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

778 Abstracts 41179-41183

12th World AIDS Conference

Conclusion: The ability of triple combination therapy during asymptomatic HIVinfection to partially reverse disease-induced peripheral blood T-cell activation
and maturation abnormalities supports the proposal that therapeutic advantage
is gained by early commencement of highly active anti-retroviral therapy.
41179 Dynamics of CD4+ T cell recovery in a large cohort
treated with highly active antiretroviral therapies at
advanced stages of HIV disease
Marc Renaud1, H.M. Ait2, C. Katlama2, V. Calvez3, A. Mallet4, P. Debre1,
B. Autran1. 1Lab. Immunologie Cellulaire et Tissulaire 83, Bid de I'Hopital
Pitie-Salpetriere Bat. Cervi 75013 Paris; 2Department des maladies infectieuses
et tropicales Pitie-Salpetriere Paris; 3Service de virologie, Hopital
Pitie-Salpetriere; 4INSERM Unitd 194 Service de Biomathematiques CHU
Pitie-Salpetriere Paris, France
Background: Combined anti retroviral therapies with protease inhibitor (PI) allow
significant increase of CD4+ T cell counts but long term reconstitution in large
cohorts of severely immunosuppressed patients remains unknown.
Methods: In 1996, 303 patients at very advanced stages were enrolled in a
monocentric prospective study. Prior to entry, all patients were treated with two
RT-inhibitors to which PI was added at initiation of the study. Median baseline
CD4+ and CD8+ T cell counts and viral load were 51/mm3, 541/mm3 and 5.09
log RNA copies/ml respectively. Median duration of follow-up was 566 days.
Results: At 12 months (245 evaluable patients) CD4+ T cell counts and viral
load were 161/mm3 and 3.18 log copies/ml respectively. At 18 months (161
patients), median CD4+ T cell counts reached 194/mm3. Two phases in CD4+ T
cell reconstitution can be described: (1) a high speed phase during the first two
months followed (2) by a slower increase between M2 and M12 with a CD4+ T
cell counts rise of 0.168/mm3/d (~0.24) sustained until M18. Interestingly, such
second phase CD4+ T cell slope was similar in all patients when stratified according to their baseline CD4+ T cell counts. A lower delta CD4 count (<50/mm3)
was observed in 27% of the patients at M12 but only in 19% at M18. Finally,
a paradoxical evolution occurred in 13% of the patients in whom a minor delta
CD4+ T cell count (<50/mm3) contrasted with a significant viral load reduction (<
-1 log copies/ml) at 12 months.
Conclusions: Combined anti retroviral regimens allow a significant and sustained increase of CD4+ T cell over the 18 months study period in 80% of severely
immunosupressed pretreated HIV infected patients. The long term slope of CD4
recovery appears to be independent of baseline CD4 cell counts.
41180 1 Long-term suppression of HIV with a simple, non-toxic,
inexpensive combination of didanosine plus
hydroxyurea
Elena Seminari1, R. Maserati1, F. Lori2, F. Alberici1, J. Lisziewicz3. 1Pavia
"Policlinico S. Matteo" Institute of Infectious Diseases Via Taramelli 5;
2Right-Policlinico S. Matteo Pavia, Italy; 3Right-Georgetown University
Washington DC, USA
Background: The recent findings that HIV can be recovered from resting T-lymphocytes after long combination therapies including protease inhibitors indicate
that a chronic treatment might be necessary.
Methods: Twelve out of 40 pts. previously randomized to receive didanosine
+ hydroxyurea (respectively 400 mg and 1,000 mg daily), are still on treatment
and were included in a long-term analysis. Basal values were: CD4+ (cell/mcL)
277-493 - median 376; pVL (HIV copies/mL) 602-199,256 - median 20,422.
Results: The mean treatment duration was 28 mos (24-36, median 28 mos.).
In 11 cases pVL became undetectable and remained below the detection limit for
a mean time of 14 mos (6-26 mos). PVL declined to undetectable level within 1
to 29 mos (median 12 mos) after starting the therapy. Median CD4+ cell count at
the last follow up visit was 405 cell/mcL. No major adverse events were recorded
and therapy was well tolerated.
Conclusions: Plasma viremia decreased progressively in our pts and an unusual long time was required to reach undetectable levels. A sustained and
prolonged suppression of pVL can be achieved in asymptomatic HIV-positive
subjects using a relatively simple combination of two drugs that are inexpensive
and well tolerated.
553*/41181 S-1153, a new nonnucleoside reverse transcriptase
inhibitor of HIV-1
Tamio Fujiwara1, A. Sato2, M. EI-Farrash2, Y. Wu33, L. Chen4, M. Hatanaka2,
Y. Hinuma2. 1Shionogi Institute for Medical Science 2-5-1 Mishima Settsu-Shi
566; 2Shionogi Research Laboratories Osaka; 3Shinogi Bioresearch Corp.
Lexington MA; 4Dana-Farber Cancer Institute, Harvard Medical School Boston
MA, Japan
Objectives: To compare in vitro anti-HIV activity and resistance pattern of a new
nonnucleoside reverse transcriptase inhibitor (NNRTI, S-1153 which was selected

