
References
- 1.Goodson P. Questioning the HIV-AIDS hypothesis: 30 years of dissent. Front Public Health (2014) 2:154. 10.3389/fpubh.2014.00154 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 2.Gallo RC. “A single disease with a single cause”, “About causes of disease (and, in particular, why HIV is the cause of AIDS)”. In: Gallo RC, editor. Virus Hunting. AIDS, Cancer and the Human Retroviruses: A Story of Scientific Discovery. New York: BasicBooks; (1991). p. 127–62, 276–97. [Google Scholar]
- 3.Cohen J. The Duesberg phenomenon. Science (1994) 266:1642–4. 10.1126/science.7992043 [DOI] [PubMed] [Google Scholar]
- 4.Abdool Karim Q, Abdool Karim SS, Abimiku A, Abiola N, Adjorlolo-Johnson G, Adler M, et al. The Durban Declaration. Nature (2000) 406:15–6. 10.1038/35017662 [DOI] [PubMed] [Google Scholar]
- 5.Smith TC, Novella SP. HIV denial in the Internet era. PLoS Med (2007) 4(8):e256. 10.1371/journal.pmed.0040256 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Specter M. Denialism: How Irrational Thinking Hinders Scientific Progress, Harms the Planet, and Threatens Our Lives. New York, NY: The Penguin Press; (2009). 294 p. [Google Scholar]
- 7.Kalichman SC. Denying AIDS: Conspiracy Theories, Pseudoscience, and Human Tragedy. New York, NY: Copernicus/Springer; (2009). 205 p. [Google Scholar]
- 8.Kalichman SC. Commentary on “Questioning the HIV-AIDS hypothesis: 30 years of dissent”. Front Public Health (2015) 3:30. 10.3389/fpubh.2015.00030 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Chigwedere P, Essex M. AIDS denialism and public health practice. AIDS Behav (2010) 14:237–47. 10.1007/s10461-009-9654-7 [DOI] [PubMed] [Google Scholar]
- 10.Goertzel T. Conspiracy theories in science. EMBO Rep (2010) 11:493–9. 10.1038/embor.2010.84 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Nattrass N. Defending the boundaries of science: AIDS denialism, peer review and the Medical Hypotheses saga. Sociol Health Illn (2011) 33:507–21. 10.1111/j.1467-9566.2010.01312.x [DOI] [PubMed] [Google Scholar]
- 12.Nattrass N. The AIDS Conspiracy: Science Fights Back. New York, NY: Columbia University Press; (2012). 225 p. [Google Scholar]
- 13.Oliver JE, Wood T. Medical conspiracy theories and health behaviors in the United States. JAMA Intern Med (2014) 174:817–8. 10.1001/jamainternmed.2014.190 [DOI] [PubMed] [Google Scholar]
- 14.Harden VA. Koch’s postulates and the etiology of AIDS: an historical perspective. Hist Philos Life Sci (1992) 14:249–69. [PubMed] [Google Scholar]
- 15.O’Brien SJ, Goedert JJ. HIV causes AIDS: Koch’s postulates fulfilled. Curr Opin Immunol (1996) 8:613–8. 10.1016/S0952-7915(96)80075-6 [DOI] [PubMed] [Google Scholar]
- 16.Schechter MT, Craib KJ, Gelmon KA, Montaner JS, Le TN, O’Shaughnessy MV. HIV-1 and the aetiology of AIDS. Lancet (1993) 341:658–9. 10.1016/0140-6736(93)90421-C [DOI] [PubMed] [Google Scholar]
- 17.Jackson JB, Kwok SY, Sninsky JJ, Hopsicker JS, Sannerud KJ, Rhame FS, et al. Human immunodeficiency virus type 1 detected in all seropositive symptomatic and asymptomatic individuals. J Clin Microbiol (1990) 28:16–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med (1995) 332:201–8. 10.1056/NEJM199501263320401 [DOI] [PubMed] [Google Scholar]
- 19.Pantaleo G, Menzo S, Vaccarezza M, Graziosi C, Cohen OJ, Demarest JF, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med (1995) 332:209–16. 10.1056/NEJM199501263320402 [DOI] [PubMed] [Google Scholar]
