Program Supplement [International Conference on AIDS (14th: 2002: Barcelona, Spain)]

huge numbers of infected CD4 lymphocytes. The potential
importance of this antigen presentation mechanism in the
generation of an effective immune response during HIV
infection will be discussed.
Corresponding author: Marafi6n, Concepci6n, Institut Cochin,
Dpartement d'lmmunologie, 27, rue du Fbg St-Jacques, 75014
Paris, France, Tel: [phone], Fax: [phone],
Email: [email protected]
LBPEA9007]
L-87o,81o: A potent antiviral HIV integrase inhibitor with
potential clinical utility
Young, Steven, and The HIV Integrase Inhibitor Discovery Team
(United States)
Current therapies available for treatment of HIV infection target
only two of the three constitutive viral enzymes required for
replication, namely the reverse transcriptase and protease. The
third enzyme, HIV-1 integrase, is an attractive target for
chemotherapeutic intervention in the treatment of AIDS in large
part due to the absence of viruses harboring resistance to yet
unknown integrase inhibitors. Unlike the reverse transcriptase
and protease enzymes, successful drug candidates based on
inhibition of integrase have yet to emerge. Previously, we
disclosed a series of integrase inhibitors discovered through
screening that have anti-replicative activity in cell culture. These
leads come from a single class of molecules: 4-aryl-2,4 -diketobutanoic acids (DKAs). While optimization of these leads
produced DKA compounds with promising antiviral activity,
concerns about their metabolic reactivity caused us to seek
alternatives for the DKA pharmacophore. Replacement of
critical elements of the pharmacophore led to a novel,
metabolically stable series of heterocyclic compounds. These
compounds are potent inhibitors of HIV-1i integrase strand
transfer functionality. In cell culture the antiviral activity of
these agents against wild type virus is similar to that of the
more potent approved antiretroviral drugs. The antiviral activity
of these compounds is undiminished against a variety of
diverse clades and viral variants expressing significant
resistance to all of the currently available licensed HIV-1i
inhibitors, including PIs, NRTIs and NNRTIs. The leading
compound, L-87o,81o, has good pharmacokinetics in rats, dogs
and rhesus macaques. Its absolute oral bioavailability and halflife in these species, along with its stability in isolated human
hepatocytes, suggests a high potential for good
pharmacokinetics in humans. Following preliminary safety
assessment studies, this compound has moved into Phase I
clinical trials for evaluation in healthy volunteers.
Corresponding author: Young, Steven, Dept of Medicinal
Chemistry, Merck & Co. WP14-3, West Point, Pennsylvania,
19486, United States, Tel: [phone],
Fax: +i 215 652 3971, Email: [email protected]
[LBPEA9008
Non-B dade strains of HIV-1 cause rapid CD4+ lymphocyte
depletion and higher levels of viremia in hu-PBL-SCID mice
K'Aluoch, Okumu, Sheppard, Haynes, Krowka, john
(United States)
Background: Some studies have suggested that in comparison
to clade B strains of HIV-1, the clade A and C are more
pathogenic in humans. This is reflected in the high morbidity
and mortality in areas with these non-B clades. However,

differences in the study populations have made this
hypothesis difficult to confirm. The goal of this study is to
compare the rates of CD4+ lymphocyte depletion and viremia
in Severe Combined Immune Deficient (SCID) mice that have
been reconstituted with normal human peripheral blood
lymphocytes (PBL).
Methods: Non-obese diabetic (NOD) SCID mice were
inoculated intraperitoneally with 2-3 X 1o7 normal human PBL
to create hu-PBL-SCID mice. At approximately 30 days after
reconstitution with same donor PBL, mice with detectable
CD4+ cells were infected with different HIV-1i clades. B clade
isolates derived from slow or rapid progressors in the San
Francisco Men's Health Study were compared against each
other and also against clade A or C isolates or uninfected
controls. At 12 days post infection blood and plasma were
analysed for levels of CD4+ lymphocytes by flow cytometry and
for HIV-1 RNA levels using the Roche Amplicor vi.5 assay.
Results: The hu-PBL-SCID mice infected with clade B isolates
from rapid and slow progressors were not significantly different
from each other in terms of CD4+ lymphocyte depletion (p =
0.7161, Mann-Whitney test). In contrast the hu-PBL-SCID mice
that were infected with non-B (A and C) clade isolates showed
significantly more rapid depletion of CD4+ lymphocytes (p <
o.oool) and higher levels of plasma HIV-1 RNA (p <o0.05) at 12
days post infection in comparison to cade B infected mice.
Conclusions: The significantly more rapid depletion of CD4+
lymphocytes and higher levels of plasma HIV-1 RNA in hu-PBLSCID mice infected with A- and C-clade HIV-1 isolates in
comparison to B-clade-infected mice are consistent with the
hypothesis that non-B clade HIV-1 strains may be more
pathogenic in humans.
Corresponding author: Sheppard, Haynes, Viral and Rickettsial
Disease Laboratory, California Department of Health Services,
850 Marina Bay Parkway, Richmond, CA, United States,
Tel: [phone], Fax: [phone]ol,
Email: [email protected]
[LBPEA9009
Cross reactive HIV-1 clade B cytotoxic T lymphocytes in
patients infected with HIV-i subtype A/G (CRFo2), in Abidjan,
Ivory Coast (West Africa)
Inwoley, Andr&l, Recordon, Patricia2, Minga, Albert', Gaston,
Jessintha2, Dupuis, marion2, Fleury, Herv62, Rouet,
Frangoisl, Guillet, jean-Gdrard2, Andrieu, Muriel2,
The Primo-CI group,2 (1C6te d'lvoire; 2France)
Background: The great variability of protein sequences from
HIV-1 may represent a major obstacle to the development of an
effective vaccine against the virus. In this study we evaluate
the impact of variability among different HIV-1 clades on CD8 T
recognition. We analysed whether CD8 T cells from Ivorian
patients infected with viruses belonging to clade A/G were
able to recognize clade B epitopes; as control we used French
individuals infected with clade B viruses.
Methods: Fresh whole blood samples were collected from 9
Ivorians of the PRIMOCI cohort infected with HIV-1 CRFo2-AG
subtype. CD8 T lymphocyte responses against 11o HIV-1 clade
B peptides that are well defined CTL epitopes (in Nef, Gag, RT
and Env regions) and pooled by lo, were measured by Elispot
IFN,,. We thereafter determined the H LA-A and -B types of the
patients and individual peptides recognized by each patient
were identified. We also sequenced rt, gag and nef genes of
the these patients in order to identify if there were variations
in the epitope sequences.

Program Supplement