by using known NNRTI resistant mutants, with those of known anti-HIV agents.
Methods: Anti-HIV activities of S-1153 and other anti-HIV agents were assayed
by inhibition of HIV-1 IIIB-induced cytopathic effect to MT-4 cells based on an
MTT assay. Assays using HIV-1 strains SF33, SF2, NL432 and various clinical
isolates were also conducted. S-1153 resistant variants were selected from HIV-1
IIIB clone 3/M8166 cells with gradual increase of S-1153 concentration. Various
amino acids substitutions were introduced in RT region of HIV-1 molecular clone

NL432 and sensitivity of these molecular clones to S-1153 and other anti-HIV
agents were compared.
Results: EC90 of S-1153, nevirapine and delavirdine were 5.9 nM, 170 nM and
68 nM in MTT assay. S-1153 was more potent than various nucleoside analogues
or protease inhibitors, and active against known anti-HIV agent resistant strains.
One month or more cultivation was necessary to isolate variants 100 times or
more resistant to S-1153 compared to about one week for nevirapine resistant
variants. Genotypic analyses of these variants revealed that two or three amino
acids substitutions including F227L or L2341 were involved for S-1153 resistance.
Consistently, assay using various molecular clones having single amino acid
substitution showed not more than 20 times resistant to S-1153. Important observation was that combination of S-1153 resistant L2341 with AZT resistant T215Y
became sensitive to both S-1153 and AZT to the level of parental strain.
Conclusion: S-1153 is a highly potent new NNRTI which overcome previous
problems of NNRTIs such as cross resistance and easy emergence of resistant
variants. S-1153 may be an appropriate candidate for two- to three-drug combination therapy for infection. Clinical trials with promising results will be presented
separately in the conference.
S41182 Specific inhibition of T-lymphocyte- and
macrophage-tropic HIV entry by a V3 loop mimicking
pseudopeptide that binds cell-surface proteins
Nabila Seddiki1, E. Dam1, S. Nisole1, C. Callebaut1, B. Krust1, J.P. Briand2,
A.G. Hovanessian1. 1nstitut Pasteur Unite V.I.C. 28, Rue du Dr. Roux 75724,
Paris, Cedex 15; 2IBMC CNRS, Strasbourg, France
Objectives: The specific and potent anti-HIV effect of the pseudopeptide
5[KtPR]-TASP.
Background: The V3 loop mimicking pseudopeptide TASP binds protein components on the cell surface and inhibits HIV infection (Virology 218, 181, 1996; J.
Biol. Chem. 272, 7159, 1997). Indeed, TASP blocks the binding of HIV particles
to CD4+ cells, as it is the case with neutralizing antibodies specific for the V3 loop
or the CD4 receptor (J. Virol. 71, 8289, 1997). Further work has shown that TASP
binds nucleolin, PHAP II, and PHAP I which serve as V3 loop binding proteins.
Methods: Two types of CXCR4+ HeLa cells harboring the bacterial lacZ gene
under the control of the HIV-1 LTR and also expressing recombinant CD4 or
CD4/CCR5 were used. HIV entry and replication was then monitored by measuring the beta-galactosidase activity at 24 and 48 hours. Infection of PHA-activated
PBMC and primary macrophage cultures were as described before.
Results: The pseudopeptide TASP inhibited viral entry in HeLa cells infected