- 20.Mellors JW, Muñoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med (1997) 126:946–54. 10.7326/0003-4819-126-12-199706150-00003 [DOI] [PubMed] [Google Scholar]
- 21.Barker E, Mackewicz CE, Reyes-Terán G, Sato A, Stranford SA, Fujimura SH, et al. Virological and immunological features of long-term human immunodeficiency virus-infected individuals who have remained asymptomatic compared with those who have progressed to acquired immunodeficiency syndrome. Blood (1998) 92:3105–14. [PubMed] [Google Scholar]
- 22.Palumbo PE, Raskino C, Fiscus S, Pahwa S, Fowler MG, Spector SA, et al. Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in HIV-infected infants and children. JAMA (1998) 279:756–61. 10.1001/jama.279.10.756 [DOI] [PubMed] [Google Scholar]
- 23.Taha TE, Kumwenda NI, Hoover DR, Biggar RJ, Broadhead RL, Cassol S, et al. Association of HIV-1 load and CD4 lymphocyte count with mortality among untreated African children over one year of age. AIDS (2000) 14:453–9. 10.1097/00002030-200003100-00021 [DOI] [PubMed] [Google Scholar]
- 24.Ades AE, Newell ML, Peckham CS, Giaquinto C, Zacchello F, De Rossi A, et al. Children born to women with HIV-1 infection: natural history and risk of transmission. European Collaborative Study. Lancet (1991) 337:253–60. 10.1016/0140-6736(91)90866-N [DOI] [PubMed] [Google Scholar]
- 25.Sax PE, Cohen CJ, Kuritzkes DR, Cunha BA, Kubiak DW. Prophylaxis and treatment of opportunistic infections. In: Sax PE, Cohen CJ, Kuritzkes DR, editors. HIV Essentials. 7th ed Burlington, MA: Jones & Bartlett Learning; (2014). p. 72–133. [Google Scholar]
- 26.Thea DM, St Louis ME, Atido U, Kanjinga K, Kembo B, Matondo M, et al. A prospective study of diarrhea and HIV-1 infection among 429 Zairian infants. N Engl J Med (1993) 329:1696–702. 10.1056/NEJM199312023292304 [DOI] [PubMed] [Google Scholar]
- 27.Ackah AN, Coulibaly D, Digbeu H, Diallo K, Vetter KM, Coulibaly IM, et al. Response to treatment, mortality, and CD4 lymphocyte counts in HIV-infected persons with tuberculosis in Abidjan, Côte d’Ivoire. Lancet (1995) 345:607–10. 10.1016/S0140-6736(95)90519-7 [DOI] [PubMed] [Google Scholar]
- 28.Borgdorff MW, Barongo LR, Klokke AH, Newell JN, Senkoro KP, Velema JP, et al. HIV-1 incidence and HIV-1 associated mortality in a cohort of urban factory workers in Tanzania. Genitourin Med (1995) 71:212–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Darby SC, Ewart DW, Giangrande PL, Dolin PJ, Spooner RJ, Rizza CR. Mortality before and after HIV infection in the complete UK population of haemophiliacs. UK Haemophilia Centre Directors’ Organisation. Nature (1995) 377:79–82. 10.1038/377079a0 [DOI] [PubMed] [Google Scholar]
- 30.Leroy V, Msellati P, Lepage P, Batungwanayo J, Hitimana DG, Taelman H, et al. Four years of natural history of HIV-1 infection in African women: a prospective cohort study in Kigali (Rwanda), 1988-1993. J Acquir Immune Defic Syndr Hum Retrovirol (1995) 9:415–21. 10.1097/00042560-199508000-00013 [DOI] [PubMed] [Google Scholar]
- 31.Nunn AJ, Mulder DW, Kamali A, Ruberantwari A, Kengeya-Kayondo JF, Whitworth J. Mortality associated with HIV-1 infection over five years in a rural Ugandan population: cohort study. BMJ (1997) 315:767–71. 10.1136/bmj.315.7111.767 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Spira R, Lepage P, Msellati P, Van De Perre P, Leroy V, Simonon A, et al. Natural history of human immunodeficiency virus type 1 infection in children: a five-year prospective study in Rwanda. Mother-to-Child HIV-1 Transmission Study Group. Pediatrics (1999) 104(5):e56. 10.1542/peds.104.5.e56 [DOI] [PubMed] [Google Scholar]
