Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection.
Journal: 1998/March - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
PUBMED: 9448301
Abstract:
Potent combinations of antiretroviral drugs diminish the turnover of CD4+ T lymphocytes productively infected with HIV-1 and reduce the large pool of virions deposited in lymphoid tissue (LT). To determine to what extent suppression of viral replication and reduction in viral antigens in LT might lead correspondingly to repopulation of the immune system, we characterized CD4+ T lymphocyte populations in LT in which we previously had quantitated viral load and turnover of infected cells before and after treatment. We directly measured by quantitative image analysis changes in total CD4+ T cell counts, the CD45RA+ subset, and fractions of proliferating or apoptotic CD4+ T cells. Compared with normal controls, we documented decreased numbers of CD4+ T cells and increased proliferation and apoptosis. After treatment, proliferation returned to normal levels, and total CD4+ T and CD45RA+ cells increased. We discuss the effects of HIV-1 on this subset based on the concept that renewal mechanisms in the adult are operating at full capacity before infection and cannot meet the additional demand imposed by the loss of productively infected cells. The slow increases in the CD45RA+ CD4+ T cells are consistent with the optimistic conclusions that (i) renewal mechanisms have not been damaged irreparably even at relatively advanced stages of infection and (ii) CD4+ T cell populations can be partially restored by control of active replication without eradication of HIV-1.
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Proc Natl Acad Sci U S A 95(3): 1154-1159

Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection

+8 authors
Departments of Microbiology, Cell Biology and Neuroanatomy, Medicine, and Otolaryngology, University of Minnesota Medical School, Minneapolis, MN 55455; Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; HIV Program, St. Paul-Ramsey Medical Center, St. Paul, MN 55101; Gilead Sciences, Foster City, CA 94404; and Glaxo–Wellcome Research and Development, Greenford, United Kingdom
To whom reprint requests should be addressed.
Edited by Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved October 30, 1997
Edited by Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved October 30, 1997
Received 1997 Aug 29

Abstract

Potent combinations of antiretroviral drugs diminish the turnover of CD4+ T lymphocytes productively infected with HIV-1 and reduce the large pool of virions deposited in lymphoid tissue (LT). To determine to what extent suppression of viral replication and reduction in viral antigens in LT might lead correspondingly to repopulation of the immune system, we characterized CD4+ T lymphocyte populations in LT in which we previously had quantitated viral load and turnover of infected cells before and after treatment. We directly measured by quantitative image analysis changes in total CD4+ T cell counts, the CD45RA+ subset, and fractions of proliferating or apoptotic CD4+ T cells. Compared with normal controls, we documented decreased numbers of CD4+ T cells and increased proliferation and apoptosis. After treatment, proliferation returned to normal levels, and total CD4+ T and CD45RA+ cells increased. We discuss the effects of HIV-1 on this subset based on the concept that renewal mechanisms in the adult are operating at full capacity before infection and cannot meet the additional demand imposed by the loss of productively infected cells. The slow increases in the CD45RA+ CD4+ T cells are consistent with the optimistic conclusions that (i) renewal mechanisms have not been damaged irreparably even at relatively advanced stages of infection and (ii) CD4+ T cell populations can be partially restored by control of active replication without eradication of HIV-1.

Abstract

In the lymphatic tissues of HIV-1-infected individuals, ongoing cycles of productive infection generate large numbers of virions, most of which are stored like other antigens in immune complexes associated with follicular dendritic cells (1, 2). However, unlike conventional antigens, the HIV-1 follicular dendritic cell pool represents a large and persistent antigenic stimulus of >10 virions that presumably drives activation, proliferation, and programmed cell death, processes that, along with the loss of productively infected cells, are directly or indirectly responsible for immune depopulation and depletion (310). We recently investigated viral replication and load in lymphoid tissue (LT) in a cohort of previously untreated HIV-1-infected individuals given a combination of antiretroviral drugs and found that, by the end of the third week of treatment, the cells that account for most of the production of virus were barely detectable and that, by 6 months, the pool of HIV-1 associated with follicular dendritic cells in LT was reduced 3,000-fold (2). This suppression of active replication of HIV-1 and reduced antigenic mass in LT might provide a milieu in which some of the abnormalities in CD4+ T cell populations might be reversed, and indeed Autran et al. (11) recently showed that antiretroviral therapy does have positive effects on CD4+ T cells in blood. To directly examine the treatment-associated effects on CD4+ T cell populations in LT where most of the cells reside, we devised a quantitative image analysis technique to directly measure LT CD4+ T cell subsets, proliferation, and apoptosis in small samples of LT before and after treatment. From comparable measurements in the LT of HIV-1-seronegative individuals, we also determined and describe the effects of HIV-1 infection on CD4+ T cell populations. Based on these analyses, we advance hypotheses about the mechanisms of depletion and repopulation of CD4+ T cells in LT.

