Abstract Book Vol. 2 [International Conference on AIDS (14th: 2002: Barcelona, Spain)]

XIV International AIDS Conference

Abstracts ThPeA7141-ThPeA7145 369

Presenting author: Miguel Alfonzo Diaz, 25 Rue du Dr. Roux, Paris 75015,
France, Tel.: [phone], Fax: [phone], E-mail: [email protected]
ThPeA7141 I The binding subunit of pertussis toxin uncouples T
cell activation from HIV-1 replication in lymphoid
tissue.
M. Alfano1, J.C. Grivel2, G. Poli1, L. Margolis2. 1Dibit, Via Olgettina, 58, 20132
Milano, Italy; 2NIH, Bethesda, United States
Background: Both pertussis toxin (PTX) and its non-toxic subunit (PTX Boligomer, PTX-B) have shown inhibitory activity against HIV-1 replication in several models of in vitro infection, including mitogen-activated PBMC, monocytederived macrophages (MDM), and chronically infected U1 cells stimulated by cytokines. In addition, PTX has been reported to possess antiviral effects in vivo
when administered to macaques infected with SIV. PTX-B has been demonstrated to inhibit entry of CCR5-dependent (R5) HIV-1 strains and, in addition,
to suppress both R5 and CXCR4-dependent (X4) virus replication at a post-entry
level. Here we investigated whether PTX-B maintains anti-HIV-1 effects in lymphoid tissues infected ex vivo, a model system that retains the in vivo cytoarchitecture of the tissue and does not require in vitro-activation for productive infection.
Methods: Human lymphoid tissue was analyzed for various cellular subpopulations, HIV-induced cell depletion, and viral production, both in the absence
and in the presence of PTX-B.
Results: PTX-B inhibited both R5 and X4 HIV-1 replication in lymphoid tissues.
Maximal inhibition was achieved at concentrations up to 100 times lower than
those required for inhibition of in vitro-infected PBMC or MDM. Higher concentrations of PTX-B were less inhibitory on virus replication and induced activation and
proliferation of CD4+ T lymphocytes. R5 infection synergized with the mitogenic
effect of PTX-B whereas X4 HIV did not. However these interactions did not result in the up-regulation of virus replication. Similar results were obtained with a
genetically modified PTX, PT-9K/129G, which retains all the PTX-B activities and
is used to vaccinate against Bordetella pertussis.
Conclusion: PTX-B represents a novel class of anti-HIV molecules encompassing both immune-activating capacities and antiviral properties.
Presenting author: Massimo Alfano, Via Olgettina, 58, 20132 Milano, Italy, Tel.:
+39-02-2643.4902, Fax: [phone], E-mail: [email protected]
ThPeA7142 Immune phenotype and function are comparable in
chronically HIV-1 patients treated with HAART with
absent or strong T-helper cell responses to HIV gag
antigen
C.G. Lange1, P. Shankar2, H. Valdez3, R.S. Lee4, J. Lieberman5,
M.M. Lederman3. 1Medical Clinic, Research Center Borstel, Medizinische Klinik,
Parkallee 35 Forschungszentrum Borstel, 23845 Borstel, Germany; 2Center for
Blood Research, Harvard Medical School, Boston, United States; 3Center for
AIDS Research, University Hospitals, Case Western Reserve University,
Cleveland, OH, United States; 4 Dana Faber Cancer Institute, Harvard Medical
School, Boston, United States; 5 The Center for Blood Research, Harvard
Medical School, Boston, United States
Background: Persistent CD4+ T-cell lymphoproliferation (LP) in response to HIV
p24 antigen has been related to cytotoxic T-lymphocyte (CTL) mediated control of
viremia in patients with acute HIV-1 infection treated with HAART and long term
asymptomatic (LTA) therapy naive patients. Whether the presence of HIV-1 specific helper cell responses alters immune phenotype and function in chronically
HIV-1 infected patients treated with HAART is unknown.
Methods: Lymphocyte subpopulations, LP in response to tetanus toxoid (TT),
HIVp24, Candida albicans (CA), streptokinase (SK), Mycobacterium avium complex (MAC) and Cytomegalovirus (CMV), delayed- type-hypersensitivity (DTH)
skin tests in response to TT and CA were examined in HIV-infected patients
with HIV-RNA <400 copies/mL for >12 months and strong (stimulation index (SI)
>10,n=21) or absent (S1<3,n=18) LP to HIVp24 antigen. Cell surface markers
and cytolytic molecules on HIV-tetramer-positive CD8+ cells were also examined
(SI >10,n=6;Sl<3,n=7). Group comparison was performed by non-parametric
Whitney-Mann test.
Results: Medians of current CD4+ T-cell counts (744 and 731 cells/iL), lowest
recorded CD4+ T-cell counts (266 and 299 cells/kL), the duration of HIV-RNA
<400 copies/mL on therapy (38 and 35 months) numbers of naive, memory and
CD28+ CD4+ T cells, CD8+ T-cells expressing CD45RA, CD62L, CD28, HLADR
CD38, CCR7, LP and DTH responses to non-HIV antigens were comparable between patients with absent and strong LP in response to HIVp24. In relation to
granzyme A, expression of perforin was lower in HIV-1 specific CD8+ T-cells of
patients with absent LP responses to HIVp24 (p<0.05).
Conclusion: HIV-1 specific T-helper cell responses in HIV-1 infected patients
with suppression of viral replication on HAART are not related to changes in the
immune-phenotype and -function in response to non-HIV antigens but may be

associated with improved cytotoxic function of HIV-1 specific CD8+ T-cells.
Presenting author: Christoph Lange, Medizinische Klinik, Parkallee 35
Forschungszentrum Borstel, 23845 Borstel, Germany, Tel.: [phone], Fax:
[phone], E-mail: cgmlange @ hotmail.com