- 33.Taha TE, Kumwenda NI, Broadhead RL, Hoover DR, Graham SM, Van Der Hoven L, et al. Mortality after the first year of life among human immunodeficiency virus type 1-infected and uninfected children. Pediatr Infect Dis J (1999) 18:689–94. 10.1097/00006454-199908000-00007 [DOI] [PubMed] [Google Scholar]
- 34.Madhi SA, Petersen K, Madhi A, Khoosal M, Klugman KP. Increased disease burden and antibiotic resistance of bacteria causing severe community-acquired lower respiratory tract infections in human immunodeficiency virus type 1-infected children. Clin Infect Dis (2000) 31:170–6. 10.1086/313925 [DOI] [PubMed] [Google Scholar]
- 35.Donegan E, Stuart M, Niland JC, Sacks HS, Azen SP, Dietrich SL, et al. Infection with human immunodeficiency virus type 1 (HIV-1) among recipients of antibody-positive blood donations. Ann Intern Med (1990) 113:733–9. 10.7326/0003-4819-113-10-733 [DOI] [PubMed] [Google Scholar]
- 36.Des Jarlais DC, Friedman SR, Marmor M, Mildvan D, Yancovitz S, Sotheran JL, et al. CD4 lymphocytopenia among injecting drug users in New York City. J Acquir Immune Defic Syndr (1993) 6:820–2. [PubMed] [Google Scholar]
- 37.Vermund SH, Hoover DR, Chen K. CD4+ counts in seronegative homosexual men. The Multicenter AIDS Cohort Study. N Engl J Med (1993) 328:442. 10.1056/NEJM199302113280615 [DOI] [PubMed] [Google Scholar]
- 38.Goff SP. Retroviridae: the retroviruses and their replication. In: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, et al., editors. Fields’ Virology. 5th ed Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; (2007). p. 1999–2069. [Google Scholar]
- 39.Lackner AA, Lederman MM, Rodriguez B. HIV pathogenesis: the host. Cold Spring Harb Perspect Med (2012) 2(9):a007005. 10.1101/cshperspect.a007005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature (2014) 505:509–14. 10.1038/nature12940 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Aledort LM, Operskalski EA, Dietrich SL, Koerper MA, Gjerset GF, Lusher JM, et al. Low CD4+ counts in a study of transfusion safety. The Transfusion Safety Study Group. N Engl J Med (1993) 328:441–2. 10.1056/NEJM199302113280614 [DOI] [PubMed] [Google Scholar]
- 42.Hassett J, Gjerset GF, Mosley JW, Fletcher MA, Donegan E, Parker JW, et al. Effect on lymphocyte subsets of clotting factor therapy in human immunodeficiency virus-1-negative congenital clotting disorders. The Transfusion Safety Study Group. Blood (1993) 82:1351–7. [PubMed] [Google Scholar]
- 43.Goedert JJ. Mortality and haemophilia. Lancet (1995) 346:1425–6. 10.1016/S0140-6736(95)92440-X [DOI] [PubMed] [Google Scholar]
- 44.Sabin CA, Pasi KJ, Phillips AN, Lilley P, Bofill M, Lee CA. Comparison of immunodeficiency and AIDS defining conditions in HIV negative and HIV positive men with haemophilia A. BMJ (1996) 312:207–10. 10.1136/bmj.312.7025.207 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Chao C, Jacobson LP, Tashkin D, Martínez-Maza O, Roth MD, Margolick JB, et al. Recreational drug use and T lymphocyte subpopulations in HIV-uninfected and HIV-infected men. Drug Alcohol Depend (2008) 94:165–71. 10.1016/j.drugalcdep.2007.11.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science (1983) 220:868–71. 10.1126/science.6189183 [DOI] [PubMed] [Google Scholar]
- 47.Gallo RC, Salahuddin SZ, Popovic M, Shearer GM, Kaplan M, Haynes BF, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science (1984) 224:500–3. 10.1126/science.6200936 [DOI] [PubMed] [Google Scholar]