The number of CD4+ T cells/mm in blood was determined by FACS analysis (NT, not tested). The CD4+ T cell count per microgram in LT was determined by QIA of sections in which CD4+ T cells had been stained immunohistochemically. At least 20 sections distributed throughout the tissue specimen were examined at a magnification of ×160, and the number of CD4+ T cells was determined at least twice, with values that agreed to within ±5%, in representative fields that had well defined lymphoid follicles and paracortical regions. The microgram of LT was determined from the area examined (3.75 × 10 cm at ×160) the section thickness (5 × 10 cm) × the previously determined (1) density of ≈1 gm/cm. The percentage of CD45RA+ CD4+ T cells was determined by manually counting ≈1,000 double-labeled cells. The percentage of CD4+ T cells undergoing proliferation or apoptosis was determined by double labeling with first anti-CD4+ and then anti-Ki67 or TUNEL assay, respectively, as described in Materials and Methods. Single- and double-positive CD4+ T cells were quantitated by QIA and binary multiplication. An average of 3,680 CD4+ cells was counted to determine the percentage of double-positives.

See Table Table11 legend.

Acknowledgments

We thank M. Bahan, C. O’Neill, and T. Leonard for preparation of the manuscript and figures, Q. Li and K. Staskus for helpful discussion, and the Ramsey Foundation, the National Institutes of Health, Abbott Laboratories, and Glaxo–Wellcome for support. The peripheral blood CD4+ T cell counts were performed by the Department of Clinical Viro-Immunology, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam. We thank R. H. Kauffmann, M.D., Ph.D., Leyenburg Hospital, The Hague, The Netherlands, P. L. Meenhorst, M.D., Ph.D., Slotervaart Hospital, Amsterdam, and N. A. Foudraine, M.D., Municipal Health Service, Amsterdam, and their patients for participating in these studies.

Acknowledgments

Footnotes

This paper was submitted directly (Track II) to the Proceedings Office.

Abbreviations: LT, lymphoid tissue; TUNEL, terminal deoxynucleotidyltransferase-mediated UTP end labeling.