ThPeA7143 Thymic output and interleukin-7 (IL-7) levels during
primary HIV-infection
J.P Routy1, M.R. Boulassel1, M. Sylvestre2, J.F Poulin2, R.P. Sekaly2,
R. Cheynier2. 1Div of Hematology, McGill University Health Centre, Royal
Victoria Hospital, Montreal, QC, Canada; 2Dept. of Immunology, University of
Montreal, Montreal, Canada
Background: Increased IL-7 levels have been associated with lymphopenia induced by HIV, chemotherapy or bone marrow transplantation. Recent reports in
HIV-infected patients have shown a strong inverse correlation between IL-7 and
lymphopenia. We have shown that this correlation is still maintained in patients
with primary HIV infection having CD4 cells <450/ml. To understand the relationship between IL-7 and T cell production, we monitored IL-7 levels and the
frequency of recent thymic emigrants (RTEs) in the blood of patients with primary
HIV infection before and during active antiretroviral therapy.
Methods: A PCR assay for the detection of TCR excision circles (sjTRECs)
was used to evaluate the peripheral blood mononuclear cells (PBMC) RTEs frequency. TRECs frequency and plasma IL-7 were assessed longitudinally over 18
months in 16 patients with primary HIV infection (<6 months). Correlations between TRECs frequency, IL-7, CD4 and CD8 counts and plasma HIV-RNA were
analyzed according to response to antiretroviral therapy.
Results: At baseline, median TRECs frequency was 387.0/105 PBMC (range,
0.0-2151), median IL-7 was 12.4 pg/ml (range, 5.6-28) and median CD4 was
529/mm3 (range, 271-1225/mm3). Before treatment, correlations were found between TRECs frequency and CD8 (r= -0.56, P=0.02) and plasma HIV-RNA (r=
-0.59, p= 0.01) but not with IL-7 (r= -0.06, p=0.8) or CD4 (r=0.28, p=0.29). During
the treatment at months 3, 6 and 18 no significant correlations were observed
for any parameters. Only patients with reduced TRECs frequency at baseline
(<100/105 PBMC) presented a significant increase during treatment. Reduced
numbers of RTEs in the blood were observed in patients with elevated HIV-RNA
and CD8 counts independently of IL-7 levels.
Conclusions: No relationship between IL-7 and TRECs was found in this study
Treatment intervention preserves thymic output in recently infected patients.
Presenting author: Jean-Pierre Routy, Royal Victoria Hospital, 687 Ave. des
Pins West, c6.92, Montreal, Qc., H3A 1A1, Canada, Tel.: [phone],
Fax: [phone], E-mail: [email protected]
ThPeA7144 High levels of cAMP contribute to the T cell
dysfunction in HIV: Protein kinase A type I
antagonist increases HIV and CMV specific immune
responses in T cells from HIV patients
E.M. Aandahl', W.J. Morettol, J. Harris1, D. Schmidt', J.M. McCune1,
RA. Haslett2, K. Tasken3, D.F. Nixon1. 1Gladstone Institute of Virology and
Immunology UCSF San Francisco CA, United States; 2Laboratory of Cellular
Physiology and Immunology, Rockefeller University, New York, United States;
3Department of Medical Biochemsitry University of Oslo, Oslo, Norway
Background: Cyclic AMP inhibits T cell proliferation and cytokine production
through activation of protein kinase A type. We have previously shown that T
cells from HIV patients have elevated levels of cAMP, and that antagonists specific to PKA type I selectively increase anti-CD3 induced T cell proliferation in T
cells from HIV patients and not from seronegative controls.
Methods: In this study, we examined the effect of a PKA type I antagonist on HIV
and CMV specific antigen responses by intracellular flow cytometry in T cells from
HIV patients on a STI protocol.
Results: We report that the PKA type I antagonist Rp-8-Br-cAMPS increases
the expression of IFN-y in a concentration dependent manner in both CD4+ and
CD8+ T cells induced by HIV gag (p=0,008 and p<0,001) and CMV (p=0,001
and p=0,020) peptide pools. The improvement of the immune responses occurred
both on and off HAART
Conclusions: This supports the recognition of PKA type I as a potential target
for immunostimulating therapy in
HIV infection. Therapeutic strategies inhibiting the cAMP/PKA type I pathway may
be a useful adjuvant to current HAART regimens and STI protocols.
Presenting author: Einar Martin Aandahl, Gladstone Institute of Virology and Immunology, RO. Box 419100, San Francisco CA 94141-9100, United States, Tel.:
[phone], Fax: [phone], E-mail: [email protected]
ThPeA7145 Influence of HIV viremia and T-lymphopenia on the
regulation of plasma interleukin-7 (IL-7) levels
M.R. Boulassel1, J.P Routy1, G.H.R. Smith1, M. Klein1, J. MacLeod1,
N. Gilmore1, S. Bruce1, PR. Sekaly2, R.G. Lalonde1. 'Ilmmunodeficiency
Service, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC,
Canada; 2Department of Immunology, University of Montreal, Montreal, Canada

Background: IL-7 contributes to the regulation of the T-cell pool. Recent reports
have shown an inverse correlation between IL-7 and T-lymphopenia in advanced
HIV-patients. IL-7, like IL-2, has been shown to increase viral replication in vitro.
We hypothesize the increased IL-7 levels are caused by T-lymphopenia and not
HIV viremia. To answer this, we analyzed changes in IL-7 levels longitudinally and
correlated these changes with CD4, CD8 counts and viremia in advanced and in
primary/early phase HIV patients.
Methods: Plasma IL-7 levels were measured at baseline, week 4, 12 and 24 in