ISSN 0269-9370 © 1999 Lippincott Williams & Wilkins
HAART in HIV-infected patients: restoration of
antigen-specific CD4 T-cell responses in vitro is
correlated with CD4 memory T-cell reconstitution,
whereas improvement in delayed type
hypersensitivity is related to a decrease in viraemia
Thomas Wendland, Hansjakob Furrera, Pietro L. Vernazzab,
Karin Frutig, Anna Christena, Lukas Matterc, Raffaele Malinvernia
and Werner J. Pichler
Objective: To analyse prospectively the effect of highly active antiretroviral
treatment (HAART) on CD4 T-cell responses in vitro and in vivo in HIV-infected
Design: Prospective study with 49 protease inhibitor-naive adult patients. Data were
collected at baseline and after 3 and 6 months of HAART.
Methods: In vitro CD4 T-cell reactivity was analysed by stimulation of peripheral
blood mononuclear cells with several antigens. In vivo CD4 T-cell reactivity (delayed
type hypersensitivity) was assessed by Multitest Merieux. Both measurements were
correlated to CD4 (memory) T-cell count and HIV-1 viraemia.
Results: Restoration of specific CD4 T-cell proliferation was observed in most
patients. The in vitro T-cell response was restored more frequently against antigens
to which the immune system is constantly exposed (Candida albicans,
Mycobacterium tuberculosis, M. avium) as compared with a low-exposure antigen
(tetanus toxoid). Overall, delayed type hypersensitivity detection rate increased
under HAART. Multivariate analysis showed improvement of antigen-specific T-cell
proliferation to be significantly associated with an increase in memory CD4 T-cells,
whereas improvement of the delayed type hypersensitivity response was associated
with a decrease in plasma HIV-1 RNA.
Conclusions: HAART for 6 months restored antigen-specific CD4 T-cell response to
several antigens. In vitro immune reconstitution was closely correlated with an
increase in memory CD4 cells. Restoration of delayed type hypersensitivity was
associated with suppression of viraemia. It appears that in addition to expansion of
memory CD4 cells, suppression of viraemia following HAART may allow an improved
inflammatory reaction, thus providing even stronger immune reconstitution.
© 1999 Lippincott Williams & Wilkins
AIDS 1999, 13:1857–1862
Keywords: CD4, cellular immunity, delayed type hypersensitivity,
opportunistic infections, combination therapy
From the Institute of Immunology and Allergology, the aAIDS Unit, Inselspital Bern, the bAIDS Unit, Kantonsspital St. Gallen,
and the cInstitute of Medical Microbiology, Inselspital Bern, Switzerland.
Sponsorship: Supported by the Swiss National Foundation grant no.: 31-50482.97 (National AIDS-research program of the
BAG, to W.J.P.) and 3233-048902.96 to P.V.
Correspondence to Werner J. Pichler, Clinic for Rheumatology, Clinical Immunology/Allergology, University Hospital Bern,
Freiburgstrasse, CH-3010 Bern, Switzerland.
Received: 8 May 1999; revised: 27 July 1999; accepted: 28 August 1999.
AIDS 1999, Vol 13 No 14
with higher CD4 cell counts showed proliferation
against C. albicans. The rapid recovery of the Candida-
specific CD4 T-cell proliferation is in accordance with
epidemiological data showing a rapid decrease in the
incidence of candidal oesophagitis after a few months
of HAART treatment in patients with advanced
immune dysfunction . Furthermore, the beneficial
effect of HAART extends to other antigens as well, as
shown most recently after stopping primary and sec-
ondary prophylaxis against Pneumocystis carinii, and, pos-
sibly, T. gondii and cytomegalovirus [15–17].
In conclusion, HAART results in a significant restora-
tion of multi-specific CD4 T-cell responses, but the
degree of this effect is different when in vitro or in vivo
methods are used. Functional studies of CD4 T cells
might help to guide decisions regarding discontinuation
of prophylactic medication against opportunistic infec-
tions in patients with undetectable viral load under
The authors thank all patients for their participation
and the staff of the AIDS-units in Bern and St. Gallen
for their efforts making the study possible. Furthermore
we thank D. Züllig for excellent technical support and
M. Zanni, C. Burkhart and S. von Greyerz for helpful
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