- 48.Levy JA, Hoffman AD, Kramer SM, Landis JA, Shimabukuro JM, Oshiro LS. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science (1984) 225:840–2. 10.1126/science.6206563 [DOI] [PubMed] [Google Scholar]
- 49.Albert J, Gaines H, Sönnerborg A, Nyström G, Pehrson PO, Chiodi F, et al. Isolation of human immunodeficiency virus (HIV) from plasma during primary HIV infection. J Med Virol (1987) 23:67–73. 10.1002/jmv.1890230108 [DOI] [PubMed] [Google Scholar]
- 50.Chiodi F, Albert J, Olausson E, Norkrans G, Hagberg L, Sönnerborg A, et al. Isolation frequency of human immunodeficiency virus from cerebrospinal fluid and blood of patients with varying severity of HIV infection. AIDS Res Hum Retroviruses (1988) 4:351–8. 10.1089/aid.1988.4.351 [DOI] [PubMed] [Google Scholar]
- 51.Jackson JB, Coombs RW, Sannerud K, Rhame FS, Balfour HH, Jr. Rapid and sensitive viral culture method for human immunodeficiency virus type 1. J Clin Microbiol (1988) 26:1416–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Evans LA, Moreau J, Odehouri K, Seto D, Thomson-Honnebier G, Legg H, et al. Simultaneous isolation of HIV-1 and HIV-2 from an AIDS patient. Lancet (1988) 2:1389–91. 10.1016/S0140-6736(88)90586-7 [DOI] [PubMed] [Google Scholar]
- 53.Eilbott DJ, Peress N, Burger H, LaNeve D, Orenstein J, Gendelman HE, et al. Human immunodeficiency virus type 1 in spinal cords of acquired immunodeficiency syndrome patients with myelopathy: expression and replication in macrophages. Proc Natl Acad Sci U S A (1989) 86:3337–41. 10.1073/pnas.86.9.3337 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Brown BK, Darden JM, Tovanabutra S, Oblander T, Frost J, Sanders-Buell E, et al. Biologic and genetic characterization of a panel of 60 human immunodeficiency virus type 1 isolates, representing clades A, B, C, D, CRF01_AE, and CRF02_AG, for the development and assessment of candidate vaccines. J Virol (2005) 79:6089–101. 10.1128/JVI.79.10.6089-6101.2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Gorantla S, Che M, Gendelman HE. Isolation, propagation, and HIV-1 infection of monocyte-derived macrophages and recovery of virus from brain and cerebrospinal fluid. Methods Mol Biol (2005) 304:35–48. 10.1385/1-59259-907-9:035 [DOI] [PubMed] [Google Scholar]
- 56.Gorry PR, Sonza S, Kedzierska K, Crowe SM. Isolation of human immunodeficiency virus type 1 from peripheral blood monocytes. Methods Mol Biol (2005) 304:25–33. 10.1385/1-59259-907-9:025 [DOI] [PubMed] [Google Scholar]
- 57.Kiessling AA. Isolation of human immunodeficiency virus type 1 from semen and vaginal fluids. Methods Mol Biol (2005) 304:71–86. 10.1385/1-59259-907-9:071 [DOI] [PubMed] [Google Scholar]
- 58.Schuitemaker H, Kootstra NA. Isolation, propagation, and titration of human immunodeficiency virus type 1 from peripheral blood of infected individuals. Methods Mol Biol (2005) 304:17–24. 10.1385/1-59259-907-9:017 [DOI] [PubMed] [Google Scholar]
- 59.Tamalet C. Isolation and quantification of HIV from lymph nodes. Methods Mol Biol (2005) 304:87–94. 10.1385/1-59259-907-9:087 [DOI] [PubMed] [Google Scholar]
- 60.Ott DE. Purification of HIV-1 virions by subtilisin digestion or CD45 immunoaffinity depletion for biochemical studies. Methods Mol Biol (2009) 485:15–25. 10.1007/978-1-59745-170-3_2 [DOI] [PubMed] [Google Scholar]
