Springer Seminars in Immunopathology

, Volume 18, Issue 3, pp 267–283 | Cite as

The role of viral dynamics in the pathogenesis of HIV disease and implications for antiviral therapy

  • Diane V. Havlir
  • Douglas D. Richman
Article

Keywords

Internal Medicine Antiviral Therapy Viral Dynamic 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Armstrong JA, Home R (1984) Follicular dendritic cells and virus-like particles in AIDS-related lymphadenopathy. Lancet 11:370Google Scholar
  2. 2.
    Bagasra O, Hauptman SP, Lischner HW, Sachs M, Pomerantz RJ (1992) Detection of human immunodeficiency virus type 1 provirus in mononuclear cells by in situ polymerase chain reaction. N Engl J Med 326:1385Google Scholar
  3. 3.
    Baroni CD, Pezzella F, Mirolo M, Ruco LP, Rossi GB (1986) Immunohistochemical demonstration of p24 HTLV III major core protein in different cell types within lymph nodes from patients with lymphadenopathy syndrome (LAS). Histopathology 10:5Google Scholar
  4. 4.
    Biberfeld P, Chayt KJ, Marselle LM, Biberfeld G, Gallo RC, Harper ME (1986) HTLV-III expression in infected lymph nodes and relevance to pathogenesis of lymphadenopathy. Am J Pathol 125:436Google Scholar
  5. 5.
    Cao Y, Qin L, Zhang L, Safrit J, Ho DD (1995) Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 332:201Google Scholar
  6. 6.
    Carpenter CCJ, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner J, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA, for the International AIDS Society — USA (1996) Antiretroviral therapy for HIV infection in 1996. JAMA 275:(in press)Google Scholar
  7. 7.
    Cheeseman SH, Havlir DV, McLaughlin M, Greenough TC, Sullivan JL, Hall D, Hattox SE, Spector SA, Stein DS, Myers M, Richman DD (1995) Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol 8:141Google Scholar
  8. 8.
    Clark SJ, Saag MS, Decker WD, Campbell-Hill S, Roberson JL, Veldkamp PJ, Kappes JC, Hahn BH, Shaw GM (1991) High titers of cytopathic virus in plasma of patients with symptomatic primary HIVGoogle Scholar
  9. 9.
    Coffin JM (1995) HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267:483Google Scholar
  10. 10.
    Cohen OJ, Pantaleo G, Holodniy M, Schnittman S, Niu M, Graziosi C, Pavlakis GN, Lalezari J, Bartlett JA, Steigbigel RT (1995) Decreased human immunodeficiency virus type 1 plasma viremia during antiretroviral therapy reflects downregulation of viral replication in lymphoid tissue. Proc Natl Acad Sci USA 92:6017Google Scholar
  11. 11.
    Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M (1995) In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 374:569Google Scholar
  12. 12.
    Coombs RW, Collier AC, Allain JP, Nikora B, Leuther M, Gjerset GF, Corey L (1989) Plasma viremia in human immunodeficiency virus infection. N Engl J Med 321:1626Google Scholar
  13. 13.
    Coombs RW, Welles SL, Hooper C, et al (1996) Association of plasma human immunodeficiency virus type-1 RNA level with risk of clinical progression in patients with advanced infection. J Infect Dis: in pressGoogle Scholar
  14. 14.
    Cooper DA, Gatell JM, Kroon S, Clumeck N, Millard J, Goebel FD, Bruun JN, Stingl G, Melville RL, Gonzalez-Lahoz J, Stevens JW, Fiddian AP (1993) Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 cubic millimeter. N Engl J Med 329:297Google Scholar
  15. 15.
    Daar ES, Moudgil T, Meyer RD, Ho DD (1991) Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med 324:961Google Scholar
  16. 16.
    D'Aquila RT, Johnson VA, Welles SL, Japour AJ, Kuritzkes DR, DeGruttola V, Reichelderfer PS, Coombs RW, Crumpacker CS, Kahn JO (1995) Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. AIDS Clinical Trials Group Protocol 11613/117 Team and the Virology Committee Resistance Working Group. Ann Intern Med 122:401Google Scholar
  17. 17.
