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

352 Abstracts ThOrA1482-ThPpA2127

XIV International AIDS Conference

ThOrAl482 3-year evaluation of a therapeutic vaccine (HIV-1
Immunogen) administred with antiretrovirals
versus antiretroviral therapy alone in patients with
HIV chronic infection
E. Fernandez-Cruz', J. Navarro', M.L. Abad', L. Diaz', C. Canto-Nogues',
M.C. Rodriguez-Sainz', J. Carbone', M.A. Munoz-Fernandez', S. Moreno2,
J. Perez-Molina', B. Clotet3, J.M. Gatell4, D. Podzamczer5,
J. Gonzalez-Lahoz6. 1Hospital General Univ Gregorio Maranon, Division of
Immunology Hospital Gral Univ Gregorio Maraft6n, C/ Dr Esquerdo 46, 28007
Madrid, Spain; 2Hospital Ramon y Cajal, Madrid, Spain; 3Hospital Germans
Trias i Pujol, Badalona, Spain; 4Hospital Clinic i Provincial, Barcelona, Spain;
5CS Bellvitge, Barcelona, Spain; 6Hospital Carlos Ill, Madrid, Spain
Background: We evaluated the efficacy of therapeutic vaccine with an inactivated
gpl20-depleted HIV-1 immunogen in IFA (REMUNETM) in 243 HIV+ chronically
infected subjects while receiving either ART or HAART (ARTs) in a three year,
double-blind, placebo (IFA) controlled trial. We determined the impact on viral
rebound or CD4 cell decline.
Results: REMUNE impacted significantly on virologic failure in patients on ARTs
(Fisher's Exact test, p<0.05). Also, there was a significant delay in the time
to reach virologic failure that was impacted by baseline viral load and CD4 inpatients on ARTs (Cox Regression Model, p<0.05). REMUNE also improved
the maintenance of virologic suppression in patients on ARTs (Gompertz model,
p<0.001). In a pre-specified subgroup of 54 subjects a significant lymphoproliferative response (LPR) was also observed in REMUNE-patients as compared with
IFA group. (stimulation index=29.6 vs 5.8, p<0.005). An increase of CD8 memory T cells (CD8+CD45RO+) was observed in REMUNE-Group (n=27) vs IFAGroup (n=27) (p<0.05). Also, high levels of HIV-1 Gag/pol-specific CTL precursors were observed in REMUNE group vs IFA-Group (mean: 3.224 CTLp vs 169
CTLp/106 PBMC; P<0.05). CTL precursors correlated negatively with viral load in
the REMUNE group (R= -0.58; P<0.05) but not in the IFA group. LPR correlated
positively with CTL precursors (R=0.498, p<0.05) and with Lytic Units (R=0.686,
p<0.005). We found a positive correlation between CD38+DR+ (R=0.60, p<0.05)
and CD45RO+DR+ (R=0.44, p<0.05) CD4+ T cells with viral load in IFA-Group,
but not in REMUNE-Group. Increased CD11 b+ (p<0.05) and decreased HLADR+
(p<0.005) CD8+- T-cells was only found in REMUNE-treated patients who developed high HIV-specific CTLs.
Conclusions: Therapeutic vaccination induces a decrease of immune system
activation, an increase of HIV-specific helper and CTL immune responses, and
induces a positive impact on the control of viral load in immunocompetent HIV-1
infected patients on ARTs.
Presenting author: Eduardo Fernandez-Cruz, Division of Immunology, Hospital Gral Univ. Gregorio Marahi6n, C/ Dr Esquerdo 46, 28007 Madrid, Spain, Tel.:
[phone], Fax: [phone], E-mail: [email protected]
ThOrA1483 The effects of immunotherapy with cytokine and/or
vaccine in HAART treated patients
F.M. Gotch1, G. Hardy', N. Imami', A. Sullivan', M. Nelson1, C. Burton1,
J. Pido Lopez', R. Moss2, B. Gazzard'. 'Imperial College of Science,
Technology and Medicine, Dept Immunology, ICSTM, Chelsea and Westminster
Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom; 2Immune
Response Corp, San Diego, United States
Background: Failure of HIV.1 specific CD4 helper T lymphocyte (HTL) and
CD8 cytotoxic T lymphocyte (CTL) responses to re-emerge following successful diminution of plasma viraemia with HAART, has necessitated studies of novel
immunotherapeutic approaches.
Methods: A randomised, phase 1 study of HAART with or without IL2 and/or
an inactivated gp120 depleted HIV.1 immunogen (Remune) was conducted in
chronically infected patients with a mean baseline CD4 T cell count of 303 cells/ul
blood. 36 patients were treated with HAART for 16 weeks before randomisation to:
HAART alone; HAART + IL2; HAART + IL2 + Remune; HAART + Remune. CD4
responses to HIV antigens, recall antigens and mitogens were assessed, CTL responses measured by Elispot assays, levels of MIPla in plasma were measured,
TREC levels were quantified, phenotypic analysis was undertaken and CD4 T cell
numbers and viral loads were monitored.
Results: HAART alone was insufficient to allow regeneration of HIV-specific responses. IL2 therapy resulted in improved CD4 HTL responses to recall antigens,
substantially increased CD4 T cell counts and induced transient viraemia which
was less marked in patients receiving Remune with IL2. TREC levels were significantly reduced in patients receiving IL2. No changes were seen in plasma MIPla
levels in any patients. No differences were seen in the induction of HIV specific
HTL or CTL responses in groups receiving IL2 and/or Remune despite an apparently protective effect against virological events by their combination. In patients
who experienced therapeutic failure in the context of immunotherapy leading to
virological breakthrough, strong CD4 HTL and CD8 CTL responses to HIV were
induced.

Conclusions: Transient regeneration of HIV specific immune responses could be
induced by IL2 +/- Remune. Autoimmunisation in the context of immunotherapy
led to the most promising responses.
Presenting author: Frances Gotch, Dept Immunology, ICSTM, Chelsea and
Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom,
Tel.: [phone], Fax: [phone], E-mail: [email protected]

ThOrAl 484 Enhancement of human T-lymphopoiesis by growth
hormone
L.A. Napolitano', A.J. Chien2, M.B. Hanley3, M.B. Moreno3, J. Rivera3
J. Bare3, C.A. Stoddart3, J.M. McCune'. 'Gladstone Institute of Virology and
Immunology/UCSF, Gladstone Institute of Virology and Immunology, PO. Box
419100, San Francisco, CA, 94141-9100, United States; 2Gladstone Institute of
Virology and Immunology / Harvard Medical School, San Francisco, CA /
Boston, MA, United States; 3Gladstone Institute of Virology and Immunology
San Francisco, CA, United States
Background: Animal studies indicate that growth hormone (GH) plays an important role in mammalian thymopoiesis, raising the possibility that its administration
may be of therapeutic benefit in human immunodeficiency. We previously hypothesized that GH treatment would stimulate thymopoiesis during HIV-1-infection.
In a prospective study of 5 HIV-1-infected adults, we found that GH treatment
was associated with a marked increase in thymic tissue in all GH recipients as
measured by thymic computed tomography with quantitative density and volume
analysis. Increased thymic mass was accompanied by a significant rise in circulating CD4+,CD45RA+,CD62L+ naive T cells in all subjects, suggesting that GH
enhances thymopoiesis.
Results: Studies were performed to examine the mechanisms underlying GH
effects on human thymopoiesis. GH was found to induce human thymic hyperplasia in a dose-dependent manner in the SCID-hu Thy/Liv mouse model. Multiparameter flow cytometry was performed to determine which thymocyte subpopulations might have expanded in response to GH. Despite a marked increase in
thymic cellularity in the GH-treated animals, there was no differential expansion
of any thymocyte subpopulation including rare CD34+ progenitor cells, immature CD4+CD8+ thymocytes, and mature CD4+ or CD8+ medullary thymocytes.
These findings were corroborated by a series of in vitro studies. Pediatric and fetal thymic organ cultures were established in the presence of GH under a variety
of conditions. No effect of GH was seen on thymocyte cell number, apoptosis, or
proliferation within any thymocyte subpopulation.
Conclusions: GH treatment of HIV-1-infected adults is associated with a striking
increase in thymic tissue and circulating naive CD4+ T cells, suggesting that GH
enhances human thymopoiesis. Further in vivo and in vitro analyses suggest that
the primary cellular targets of GH appear to be pre-thymic hematopoietic progenitor cells or thymic stroma, and not thymocytes.
Presenting author: Laura Napolitano, Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA, 94141-9100, United States, Tel.:
[phone], Fax: [phone], E-mail: [email protected]
ThPpA2127 Genetic determinants of immune restoration
diseases in HIV-1 patients receiving highly active
anti-retroviral therapy
P. Price'1, G. Morahan2, L. Abraham3, M.A. French'. 'Department of Clinical
Immunology, Royal Perth Hospital and the Department of Pathology, University
of Western Australia, Department of Clinical Immunology Royal Perth Hospital,
Wellington Street, Perth WA 6000, Australia; 2Walter and Eliza Hall Institute,
Parkville, Australia; 3Department of Biochemistry, University of Western
Australia, Perth, Australia
Background: Immune Restoration Diseases (IRD) are immunopathological responses to pre-existing opportunistic infections in HIV patients who have responded to highly active anti-retroviral therapy (HAART). This study explores
whether polymorphisms in cytokine genes potentiate particular IRD. IRD included
atypical manifestations of cytomegalovirus retinitis (CMVR), and disease associated Mycobacterium avium complex, Mycobacterium tuberculosis, varicella zoster
virus (VZV), herpes simplex virus (HSV) or hepatitis C virus (HCV) infections.
Methods: Allele frequencies in IRD patients (n=50) were compared with patients
without clinical evidence of IRD who had <100 CD4 T-cells/[tl before HAART and
an increase of greater than four-fold or to >200 CD4 T-cells/[l (n=33).
Results: Homozygosity for the G allele at IL6-174 was more common (p=0.05)
and carriage of allele 2 at TNFA-308 was not seen amongst patients who had IRD
associated with Mycobacterium sp.
In contrast, no patients who experienced an IRD manifested as CMVR, HSV
encephalomyelitis or dermatomal zoster carried allele 2 of the 3'UTR of IL12p40, compared with 42-54% of patients who experienced Mycobacterium sp,
cutaneous HSV or HCV IRD. Approximately 70% of all subjects with TNFA308*2 carried BATi(introni0)*2 marking the Caucasian disease-associated
HLA-A1,B8,DR3 haplotype. However, most patients with CMVR or HSV encephalomyelitis IRD carry a HLA-A2, B44 haplotype which includes TNFA-308*2
without BATl(introni0)*2. Single nucleotide polymorphisms in the IL-12p40 promoter, IL-1A-889 and IL-1B+3953, and a polymorphic microsatellite in the CD30
gene promoter were not associated with any IRD.
Conclusions: These results suggest that cytoline production affects the pathogenesis of IRD and that distinct immunological mechanisms are responsible for
IRD associated with CMVR, VZV and mycobacterial infections.

Presenting author: Patricia Price, Department of Clinical Immunology, Royal
Perth Hospital, Wellington Street, Perth WA 6000, Australia, Tel.: [phone]
2899, Fax: [phone], E-mail: [email protected]