- 61.Karetnikov A, Suomalainen M. Tethered virions are intermediates in the assembly and release of HIV-1 particles. Virology (2010) 407:289–95. 10.1016/j.virol.2010.08.020 [DOI] [PubMed] [Google Scholar]
- 62.Dispinseri S, Saba E, Vicenzi E, Kootstra NA, Schuitemaker H, Scarlatti G. HIV-1 isolation from infected peripheral blood mononuclear cells. Methods Mol Biol (2014) 1087:187–96. 10.1007/978-1-62703-670-2_15 [DOI] [PubMed] [Google Scholar]
- 63.Achilli G, Barbarini G, Cattaneo E, Cecchini A, Concia E, De Rocco L, et al. AIDS nosography. In: Rondanelli EG, editor. AIDS: Clinical and Laboratory Atlas. Pavia: Edizione Medico-Scientifiche; (1989). p. 10–40. [Google Scholar]
- 64.Schur FK, Hagen WJ, Rumlová M, Ruml T, Müller B, Kräusslich HG, et al. Structure of the immature HIV-1 capsid in intact virus particles at 8.8 Å resolution. Nature (2015) 517:505–8. 10.1038/nature13838 [DOI] [PubMed] [Google Scholar]
- 65.Woodward CL, Cheng SN, Jensen GJ. Electron cryotomography studies of maturing HIV-1 particles reveal the assembly pathway of the viral core. J Virol (2015) 89:1267–77. 10.1128/JVI.02997-14 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.McDonald D, Vodicka MA, Lucero G, Svitkina TM, Borisy GG, Emerman M, et al. Visualization of the intracellular behavior of HIV in living cells. J Cell Biol (2002) 159:441–52. 10.1083/jcb.200203150 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Hübner W, McNerney GP, Chen P, Dale BM, Gordon RE, Chuang FY, et al. Quantitative 3D video microscopy of HIV transfer across T cell virological synapses. Science (2009) 323:1743–7. 10.1126/science.1167525 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Marcus R, Kay K, Mann JM. Transmission of human immunodeficiency virus (HIV) in health-care settings worldwide. Bull World Health Organ (1989) 67:577–82. [PMC free article] [PubMed] [Google Scholar]
- 69.Sipsas NV, Kalams SA, Trocha A, He S, Blattner WA, Walker BD, et al. Identification of type-specific cytotoxic T lymphocyte responses to homologous viral proteins in laboratory workers accidentally infected with HIV-1. J Clin Invest (1997) 99:752–62. 10.1172/JCI119221 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Seabra Santos NJ, Carvalho Monteiro AL, Catapano Ruiz EA. The first case of AIDS due to occupational exposure in Brazil. Braz J Infect Dis (2002) 6:140–1. 10.1590/S1413-86702002000300007 [DOI] [PubMed] [Google Scholar]
- 71.Ciesielski CA, Marianos DW, Schochetman G, Witte JJ, Jaffe HW. The 1990 Florida dental investigation. The press and the science. Ann Intern Med (1994) 121:886–8. 10.7326/0003-4819-121-11-199412010-00011 [DOI] [PubMed] [Google Scholar]
- 72.van den Berg H, Gerritsen EJ, van Tol MJ, Dooren LJ, Vossen JM. Ten years after acquiring an HIV-1 infection: a study in a cohort of eleven neonates infected by aliquots from a single plasma donation. Acta Paediatr (1994) 83:173–8. 10.1111/j.1651-2227.1994.tb13045.x [DOI] [PubMed] [Google Scholar]
- 73.Mintz M, Boland M, O’Hara MJ, Barros J, Hansen C, Denny TN, et al. Pediatric HIV infection in Elista, Russia: interventional strategies. Am J Public Health (1995) 85:586–8. [PubMed] [Google Scholar]
- 74.Sliva K. Latest animal models for anti-HIV drug discovery. Expert Opin Drug Discov (2015) 10:111–23. 10.1517/17460441.2015.975201 [DOI] [PubMed] [Google Scholar]