    Delwart EL, Sheppard HW, Walker BD, Goudsmit J, Mullins JI (1994) Human immunodeficiency virus type 1 evolution in vivo tracked by DNA heteroduplex mobility assays. J Virol 68:6672Google Scholar
  18. 18.
    Demarest IF, Daucher M, Vaccarezza M, Graziosi C, Cohen OJ, Tambussi G, Corey L, Pantaleo G, Fauci AS (1996) Qualitative differences in the primary immune response to HIV infection may be predictive of subsequent clinical outcome. Abstracts of the 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, Jan 29–Feb 1. IDSA Alexandria, VA, abstr. no. 420Google Scholar
  19. 19.
    Dewar RL, Highbarger HC, Sarmiento MD, Todd JA, Vasudevachari MB, Davey RTJ, Kovacs JA, Salzman NP, Lane HC, Urdea MS (1994) Application of branched DNA signal amplification to monitor human immunodeficiency virus type 1 burden in human plasma. J Infect Dis 170:1172Google Scholar
  20. 20.
    Di Stefano M, Norkrans G, Chiodi F, Hagberg L, Nielsen C, Svennerholm B (1993) Zidovudineresistant variants of HIV-1 in brain [letter]. Lancet 342:865Google Scholar
  21. 21.
    Embretson J, Zupancic M, Ribas JL, Burke A, Racz P, Tenner-Tacz K, Haase AT (1993) Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period AIDS. Nature 362:359Google Scholar
  22. 22.
    Eron JJ, Benoit SL, Jemsek J, MacArthur RD, Santana J, Quinn JB, Kuritzkes DR, Fallon MA, Rubin M (1995) Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cell per cubic millimeter. North American Working Party. N Engl J Med 333:1662Google Scholar
  23. 23.
    Gulick R, Mellors J, Havlir D, Eton J, Gonzalez C, McMahon D, Richman D, Valentine F, Jonas L, Meibohm A, Chiou R, Deutsch P, Emini E, Chodakewitz J (1996) Potent and sustained antiretroviral activity of indinavir (IDV) in combination with zidovudine (ZDV) and lamivudine (3TC). Abstracts of the 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, Jan 29–Feb 1. IDSA Alexandria, VA, LB7Google Scholar
  24. 24.
    Hammer S, Katzenstein D, Hughes M, Gundacker H, Hirsch M, Merigan T (1995) Nucleoside monotherapy versus combination therapy in HIV-infected adults: a randomized, double-blind, placebo-controlled trial in persons with CD4 cell counts 200–500/mm3. Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., Sept 17–20. ASM Washington, DC, no. LB-1Google Scholar
  25. 25.
    Havlir DV, Richman DD (1996) Viral dynamics of HIV: implications for drug development and therapeutic strategies. Ann Intern Med 124:984Google Scholar
  26. 26.
    Havlir D, Eastman S, Richman DD (1995) HIV-1 kinetics: rates of production and clearance of viral populations in asymptomatic patients treated with nevirapine. Abstracts of the 2nd National Conference on Human Retroviruses and Related Infections, Washington, DC, Jan 29–Feb 2. ASM Washington, DC, abstr. no. 229Google Scholar
  27. 27.
    Henrard DR, Daar E, Farzadegan H, Clark SJ, Phillips J, Shaw GM, Busch MP (1995) Virologic and immunologic characterization of symptomatic and asymptomatic primary HIV-1 infection. J Acquir Immune Defic Syndr Hum Retrovirol 9:305Google Scholar
  28. 28.
    Henrard DR, Phillips JF, Muenz LR, Blattner WA, Wiesner D, Eyster ME, Goedert JJ (1995) Natural history of HIV-1 cell-free viremia. JAMA 274:554Google Scholar
  29. 29.
    Ho DD (1992) HIV-1 viraemia and influenza [letter]. Lancet 339:1549Google Scholar
  30. 30.
    Ho DD, Moudgil T, Alam M (1989) Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Engl J Med 321:1621Google Scholar
  31. 31.
    Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123Google Scholar
  32. 32.
    Hollander H, Levy JA (1987) Neurologic abnormalities and recovery of human immunodeficiency virus from cerebrospinal fluid. Ann Intern Med 106:692Google Scholar
  33. 33.
    Jurriaans S, Van Gemen B, Weverling GJ, Van Strijp D, Nara P, Coutinho R, Koot M, Schuitemaker H, Goudsmit J (1994) The natural history of HIV-1 infection: virus load and virus phenotype independent determinants of clinical course? Virology 204:223Google Scholar
  34. 34.
    Katzenstein D, Hammer S, Hughes M, Gundacker H, Jackson B, Merigan T, Hirsch M, for the ACTG 175 Virology Team (1995) Plasma virion RNA in response to early antiretroviral drug therapy in ACTG 175. Do changes in virus load parallel clinical and immunologic outcomes? Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., Sept 17–20. ASM Washington, DC, abstr. no. LB-2Google Scholar
  35. 35.
    Kinloch-De Loes S, Hirschel BJ, Hoen B, Cooper DA, Tindall B, Carr A, Saurat JH, Clumeck N, Lazzarin A, Mathiesen L (1995) A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med 333:408Google Scholar
  36. 36.
    Kirchhoff F, Greenough TC, Brettler DB, Sullivan JL, Desrosiers RC (1995) Brief report: absence of intactnef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med 332:228Google Scholar
  37. 37.
    Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, Farthing C, Ho DD (1994) Temporal association of cellular immune responses with the initial control of viremia in primary human immdnodeficiency virus type 1 syndrome. J Virol 68:4650Google Scholar
  38. 38.
    Larder BA, Kemp SD (1989) Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 246:1155Google Scholar
  39. 39.
    Larder BA, Darby G, Richman DD (1989) HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243:1731Google Scholar
  40. 40.
    Larder BA, Kemp SD, Harrigan PR (1995) Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 269:696Google Scholar
  41. 41.
    Le Toumeau A, Audouin J, Diebold J, Marche C, Tricottet V, Reynes M (1986) LAV-like viral particles in lymph node germinal centers in patients with the persistent lymphadenopathy syndrome and the acquired immunodeficiency syndrome-related complex: an ultrastructural study of 30 cases. Hum Pathol 17:1047Google Scholar
  42. 42.
    Markowitz M, Sang M, Powderly WG, Hurley AM, Hsu A, Valdes JM, Henry D, Sattler F, La Marca A, Leonard JM (1995) A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 333:1534Google Scholar
  43. 43.
    Mellors JW, Kingsley LA, Rinaldo CRJ, Todd JA, Hoo BS, Kokka RP, Gupta P (1995) Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med 122:573Google Scholar
  44. 44.
    Mellors JW, Rinaldo Jr. CR, Gupta P, White RM, Todd JA, Kingsley LA (1996) Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272:1167Google Scholar
  45. 45.
    Moutouh L, Corbeil J, Richman DD (1996) Recombination leads to the rapid emergence of HIV-1 dually resistant mutants under selective drug pressure. Proc Natl Acad Sci USA 93:6106Google Scholar
  46. 46.
    Mulder J, McKinney N, Christopherson C, Sninsky J, Greenfield L, Kwok S (1994) Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection. J Clin Microbiol 32:292Google Scholar
  47. 47.
    Munoz A, Kirby AJ, He YD, Margolick JB, Visscher BR, Rinaldo CR, Kaslow RA, Phair JP (1995) Long-term survivors with HIV-1 infection: incubation period and longitudinal patterns of CD4+ lymphocytes. J Acquit Immune Defic Syndr Hum Retrovirol 8:496Google Scholar
  48. 48.
    Najera I, Richman DD, Olivares I, Rojas JM, Peinado MA, Perucho M, Najera R, Lopez-Galindez C (1994) Natural occurrence of drug-resistant mutations in the reverse transcriptase of human immunodeficiency virus type 1 isolates. AIDS Res Hum Retroviruses 10:1479Google Scholar
  49. 49.
