Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jun 20;92(13):6017–6021. doi: 10.1073/pnas.92.13.6017

Decreased human immunodeficiency virus type 1 plasma viremia during antiretroviral therapy reflects downregulation of viral replication in lymphoid tissue.

O J Cohen 1, G Pantaleo 1, M Holodniy 1, S Schnittman 1, M Niu 1, C Graziosi 1, G N Pavlakis 1, J Lalezari 1, J A Bartlett 1, R T Steigbigel 1, et al.
PMCID: PMC41633  PMID: 7597072

Abstract

Although several immunologic and virologic markers measured in peripheral blood are useful for predicting accelerated progression of human immunodeficiency virus (HIV) disease, their validity for evaluating the response to antiretroviral therapy and their ability to accurately reflect changes in lymphoid organs remain unclear. In the present study, changes in certain virologic markers have been analyzed in peripheral blood and lymphoid tissue during antiretroviral therapy. Sixteen HIV-infected individuals who were receiving antiretroviral therapy with zidovudine for > or = 6 months were randomly assigned either to continue on zidovudine alone or to add didanosine for 8 weeks. Lymph node biopsies were performed at baseline and after 8 weeks. Viral burden (i.e., HIV DNA copies per 10(6) mononuclear cells) and virus replication in mononuclear cells isolated from peripheral blood and lymph node and plasma viremia were determined by semiquantitative polymerase chain reaction assays. Virologic and immunologic markers remained unchanged in peripheral blood and lymph node of patients who continued on zidovudine alone. In contrast, a decrease in virus replication in lymph nodes was observed in four of six patients who added didanosine to their regimen, and this was associated with a decrease in plasma viremia. These results indicate that decreases in plasma viremia detected during antiretroviral therapy reflect downregulation of virus replication in lymphoid tissue.