- 75.Weber B, Gürtler L, Thorstensson R, Michl U, Mühlbacher A, Bürgisser P, et al. Multicenter evaluation of a new automated fourth-generation human immunodeficiency virus screening assay with a sensitive antigen detection module and high specificity. J Clin Microbiol (2002) 40:1938–46. 10.1128/JCM.40.6.1938-1946.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Sickinger E, Stieler M, Kaufman B, Kapprell HP, West D, Sandridge A, et al. Multicenter evaluation of a new, automated enzyme-linked immunoassay for detection of human immunodeficiency virus-specific antibodies and antigen. J Clin Microbiol (2004) 42:21–9. 10.1128/JCM.42.1.21-29.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Sax PE, Cohen CJ, Kuritzkes DR, Cunha BA, Kubiak DW. Diagnosis and evaluation of HIV infection. In: Sax PE, Cohen CJ, Kuritzkes DR, editors. HIV Essentials. 7th ed Burlington, MA: Jones & Bartlett Learning; (2014). p. 6–18. [Google Scholar]
- 78.Salminen MO, Koch C, Sanders-Buell E, Ehrenberg PK, Michael NL, Carr JK, et al. Recovery of virtually full-length HIV-1 provirus of diverse subtypes from primary virus cultures using the polymerase chain reaction. Virology (1995) 213:80–6. 10.1006/viro.1995.1548 [DOI] [PubMed] [Google Scholar]
- 79.Young NL, Shaffer N, Chaowanachan T, Chotpitayasunondh T, Vanparapar N, Mock PA, et al. Early diagnosis of HIV-1-infected infants in Thailand using RNA and DNA PCR assays sensitive to non-B subtypes. J Acquir Immune Defic Syndr (2000) 24:401–7. 10.1097/00126334-200008150-00001 [DOI] [PubMed] [Google Scholar]
- 80.Beck IA, Drennan KD, Melvin AJ, Mohan KM, Herz AM, Alarcón J, et al. Simple, sensitive, and specific detection of human immunodeficiency virus type 1 subtype B DNA in dried blood samples for diagnosis in infants in the field. J Clin Microbiol (2001) 39:29–33. 10.1128/JCM.39.1.29-33.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Rodríguez B, Sethi AK, Cheruvu VK, Mackay W, Bosch RJ, Kitahata M, et al. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA (2006) 296:1498–506. 10.1001/jama.296.12.1498 [DOI] [PubMed] [Google Scholar]
- 82.Collier AC, Coombs RW, Schoenfeld DA, Bassett RL, Timpone J, Baruch A, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med (1996) 334:1011–7. 10.1056/NEJM199604183341602 [DOI] [PubMed] [Google Scholar]
- 83.Katzenstein DA, Hammer SM, Hughes MD, Gundacker H, Jackson JB, Fiscus S, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. N Engl J Med (1996) 335:1091–8. 10.1056/NEJM199610103351502 [DOI] [PubMed] [Google Scholar]
- 84.O’Brien WA, Hartigan PM, Martin D, Esinhart J, Hill A, Benoit S, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS. N Engl J Med (1996) 334:426–31. 10.1056/NEJM199602153340703 [DOI] [PubMed] [Google Scholar]
- 85.Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al. 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. AIDS Clinical Trials Group 320 Study Team. N Engl J Med (1997) 337:725–33. 10.1056/NEJM199709113371101 [DOI] [PubMed] [Google Scholar]
- 86.Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet (1998) 351:543–9. 10.1016/S0140-6736(97)04161-5 [DOI] [PubMed] [Google Scholar]
- 87.Detels R, Muñoz A, McFarlane G, Kingsley LA, Margolick JB, Giorgi J, et al. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. JAMA (1998) 280:1497–503. 10.1001/jama.280.17.1497 [DOI] [PubMed] [Google Scholar]
- 88.Marschner IC, Collier AC, Coombs RW, D’Aquila RT, DeGruttola V, Fischl MA, et al. Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis (1998) 177:40–7. 10.1086/513823 [DOI] [PubMed] [Google Scholar]
- 89.Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet (1998) 352:1725–30. 10.1016/S0140-6736(98)03201-2 [DOI] [PubMed] [Google Scholar]