either with different T lymphocyte- and macrophage-tropic HIV-1 and HIV-2 isolates. TASP had no effect on SIVmac and on the HIV-1 pseudotype expressing
VSV envelope glycoproteins, thus indicating that it is specific to the HIV envelope glycoproteins. In PBMC, TASP inhibited infection by primary syncytium- or
non-syncytium-inducing HIV-1 isolates and also by well characterized laboratory
isolates. In primary macrophage cultures infected by HIV-1 Ba-L, the peak of
virus production at 9 days p.i. was inhibited by more than 90% at 1 micro-M of
TASP. In both HeLa and PBMC, TASP inhibited infection by anti-HIV drug resistant viral isolates. Interestingly, the chemokines RANTES, MIP-1 alpha and beta
had no significant effect on infection of HeLa cells by macrophage-tropic HIV-1
Ba-L isolate. However, these same chemokines inhibited HIV-1 Ba-L infection in
PBMC cultures. Furthermore, association of low doses of chemokines and TASP
resulted in a synergistic effect on HIV-1 Ba-L infection in PBMC.
Conclusion: Here we show that TASP is a potent inhibitor of infection of cells
by T lymphocyte and macrophage tropic HIV-1, HIV-2, primary HIV-1, and antiHIV drug resistant isolates. In view of this potent and specific anti-HIV activity,
its stability in serum, and its distinct mode of action, the pseudopeptide TASP
represents a potential anti-HIV drug to be used in AIDS patients.
41183 Anti-HIV activity of AMD3465, a novel antagonist of the
CXCR4 receptor
JosbA. Este1, C. Cabrera1, G. Henson2, B. Clotet1, G. Bridger2, D. Schols3,
E. De Clerco3. 1 rsi-Caixa, Badalona, Spain; 2Anormed, Langley, BC, Canada;
3Rega Institute, Kuleuven, Lueven, Belgium
The discovery of chemokine receptors as entry cofactors for the human immunodeficiency virus (HIV) has prompted the interest on new compounds that
inhibit virus-chemokine receptor interaction. A new tetraazamacrocycle compound, AMD3465, is a potent anti-HIV agent with a 50% inhibitory concentration
(IC50) of 1-10 ng/ml for HIV-1 strains such as IIIB, NL4-3, RF and HE, 30 ng/ml for
HIV-2 ROD and EHO, and a 50% cytotoxic concentration (CC5o) higher than 250
tpg/ml. AMD3465 acts at an early step of virus replication. However, it does not
inhibit virus binding to the CD4 receptor. AMD3465 inhibits the binding of 12G5
(IC5o 1 ng/ml), a specific anti-CXCR4 monoclonal antibody, which has anti-HIV
activity and inhibits the intracellular Ca2+ flux induced by the chemokine SDF-lI
(IC50 1 ng/ml), the natural ligand of CXCR4, suggesting that the antiviral activity
of AMD3465 is due to its interaction with the CXCR4 receptor. Resistance to
AMD3465 is associated with the emergence of mutations in the viral envelope

glycoprotein gp120, the putative viral component involved in the interaction of HIV
with the chemokine receptors. Replication of an AMD3465-resistant strain was
no longer inhibited by SDF-la, thus confirming the interaction of AMD3465 with
CXCR4. AMD3465 differs from the bicyclam AMD3100, a compound previously
reported as anti-HIV inhibitor through antagonism to CXCR4 in that only contains
one cyclam ring and a pyrimidine moiety linked through a phenyl bridge. Furthermore, AMD3465 was 10-fold more potent than AMD3100 in its capacity to inhibit