Footnotes

References

  • 1. Haase A T, Henry K, Zupancic M, Sedgewick G, Faust R A, Melroe H, Cavert W, Gebhard K, Staskus K, Zhang Z-Q, Dailey P J, Balfour H H, Jr, Erice A, Perelson A S. Science. 1996;274:985–989.[PubMed]
  • 2. Cavert W, Notermans D W, Staskus K A, Wietgrefe S W, Zupancic M, Gebhard K, Henry K, Zhang Z, Mills R, McDade H, Schuwirth C, Goudsmit J, Danner S A, Haase A T. Science. 1997;276:960–964.[PubMed]
  • 3. Fauci A S. Nature (London) 1996;384:529–534.[PubMed]
  • 4. Giorgi J V Immunology of HIV Infection. New York: Plenum; 1996. [PubMed][Google Scholar]
  • 5. Lane H C, Depper J M, Greene W C, Whalen G, Waldmann T A, Fauci A S. N Engl J Med. 1985;313:79–84.[PubMed]
  • 6. Gougeon M-L, Montagnier L. Science. 1993;260:1269–1270.[PubMed]
  • 7. Meyaard L, Otto S A, Jonker R R, Mijnster M J, Keet R P, Miedema F. Science. 1992;257:217–219.[PubMed]
  • 8. Pantaleo G, Fauci A S. Nat Med. 1995;1:118–120.[PubMed]
  • 9. Groux H, Torpier G, Monte D, Mouton Y, Capron A, Ameisen J C. J Exp Med. 1992;175:331–340.
  • 10. Muro-Cacho C A, Pantaleo G, Fauci A S. J Immunol. 1995;154:5555–5566.[PubMed]
  • 11. Autran B, Carcelain G, Li T S, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J. Science. 1997;277:112–116.[PubMed]
  • 12. Faust R A, Henry K, Dailey P, Melroe H, Sullivan C, Erice A, Haase A T, Boies L R., Jr Otolaryngol Head Neck Surg. 1996;114:593–598.[PubMed]
  • 13. Drinker C K, Yoffey J M Lymphatics, Lymph, and Lymphoid Tissue. Cambridge, MA: Harvard Univ. Press; 1941. p. 12. [PubMed][Google Scholar]
  • 14. Pilarski L M, Gillitzer R, Zola H, Shortman K, Scollay R. Eur J Immunol. 1989;19:589–597.[PubMed]
  • 15. Fujii Y, Okumura M, Inada K, Nakahara K, Matsuda H. Eur J Immunol. 1992;22:1843–1850.[PubMed]
  • 16. Erkeller-Yuksel F M, Deneys V, Yuksel B, Hannet I, Hulstaert F, Hamilton C, Mackinnon H, Stokes L T, Munhyeshuli V, Vanlangendonck F. J Pediatr. 1992;120:216–222.[PubMed]
  • 17. Mackall C L, Fleisher T A, Brown M R, Andrich M P, Chen C C, Feuerstein I M, Horowitz M E, Magrath I T, Shad A T, Steinberg S M. N Engl J Med. 1995;332:143–149.[PubMed]
  • 18. Kelleher A D, Carr A, Zaunders J, Cooper D A. J Infect Dis. 1996;173:321–329.[PubMed]
  • 19. Wei X, Ghosh S K, Taylor M E, Johnson V A, Emini E A, Deutsch P, Lifson J D, Bonhoeffer S, Nowak M A, Hahn B H. Nature (London) 1995;373:117–122.[PubMed]
  • 20. Ho D D, Neumann A U, Perelson A S, Chen W, Leonard J M, Markowitz M. Nature (London) 1995;373:123–126.[PubMed]
  • 21. Perelson A S, Neumann A U, Markowitz M, Leonard D, Ho D. Science. 1996;271:1582–1586.[PubMed]
  • 22. Paul W E In: Fundamental Immunology. Paul W E, editor. New York: Raven; 1989. [PubMed][Google Scholar]
  • 23. Janossy G, Bofill M, Rowe D, Muir J, Beverley P C L. Immunology. 1989;66:517–525.
  • 24. Collins J A, Schandl C A, Young K K, Vesely J, Willingham M C. J Histochem Cytochem. 1997;45:923–934.[PubMed]
  • 25. Røsok B I, Bostad L, Voltersvik P, Bjerknes R, Olofsson J, Asjo B, Brinchmann J E. AIDS. 1996;10:F35–F38.[PubMed]
  • 26. Grossman Z, Herberman R B. Nat Med. 1997;3:486–490.[PubMed]
  • 27. Roederer M, Dubs J G, Anderson M T, Raju P A, Herzenberg L A, Herzenberg L A. J Clin Invest. 1995;95:2061–2066.
  • 28. Stutman O. Immunol Rev. 1986;91:159–194.[PubMed]
  • 29. Zheng B, Han S, Zhu Q, Goldsby R, Kelsoe G. Nature (London) 1996;384:263–266.[PubMed]
  • 30. McLean A R, Michie C A. Proc Natl Acad Sci USA. 1995;92:3707–3711.
  • 31. Stanley S K, McCune J M, Kaneshima H, Justement J S, Sullivan M, Boone E, Baseler M, Adelsberger J, Bonyhadi M, Orenstein J. J Exp Med. 1993;178:1151–1163.
  • 32. Bonyhadi M L, Rabin L, Salimi S, Brown D A, Kosek J, McCune J M, Kaneshima H. Nature (London) 1993;363:728–732.[PubMed]
  • 33. Aldrovandi G M, Feuer G, Gao L, Jamieson B, Kristeva M, Chen I S, Zack J A. Nature (London) 1993;363:732–736.[PubMed]
  • 34. Carroll L Through the Looking-Glass. New York: MacMillan; 1871. pp. 42–43. [PubMed][Google Scholar]
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