    Najera I, Holguin A, Quinones-Mateu ME, Munoz-Fernandez MA, Najera R, Lopez-Galindez C, Domingo E (1995)pol gene quasispecies of human immunodeficiency virus: mutations associated with drug resistance in virus from patients undergoing no drug therapy. J Virol 69:23Google Scholar
  50. 50.
    O'Brien WA, Hartigan PM, Martin D, Esinhart J, Hill A, Benoit S, Rubin M, Simberkoff MS, Hamilton JD (1996) 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 334:426Google Scholar
  51. 51.
    Pantaleo GI, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci AS (1993) HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362:355Google Scholar
  52. 52.
    Pantaleo G, Menzo S, Vaccarezza M, Graziosi C, Cohen OJ, Demarest JF, Montefiori D, Orenstein JM, Fox C, Schrager LK (1995) Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 332:209Google Scholar
  53. 53.
    Patterson BK, Till M, Otto P, Goolsby C, Furtado MR, McBride LJ, Wolinsky SM (1993) Detection of HIV-1 DNA and messenger RNA in individual cells by PCR-driven in situ hybridization and flow cytometry. Science 260:976Google Scholar
  54. 54.
    Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD (1996) HIV-1 dynamics in vivo: virion clearance rate, infected cell lifetime, and viral generation time. Science 271:1582Google Scholar
  55. 55.
    Perrin L, Rakik A, Yerly S, Baumberger C, Loes SK, Pechere M, Hirschel B (1996) Combined therapy with zidovudine and L-697,661 in primary HIV infection. AIDS:(in press)Google Scholar
  56. 56.
    Phillips AN (1996) Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271:497Google Scholar
  57. 57.
    Richman DD (1995) Drug resistance in relation to pathogenesis. AIDS [Suppl A]:S49Google Scholar
  58. 58.
    Richman DD (1996) The implications of drug resistance for strategies of combination antiviral chemotherapy. Antiviral Res 29:31Google Scholar
  59. 59.
    Richman DD, Bozzette SA (1994) The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis 169:968Google Scholar
  60. 60.
    Richman DD, Grimes JM, Lagakos SW (1990) Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol 3:743Google Scholar
  61. 61.
    Richman D, Shih CK, Lowy I, Rose J, Prodanovich P, Goff S, Griffin J (1991) Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci USA 88:11241Google Scholar
  62. 62.
    Richman DD, Havlir D, Corbeil J, Looney D, Ignacio C, Spector SA, Sullivan J, Cheeseman S, Barringer K, Pauletti D, Shih CK, Myers M, Griffin J (1994) Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 68:1660Google Scholar
  63. 63.
    Saag MS, Crain MJ, Decker WD, Campbell-Hill S, Robinson S, Brown WE, Leuther M, Whitley RJ, Hahn BH, Shaw GM (1991) High-level viremia in adults and children infected with human immunodeficiency virus: relation to disease stage and CD4+ lymphocyte levels. J Infect Dis 164:72Google Scholar
  64. 64.
    Saag MS, Holodniy M, Kuritzkes DR, O'Brien WA, Coombs R, Poscher ME, Jacobsen DM, Shaw GM, Richman DD, Volberding PA (1996) HIV viral load markers in clinical practice. Nature Med 2:625Google Scholar
  65. 65.
    Schacker TW, Hughes J, Shea T, Corey L (1996) Virologic course of primary HIV infection. Abstracts of the 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, Jan 29–Feb 1. IDSA Alexandria, VA, abstr. no. 480Google Scholar
  66. 66.
    Schuurman R, Nijhuis M, van Leeuwen R, Schipper P, de Jong D, Collis P, Danner SA, Mulder J, Loveday C, Christopherson C (1995) Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC). J Infect Dis 171:1411Google Scholar
  67. 67.
    Sei S, Kleiner DE, Kopp JB, Chandra R, Klotman PE, Yarchoan R, Pizzo PA, Mitsuya H (1994) Quantitative analysis of viral burden in tissues from adults and children with symptomatic human immunodeficiency virus type 1 infection assessed by polymerase chain reaction. J Infect Dis 170:325Google Scholar
  68. 68.