Full text

PDF

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ait-Khaled M., Emery V. C. Phylogenetic relationship between human immunodeficiency virus type 1 (HIV-1) long terminal repeat natural variants present in the lymph node and peripheral blood of three HIV-1-infected individuals. J Gen Virol. 1994 Jul;75(Pt 7):1615–1621. doi: 10.1099/0022-1317-75-7-1615. [DOI] [PubMed] [Google Scholar]
  2. Aoki S., Yarchoan R., Thomas R. V., Pluda J. M., Marczyk K., Broder S., Mitsuya H. Quantitative analysis of HIV-1 proviral DNA in peripheral blood mononuclear cells from patients with AIDS or ARC: decrease of proviral DNA content following treatment with 2',3'-dideoxyinosine (ddI). AIDS Res Hum Retroviruses. 1990 Nov;6(11):1331–1339. doi: 10.1089/aid.1990.6.1331. [DOI] [PubMed] [Google Scholar]
  3. Armstrong J. A., Horne R. Follicular dendritic cells and virus-like particles in AIDS-related lymphadenopathy. Lancet. 1984 Aug 18;2(8399):370–372. doi: 10.1016/s0140-6736(84)90540-3. [DOI] [PubMed] [Google Scholar]
  4. Bagnarelli P., Valenza A., Menzo S., Manzin A., Scalise G., Varaldo P. E., Clementi M. Dynamics of molecular parameters of human immunodeficiency virus type 1 activity in vivo. J Virol. 1994 Apr;68(4):2495–2502. doi: 10.1128/jvi.68.4.2495-2502.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baroni C. D., Pezzella F., Mirolo M., Ruco L. P., Rossi G. B. Immunohistochemical demonstration of p24 HTLV III major core protein in different cell types within lymph nodes from patients with lymphadenopathy syndrome (LAS). Histopathology. 1986 Jan;10(1):5–13. doi: 10.1111/j.1365-2559.1986.tb02456.x. [DOI] [PubMed] [Google Scholar]
  6. Biberfeld P., Chayt K. J., Marselle L. M., Biberfeld G., Gallo R. C., Harper M. E. HTLV-III expression in infected lymph nodes and relevance to pathogenesis of lymphadenopathy. Am J Pathol. 1986 Dec;125(3):436–442. [PMC free article] [PubMed] [Google Scholar]
  7. Choi S., Lagakos S. W., Schooley R. T., Volberding P. A. CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine. Ann Intern Med. 1993 May 1;118(9):674–680. doi: 10.7326/0003-4819-118-9-199305010-00003. [DOI] [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. Collier A. C., Coombs R. W., Fischl M. A., Skolnik P. R., Northfelt D., Boutin P., Hooper C. J., Kaplan L. D., Volberding P. A., Davis L. G. Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection. Ann Intern Med. 1993 Oct 15;119(8):786–793. doi: 10.7326/0003-4819-119-8-199310150-00003. [DOI] [PubMed] [Google Scholar]
  10. Davey R. T., Jr, Dewar R. L., Reed G. F., Vasudevachari M. B., Polis M. A., Kovacs J. A., Falloon J., Walker R. E., Masur H., Haneiwich S. E. Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5608–5612. doi: 10.1073/pnas.90.12.5608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. DeGruttola V., Beckett L. A., Coombs R. W., Arduino J. M., Balfour H. H., Jr, Rasheed S., Hollinger F. B., Fischl M. A., Volberding P. Serum p24 antigen level as an intermediate end point in clinical trials of zidovudine in people infected with human immunodeficiency virus type 1. Aids Clinical Trials Group Virology Laboratories. J Infect Dis. 1994 Apr;169(4):713–721. doi: 10.1093/infdis/169.4.713. [DOI] [PubMed] [Google Scholar]
  12. Embretson J., Zupancic M., Ribas J. L., Burke A., Racz P., Tenner-Racz K., Haase A. T. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. doi: 10.1038/362359a0. [DOI] [PubMed] [Google Scholar]
  13. Fahey J. L., Taylor J. M., Detels R., Hofmann B., Melmed R., Nishanian P., Giorgi J. V. The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N Engl J Med. 1990 Jan 18;322(3):166–172. doi: 10.1056/NEJM199001183220305. [DOI] [PubMed] [Google Scholar]
  14. Fauci A. S. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993 Nov 12;262(5136):1011–1018. doi: 10.1126/science.8235617. [DOI] [PubMed] [Google Scholar]
  15. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  16. Fischl M. A., Richman D. D., Hansen N., Collier A. C., Carey J. T., Para M. F., Hardy W. D., Dolin R., Powderly W. G., Allan J. D. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. A double-blind, placebo-controlled trial. The AIDS Clinical Trials Group. Ann Intern Med. 1990 May 15;112(10):727–737. doi: 10.7326/0003-4819-112-10-727. [DOI] [PubMed] [Google Scholar]