- 90.Montaner JS, DeMasi R, Hill AM. The effects of lamivudine treatment on HIV-1 disease progression are highly correlated with plasma HIV-1 RNA and CD4 cell count. AIDS (1998) 12:F23–8. 10.1097/00002030-199805000-00003 [DOI] [PubMed] [Google Scholar]
- 91.Palella FJ, Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med (1998) 338:853–60. 10.1056/NEJM199803263381301 [DOI] [PubMed] [Google Scholar]
- 92.Hogg RS, Yip B, Kully C, Craib KJ, O’Shaughnessy MV, Schechter MT, et al. Improved survival among HIV-infected patients after initiation of triple-drug antiretroviral regimens. CMAJ (1999) 160:659–65. [PMC free article] [PubMed] [Google Scholar]
- 93.Ledergerber B, Egger M, Opravil M, Telenti A, Hirschel B, Battegay M, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet (1999) 353:863–8. 10.1016/S0140-6736(99)01122-8 [DOI] [PubMed] [Google Scholar]
- 94.McNaghten AD, Hanson DL, Jones JL, Dworkin MS, Ward JW. Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. Adult/Adolescent Spectrum of Disease Group. AIDS (1999) 13:1687–95. 10.1097/00002030-199909100-00012 [DOI] [PubMed] [Google Scholar]
- 95.Vittinghoff E, Scheer S, O’Malley P, Colfax G, Holmberg SD, Buchbinder SP. Combination antiretroviral therapy and recent declines in AIDS incidence and mortality. J Infect Dis (1999) 179:717–20. 10.1086/314623 [DOI] [PubMed] [Google Scholar]
- 96.Porter K. Survival after introduction of HAART in people with known duration of HIV-1 infection. The CASCADE Collaboration. Concerted Action on SeroConversion to AIDS and Death in Europe. Lancet (2000) 355:1158–9. 10.1016/S0140-6736(00)02069-9 [DOI] [PubMed] [Google Scholar]
- 97.de Martino M, Tovo PA, Balducci M, Galli L, Gabiano C, Rezza G, et al. Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection. Italian Register for HIV Infection in Children and the Italian National AIDS Registry. JAMA (2000) 284:190–7. 10.1001/jama.284.2.190 [DOI] [PubMed] [Google Scholar]
- 98.Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis (2000) 30(Suppl 1):S5–14. 10.1086/313843 [DOI] [PubMed] [Google Scholar]
- 99.Mocroft A, Katlama C, Johnson AM, Pradier C, Antunes F, Mulcahy F, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet (2000) 356:291–6. 10.1016/S0140-6736(00)02504-6 [DOI] [PubMed] [Google Scholar]
- 100.Schwarcz SK, Hsu LC, Vittinghoff E, Katz MH. Impact of protease inhibitors and other antiretroviral treatments on acquired immunodeficiency syndrome survival in San Francisco, California, 1987-1996. Am J Epidemiol (2000) 152:178–85. 10.1093/aje/152.2.178 [DOI] [PubMed] [Google Scholar]
- 101.Schneider MF, Gange SJ, Williams CM, Anastos K, Greenblatt RM, Kingsley L, et al. Patterns of the hazard of death after AIDS through the evolution of antiretroviral therapy: 1984-2004. AIDS (2005) 19:2009–18. 10.1097/01.aids.0000189864.90053.22 [DOI] [PubMed] [Google Scholar]
- 102.Holkmann Olsen C, Mocroft A, Kirk O, Vella S, Blaxhult A, Clumeck N, et al. Interruption of combination antiretroviral therapy and risk of clinical disease progression to AIDS or death. HIV Med (2007) 8:96–104. 10.1111/j.1468-1293.2007.00436.x [DOI] [PubMed] [Google Scholar]
- 103.Torian L, Chen M, Hall HI. Centers for Disease Control and Prevention (CDC). HIV surveillance – United States, 1981-2008. MMWR Morb Mortal Wkly Rep (2011) 60:689–93. [PubMed] [Google Scholar]