    Sonnerborg AB, Ehmst AC, Bergdahl SK, Pehrson PO, Skoldenberg BR, Strannegard OO (1988) HIV isolation from cerebrospinal fluid in relation to immunological deficiency and neurological symptoms. AIDS 2:89Google Scholar
  69. 69.
    Stanley SK, Ostrowski MA, Justement JS, Gantt K, Hedayati S, Mannix M, Roche K, Schwartzentruber DJ, Fox CH, Fauci AS (1996) Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1. N Engl J Med 334:1222Google Scholar
  70. 70.
    Tenner-Racz K, Racz P, Dietrich M, Kern P (1985) Altered follicular dendritic cells and virus-like particles in AIDS and AIDS-related lymphadenopathy [letter]. Lancet 1:105Google Scholar
  71. 71.
    Tenner-Racz K, Racz P, Bofill M, Schulz-Meyer A, Dietrich M, Kern P, Weber J, Pinching AJ, Veronese-Dimarzo F, Popovic M (1986) HTLV-III/LAV viral antigens in lymph nodes of homosexual men with persistent generalized lymphadenopathy and AIDS. Am J Pathol 123:9Google Scholar
  72. 72.
    Tisdale M, Kemp SD, Parry NR, Larder BA (1993) Rapid in vitro selection of human immunodeficiency virus type I resistant to 3′-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci USA 90:5653Google Scholar
  73. 73.
    Van Gemen B, Van Beuningen R, Nabbe A, Van Strijp D, Jurriaans S, Lens P, Kievits T (1994) A one-tube quantitative HIV-1 RNA NASBA nucleic acid amplification assay using electrochemi luminescent (ECL) labelled probes. J Virol Methods 49:157Google Scholar
  74. 74.
    Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, Saag MS, Shaw GM (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373:117Google Scholar
  75. 75.
    Welles SL, Jackson JB, Yen-Lieberman B (1996) Prognostic value of plasma HIV-1 RNA levels in patients with advanced HIV-1 disease and with little or no zidovudine therapy. J Infect Dis:(in press)Google Scholar
  76. 76.
    Wildemann B, Haas J, Ehrhart K, Wagner H, Lynen N, Storch-Hagenlocher B (1993) In vivo comparison of zidovudine resistance mutations in blood and CSF of HIV-1 infected patients. Neurology 43:2659Google Scholar
  77. 77.
    Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MB (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 83:7089Google Scholar
  78. 78.
    Winters MA, Tan LB, Katzenstein DA, Merigan TC (1993) Biological variation and quality control of plasma human immunodeficiency virus type 1 RNA quantitation by reverse transcriptase polymerase chain reaction. J Clin Microbiol 31:2960Google Scholar
  79. 79.
    Wolinsky SM, Wike CM, Korber BT, Hutto C, Parks WP, Rosenblum LL, Kunstman KJ, Furtado MR, Munoz JL (1992) Selective transmission of human immunodeficiency virus type-1 variants from mothers to infants [see comments]. Science 255:1134Google Scholar
  80. 80.
    Wolinsky SM, Korber BT, Neumann AU, Daniels M, Kunstman KJ, Whetsell AJ, Furtado MR, Cao Y, Ho DD, Safrit JT, Koup RA (1996) Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection. Science 272:537Google Scholar
  81. 81.
    Wong JK, Fitch NJS, Torriani F, Havlir DV, Richman DD (1994) Discordance of RT sequences conferring ZDV resistance in proviral DNA form brain and spleen. Abstracts of the 3rd International Workshop on HIV Drug Resistance, Kauai, Hawaii, Aug 2–5. abstr. no. 46Google Scholar
  82. 82.
    Zhu T, Mo H, Wang N, Nam DS, Cao Y, Koup RA, Ho DD (1993) Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 261:1179Google Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • Diane V. Havlir
    • 1
  • Douglas D. Richman
    • 1
  1. 1.Departments of Medicine and Pathology and the San Diego Veterans Affairs Medical CenterUniversity of California, San DiegoSan Diego

Personalised recommendations