  17. Fox C. H., Tenner-Rácz K., Rácz P., Firpo A., Pizzo P. A., Fauci A. S. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991 Dec;164(6):1051–1057. doi: 10.1093/infdis/164.6.1051. [DOI] [PubMed] [Google Scholar]
  18. Furtado M. R., Murphy R., Wolinsky S. M. Quantification of human immunodeficiency virus type 1 tat mRNA as a marker for assessing the efficacy of antiretroviral therapy. J Infect Dis. 1993 Jan;167(1):213–216. doi: 10.1093/infdis/167.1.213. [DOI] [PubMed] [Google Scholar]
  19. Holodniy M., Katzenstein D. A., Israelski D. M., Merigan T. C. Reduction in plasma human immunodeficiency virus ribonucleic acid after dideoxynucleoside therapy as determined by the polymerase chain reaction. J Clin Invest. 1991 Nov;88(5):1755–1759. doi: 10.1172/JCI115494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Katzenstein D. A., Holodniy M., Israelski D. M., Sengupta S., Mole L. A., Bubp J. L., Merigan T. C. Plasma viremia in human immunodeficiency virus infection: relationship to stage of disease and antiviral treatment. J Acquir Immune Defic Syndr. 1992;5(2):107–112. [PubMed] [Google Scholar]
  21. Kozal M. J., Shafer R. W., Winters M. A., Katzenstein D. A., Merigan T. C. A mutation in human immunodeficiency virus reverse transcriptase and decline in CD4 lymphocyte numbers in long-term zidovudine recipients. J Infect Dis. 1993 Mar;167(3):526–532. doi: 10.1093/infdis/167.3.526. [DOI] [PubMed] [Google Scholar]
  22. MacDonell K. B., Chmiel J. S., Poggensee L., Wu S., Phair J. P. Predicting progression to AIDS: combined usefulness of CD4 lymphocyte counts and p24 antigenemia. Am J Med. 1990 Dec;89(6):706–712. doi: 10.1016/0002-9343(90)90210-5. [DOI] [PubMed] [Google Scholar]
  23. Masur H., Ognibene F. P., Yarchoan R., Shelhamer J. H., Baird B. F., Travis W., Suffredini A. F., Deyton L., Kovacs J. A., Falloon J. CD4 counts as predictors of opportunistic pneumonias in human immunodeficiency virus (HIV) infection. Ann Intern Med. 1989 Aug 1;111(3):223–231. doi: 10.7326/0003-4819-111-3-223. [DOI] [PubMed] [Google Scholar]
  24. Neumann M., Harrison J., Saltarelli M., Hadziyannis E., Erfle V., Felber B. K., Pavlakis G. N. Splicing variability in HIV type 1 revealed by quantitative RNA polymerase chain reaction. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1531–1542. doi: 10.1089/aid.1994.10.1531. [DOI] [PubMed] [Google Scholar]
  25. Nuovo G. J., Becker J., Burk M. W., Margiotta M., Fuhrer J., Steigbigel R. T. In situ detection of PCR-amplified HIV-1 nucleic acids in lymph nodes and peripheral blood in patients with asymptomatic HIV-1 infection and advanced-stage AIDS. J Acquir Immune Defic Syndr. 1994 Sep;7(9):916–923. [PubMed] [Google Scholar]
  26. Pantaleo G., Graziosi C., Butini L., Pizzo P. A., Schnittman S. M., Kotler D. P., Fauci A. S. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9838–9842. doi: 10.1073/pnas.88.21.9838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. doi: 10.1038/362355a0. [DOI] [PubMed] [Google Scholar]
  28. Piatak M., Jr, Saag M. S., Yang L. C., Clark S. J., Kappes J. C., Luk K. C., Hahn B. H., Shaw G. M., Lifson J. D. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science. 1993 Mar 19;259(5102):1749–1754. doi: 10.1126/science.8096089. [DOI] [PubMed] [Google Scholar]
  29. Rácz P., Tenner-Rácz K., Kahl C., Feller A. C., Kern P., Dietrich M. Spectrum of morphologic changes of lymph nodes from patients with AIDS or AIDS-related complexes. Prog Allergy. 1986;37:81–181. doi: 10.1159/000318442. [DOI] [PubMed] [Google Scholar]
  30. Schwartz S., Felber B. K., Fenyö E. M., Pavlakis G. N. Env and Vpu proteins of human immunodeficiency virus type 1 are produced from multiple bicistronic mRNAs. J Virol. 1990 Nov;64(11):5448–5456. doi: 10.1128/jvi.64.11.5448-5456.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Spiegel H., Herbst H., Niedobitek G., Foss H. D., Stein H. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol. 1992 Jan;140(1):15–22. [PMC free article] [PubMed] [Google Scholar]
  32. Westermann J., Pabst R. Lymphocyte subsets in the blood: a diagnostic window on the lymphoid system? Immunol Today. 1990 Nov;11(11):406–410. doi: 10.1016/0167-5699(90)90160-b. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES