Bridging the Gap: Conference Record [Abstract book, International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

788 Abstracts 41229-41232

12th World AIDS Conference

Results: HAART +/- 11-2 lead to a rapid decay of actively replicating cells
and FDC-bound virions in LN which was paralleled by the decrease of plasma
viremia (4/8 pts. <25 RNA copies/ml at week 12). HIV-DNA positive T cells (%)
were slightly reduced in LN and more clearly in PB at week 4. At week 12 LN
and PB levels of HIV DNA+ cells were markedly reduced in all pts.; no significant
difference in the clearance rate of plasma virus and HIV DNA+ cells in LN and PB
was observed between the 11-2 group compared to HAART alone. Both therapies
lead to a substantial increase of the percentage of CD4+ T cells primarily of the
CD45RO phenotype in LN and PB. An elevated number of Ki-67+ proliferating T
cells was detected in LN suggesting true expansion of these cells. The fraction
of CD8+ T cells in cycle was clearly increased which returned to normal levels
during therapy. A down-regulation of activation markers on CD4+ and CD8+ T
cells and up-regulation of the CD28 molecule on CDS+ T cells was observed over
time which was more pronounced in 11-2 treated pts. The analysis of the TCR VB
VB repertoire revealed a polyclonal expansion of both memory- and naive-type
CD4+ and CD8+ T cells which was comparable in LN and PB.
Conclusions: HAART suppresses active HIV replication in LN and PB rapidly
and profoundly. Latently infected cells have a slower decay rate. Viral clearance
appears to be unaffected by additional 11-2 therapy. Both therapies lead to an
improvement of T cell phenotype distribution an turnover towards normal levels.
These effects seem to be augmented by adjuvant 11-2 therapy.
S41229 IL2 in HIV patients: A randomized trial comparing SC,
S PEG, CIV IL2 with AZT + ddl
Yves Levy1, C. Capitant2, S. Houhoul, I. Carriere2, J.A. Gaustaut3, J.P. Viardd,
J.P. Aboulker1. 1Hopital Henri Mondor 94010 Creteil; 2lnserm SC10 Villejuif;
3lnstitut Paoli Calnettes, France
Objectives: To evaluate the tolerance and immunological efficacy of three regimens of IL2 in antiretroviral treatment (AR) naive asymptomatic patients with
CD4 counts of 250-550 cells/mm3.
Methods: Patients were assigned to receive AZT+DDI alone (AR controls; n =
26) or combined with either SC-IL2 (3 MU/m2 bid for 5d on an outpatient basis; n
= 24), PEG-IL2 (1 IV bolus of 2 MU/m2; n = 22) or CIV-IL2 (12 MU/d for 5d; n =
22). IL2 cycles were administered every 8 weeks (7 cycles over 56 weeks).
Results: Baseline median CD4 cells, median CD4/CD8 ratio and mean HIVRNA (bDNA Chiron test) were 386/mm3, 0.41 and 4.3log10, respectively. The
mean doses given were: SC-IL2: 4.4 MU bid; PEG-IL2: 3.6 MU; CIV-IL2: 9.9
MU/d. The most frequent side effects were fever/chills for 11/24, 6/22 and 13/22
pts, respectively. 14 patients prematurely withdrew IL2 (SC-IL2 = 5/24, PEG-IL2
= 3/22, CIV-IL2 = 6/22). A peri-infusion transient increase in HIV-RNA (>0.5 log)
was observed in only 5.4% of the 241 administered SC and CIV-IL2 cycles. The
changes in immunological and virological parameters between baseline and week
56 were:

response and/or minimize side-effects for long-term tolerability. The immunologic
status of this cohort after month 6 has been monitored monthly.
Results: 39 patients elected to continue long-term therapy with intermittent
sclL-2. The current group means for this cohort are shown in the table.
Conclusions: Long-term treatment of HIV-infected outpatients with intermittent
sclL-2 therapy is well-tolerated. After initial induction with more intensive therapy,
dramatic increases in CD4 cell number can be sustained with comparatively
infrequent cycling.
59*/41231 Efficacy of aminooxypentane (AOP)-RANTES as
inhibitor of HIV-1 infectivity without impairment of
cellular proliferation
Stefano Rusconi1, M. Clerici2, S. Kurtagic3, S. La Seta-Catamancio3,
D. Arienti2, D. Trabattoni2, M. Galli3. Ilnfectious Disease Institute-Luigi Sacco
Hospital-via G.B. Grassi 74-Milan; 2Chair of Immunology-University of Milan,
Milan MI; 3 University of Milan, Milan, Italy
Objectives: The aim of the study was to investigate the anti-HIV-1 activity of the
CCR5 antagonist aminooxypentane (AOP)-RANTES on nonsyncytium-inducing
(NSI) HIV-1 isolates.
Methods: The AOP-RANTES compound (Gryphon Sciences, South San Francisco, CA) was diluted in Dulbecco-PBS medium and used at nontoxic concentrations (range 100-800 ng/ml) in peripheral blood mononuclear cells (PBMC).
Several different NSI clinical isolates and laboratory adapted strains of HIV-1
were used: 051f isolate was derived from an asymptomatic patient and grown in
monocyte/macrophages, Ba-L prototype of monocytotropic HIV-1, and JR-CSF
molecular clone of a monocytotropic HIV-1 isolate. The syncytium-inducing 14aPre
HIV-1 isolate was used as a control.
Experimental Design: Virus inhibitory assays with limited drug exposure were
conducted. Experiments were done to evaluate short exposures to AOP-RANTES
in PBMC. Three days after infection with HIV-1 and simultaneous drug exposure,
PBMC were centrifugated and supernatant fluid aspirated from pelleted cells.
Culture medium were added with either no drug or drug at nontoxic concentration. Uninfected drug-treated toxicity controls were run in parallel. Assays for cell
viability, proliferative capacity, and supernatant p24 antigen were performed at
baseline and after 3 and 6 days.
Results: All NSI viruses were effectively inhibited by nontoxic concentrations
of AOP-RANTES, whereas 14aPre replication was not influenced. The 50% inhibitory concentration of AOP-RANTES was demonstrated to be 320 ng/ml (4 nM)
with a sustained drug dose-response for all viruses. In limited drug exposure experiments, AOP-RANTES efficently inhibited viral replication in HIV-1 NSI strains,
with an average final output of 50-100 pg/ml of p24 antigen at the end of the
culture. A viral breakthrough was observed after the withdrawal of the compound
in selected conditions. The proliferative capacity was maintained in all condition
as compared to controls. Of note, we observed an increase in cell proliferative
capacity in infected conditions treated with AOP-RANTES. On the other hand,
cell proliferation decreased after drug removal.
Conclusion: These experiments confirmed that the chemokine receptor antagonist AOP-RANTES was effective as inhibitor of HIV-1 infectivity in NSI strains.
The capacity of the compound of maintaining the cellular proliferative activity
at nanomolar concentrations makes this compound an interesting candidate for
anti-HIV-1 therapy.
141232 Xenogeneic porcine thymic transplantation for the
treatment of AIDS
Boris Nikolic', K.S. Stanley2, M. Sykes'. 'Massachusetts General Hospital,
MGH-East BMT/TBRC, Bldg. 149-5012, 13th St., Boston, MA; 2NIAID, National
Institute of Health, Austin, TX, USA
Objectives: In addition to causing severe peripheral CD4+ T cell dysfunction
and depletion, HIV infects the thymus, causing destruction of thymic epithelium
and thymocytes. Thymic injury due to HIV infection, combined with the normal
post-pubertal thymic involution existing in many HIV-infected patients, could result
in a failure to generate new CD4' T cells to replace those that are destroyed in
the periphery, even with adequate retroviral suppression. In this study, we have
investigated whether swine thymus can support maturation of human T cells and
protect them from intrathymic HIV infection.
Methods: We co-transplanted porcine fetal thymus and human fetal liver
(SW/HU) under the kidney capsule of SCID mice. Control animals received human fetal thymus with human fetal liver (HU/HU) or porcine fetal thymus with
porcine fetal liver (SW/SW). We followed the appearance of human T cells in
the peripheral blood and analyzed their phenotypes by FACS, responses to
lectin stimulation, and polyclonality by RT-PCR. Alloreactivity, xenoreactivity and
tolerance toward porcine donor antigens were assessed by mixed lymphocyte
reactions. Chimeric animals were challenged with direct injection of a primary
HIV-1 isolate into the thymus grafts, and the level of HIV infection was measured
by semi-quantitative PCR and in situ hybridization.
Results: Reconstitution of polyclonal, functional human CD4~ and CD8' T cells

was observed in the peripheral lymphoid organs of SCID mice receiving porcine
fetal thymus grafts combined with human fetal liver tissue. These T cells were
specifically tolerant to MHC antigens of the porcine thymus donor, while being
responsive to non-donor porcine xenoantigens and to human alloantigens. After
HIV challenge, the HU/HU grafts (n = 8) were grossly T cell depleted and infected
with HIV. The SW/SW grafts (n = 7) appeared resistant to HIV infection, and did
not show gross evidence of T cell depletion. The SW/HU grafts (n = 7) showed at

Controls
Median CD4 cells/mm3
CD4 increase >80%
CD4/CD8 ratio >1
Mean bDNA (log10)
bDNA > 500 c/ml 12/19

SC-IL2
+55
2/22
2/22
-1.5
10/17

PEG-IL2
+564
17/22
11/22
-1.2
8/18

CIV-IL2 Global test
+105 +707
0/22 15/22
2/19 11/22
-1.2 -0.9
9/17 p > 0.50

p = 0.0001
p = 0.001
p = 0.001
p= 0.15

Conclusion: In patients with 250-550 CD4/mm3 SC and CIV-IL2 combined
with AZT+ddl resulted in a significant increase in CD4 count (>80% from baseline) in 68% and 77% of patients respectively without increase of viral replication
when compared to the AR control group. Moreover 50% patients receiving SC
and CIV-IL2 achieved a normal CD4/CD8 ratio. Results of immune restoration
will be presented.
344*/41230 Long-term follow-up of an early HIV-infected
cohort receiving intermittent outpatient treatment
with subcutaneous interleukin-2 (sclL-2)
Richard Davey, Jr., D.G. Chaitt, J.A. Kovacs, R.E. Walker, J. Falloon, M.A. Polls,
H.C. Lane. 1NIAID/NIH, Bldg. 10, Room 11C103, Bethesda, Maryland
20892-1880, USA
Background: Outpatient administration of sclL-2 in HIV-infected individuals has
been shown to be generally safe, well-tolerated, and capable of inducing marked
increases in CD4+ cells. However, the long-term effects of this therapy on immune
status have not been evaluated.
Methods: We conducted a randomized trial of the safety and efficacy of 5-day
cycles of either low-dose (1.5 MIU bid) or high-dose (7.5 MIU bid) sclL-2 either
every 4 or every 8 weeks in an initial cohort of 49 HIV-infected outpatients with
baseline CD4 counts 500 cells/mm3. After 6 months all patients were permitted to
adjust their dose and/or frequency of scIL -2 administration to optimize their CD4

Original treatment group
(current n):
CD4 (%) at mo. 0:
CD4 (%) at mo. 6:
Current Months on study:
Current CD4 count (%):
sclL-2 dose per injection:
Interval between cycles:

1.5 MIU bid
q4wk (9) q8wk (9)
704 (33%) 635 (29%)
798 (40%) 804 (34%)
25 mo. 21 mo.
1388 (49%) 1444 (44%)
5.3 MIU 5.8 MIU
9 mo. 7 mo.

q4wk (10)
621 (32%)
1371 (48%)
22 mo.
1433 (50%)
6.9 MIU
10 mo.

7.5 MIU bid
q8wk (11)
651 (31%)
1138(42%)
24 mo.
1205 (44%)
5.2 MIU
10 mo.

All (39)
653(31%)
1023(41%)
23 mo.
1361 (47%)
5.8 MIU
9 mo.