- 104.Lima VD, Lourenço L, Yip B, Hogg RS, Phillips P, Montaner JS. Trends in AIDS incidence and AIDS-related mortality in British Columbia between 1981 and 2013. Lancet HIV (2015) 2(3):e92–7. 10.1016/S2352-3018(15)00017-X [DOI] [PMC free article] [PubMed] [Google Scholar]
- 105.Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med (2012) 2(4):a007161. 10.1101/cshperspect.a007161 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.Sax PE, Cohen CJ, Kuritzkes DR, Cunha BA, Kubiak DW. Treatment of HIV infection. In: Sax PE, Cohen CJ, Kuritzkes DR, editors. HIV Essentials. 7th ed Burlington, MA: Jones & Bartlett Learning; (2014). p. 19–54. [Google Scholar]
- 107.Hoxie JA, June CH. Novel cell and gene therapies for HIV. Cold Spring Harb Perspect Med (2012) 2(10):a007179. 10.1101/cshperspect.a007179 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Hu W, Kaminski R, Yang F, Zhang Y, Cosentino L, Li F, et al. RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. Proc Natl Acad Sci U S A (2014) 111:11461–6. 10.1073/pnas.1405186111 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Le Grice SF. Targeting the HIV RNA genome: high-hanging fruit only needs a longer ladder. Curr Top Microbiol Immunol (2015) 389:147–69. 10.1007/82_2015_434 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.May MT, Sterne JA, Costagliola D, Sabin CA, Phillips AN, Justice AC, et al. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet (2006) 368:451–8. 10.1016/S0140-6736(06)69152-6 [DOI] [PubMed] [Google Scholar]
- 111.Egger M, May M, Chêne G, Phillips AN, Ledergerber B, Dabis F, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet (2002) 360:119–29. 10.1016/S0140-6736(02)09411-4 [DOI] [PubMed] [Google Scholar]
- 112.Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet (2008) 372:293–9. 10.1016/S0140-6736(08)61113-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Antiretroviral Therapy Cohort Collaboration. Zwahlen M, Harris R, May M, Hogg R, Costagliola D, et al. Mortality of HIV-infected patients starting potent antiretroviral therapy: comparison with the general population in nine industrialized countries. Int J Epidemiol (2009) 38:1624–33. 10.1093/ije/dyp306 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.HIV-CAUSAL Collaboration. Ray M, Logan R, Sterne JA, Hernández-Díaz S, Robins JM, et al. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS (2010) 24:123–37. 10.1097/QAD.0b013e3283324283 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115.Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. Young J, Psichogiou M, Meyer L, Ayayi S, Grabar S, et al. CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE. PLoS Med (2012) 9(3):e1001194. 10.1371/journal.pmed.1001194 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.May MT, Ingle SM, Costagliola D, Justice AC, de Wolf F, Cavassini M, et al. Cohort profile: antiretroviral therapy cohort collaboration (ART-CC). Int J Epidemiol (2014) 43:691–702. 10.1093/ije/dyt010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Zhu H, Napravnik S, Eron JJ, Cole SR, Ma Y, Wohl DA, et al. Decreasing excess mortality of HIV-infected patients initiating antiretroviral therapy: comparison with mortality in general population in China, 2003-2009. J Acquir Immune Defic Syndr (2013) 63(5):e150–7. 10.1097/QAI.0b013e3182948d82 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118.Chigwedere P, Seage GR, III, Gruskin S, Lee TH, Essex M. Estimating the lost benefits of antiretroviral drug use in South Africa. J Acquir Immune Defic Syndr (2008) 49:410–5. 10.1097/QAI.0b013e31818a6cd5 [DOI] [PubMed] [Google Scholar]