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

XIV International AIDS Conference

Abstracts ThPeA7107-ThPeA7110 361

different anatomic distribution between HIV- and CMV-specific memory CD8 and
CD4 T cells.
Presenting author: Kim Ellefsen, lab of AIDS Immunopathogenesis, Hopital
Beaumont-CHUV, 29 Av. Beaumont, Lausanne, Switzerland, Tel.: [phone],
Fax: [phone], E-mail: [email protected]
ThPeA7107 Skewed differentiation of HIV-specific CD4 memory
effector T cells
A. Harari, S. Petitpierre, M. Khonkarly, G.P. Rizzardi, G. Pantaleo. Lab of AIDS
Immunopathogenesis, Laboratory of AIDS Immunopathogenesis, Hopital
Beaumont-CHUV, 29 Av. Beaumont, 1011 Lausanne, Switzerland
Background: Four subsets of memory CD8 T lymphocytes can be distinguished
on the basis of the expression of CD45RA and of CCR7. Selective impairment of
the differentiation of HIV-specific memory CD8 T cells has been shown
Methods: The secretion of IFNg and of 11-2 following specific stimulation was used
to identify HIV- and CMV-specific CD4 T cells. Peripheral blood mononuclear cells
(PBMC) of 7 HIV-infected subjects with no previous ART, of 6 LTNP and of 7 HIVnegative donors were stimulated with HIV (p55) and/or Cytomegalovirus (CMV)
antigens and stained with mAbs to CD4, CCR7, CD45RA, IFNg and 11-2
Results: HIV- and/or CMV-specific IFNg-secreting (effector) cells were detected
in all individuals. In the HIV-negative donors (n=7), the proportion of CMV-specific
effector CD4 cells was similar in the pre-terminally and in the terminally differentiated subsets (CD45RA-CCR7- cells 0.69% vs CD45RA+CCR7- cells 0.44%, P =
0.49). In contrast, in the HIV-infected patients with progressive disease (n=7) the
majority (90%) of HIV-specific CD4 effector cells were mostly contained in the preterminally compared to the terminally differentiated (0.54% vs 0.04%, P=0.001)
cell population. Of interest, the distribution of HIV-specific effector CD4 T cells
in the LTNP (n=6) was very similar to that of CMV-specific effector CD4 T cells
(CD45RA-CCR7- cells 0.72% vs CD45RA+CCR7- cells 0.43%, P=0.24). Of note,
CMV-induced lymphoproliferation and 11-2 secretion were consistently found in all
three groups (all p> 0.2 and 0.05 respectively) but HIV-induced lymphoproliferation and 11-2 secretion were only found in LTNP and not in HIV-infected patients
with progressive disease (P=0.0004 and P=0.01 respectively)
Conclusions: These results demonstrate a substantial difference in the differentiation of HIV-specific compared to CMV-specific memory effector CD4 T cells
which is strongly correlated to the CD4 helper function and a selective IL-2 defect
in the HIV-specific memory CD4 T cells
Presenting author: Alexandre Harari, Laboratory of AIDS Immunopathogenesis,
Hopital Beaumont-CHUV, 29 Av. Beaumont, 1011 Lausanne, Switzerland, Tel.:
[phone], Fax: [phone], E-mail: [email protected]
ThPeA7108 I High Levels of Antibodies to the CD4 Binding
Domain of HIV-1 gpl120 Are Associated with Faster
Disease Progression
P.C. Chien', S. Cohen', C. Kleeberger2, J. Giorgi3, J. Phair4, S. Zolla-Pazner',
C.E. Hioe'. 'New York University School of Medicine and VA New York Harbor
Healthcare System, 423 E 23rd St, Rm 18-124N, New York, NY 10010, United
States; 2Johns Hopkins School of Public Health, Baltimore, United States;
3 UCLA School of Medicine, Los Angeles, United States; 4Northwestern
University Medical School, Chicago, United States
Background: HIV-specific T helper (Th) responses are considered critical for
controlling HIV viremia and disease progression, yet virus-specific Th responses,
particularly to gpl20, are weak or absent in most HIV+ individuals. We have
shown that antibodies (Abs) specific for the CD4 binding domain of gpl120
(CD4bd), when complexed with gpl120, prevent the gpl120 processing necessary
for presentation to gpl120-specific Th cells. Thus, we postulate that high levels of
anti-CD4bd Abs promote HIV pathogenesis.
Methods: To examine the role of anti-CD4bd Abs in HIV disease progression, we
compared the levels of anti-CD4bd Abs in the sera of 14 matched pairs of HIV+
rapid progressors (RPs) and slow progressors (SPs) from the Multicenter AIDS
Cohort Study.
Results: Prior to AIDS, anti-CD4bd Ab levels were higher in the sera of RPs than
in SPs. In contrast, Ab titers to whole gp1 20 and to the CS domain of gp1 20 were
not significantly different. These data indicate that the higher levels of anti-CD4bd
Abs detected in the RPs' sera are a distinct phenomenon and do not reflect a generalized increase in the Ab levels to whole gp1 20. The results also suggest that
prior to AIDS, anti-CD4bd Abs may be over-represented in the overall anti-gp12O
humoral response of the RPs. Moreover, serum anti-CD4bd Ab levels correlated
with the level of reduction in gp1 20-specific CD4 T cell proliferation seen in the
presence of the IgG fraction of sera from RPs and SPs.
Conclusions: Our findings document a novel mechanism of HIV pathogenesis
mediated by anti-CD4bd Abs, namely, that these Abs suppress gpl20 presentation to CD4 T cells, thereby blunting anti-HIV Th responses. Hence, the presence
of high levels of anti-CD4bd Abs during infection may contribute to disease pro
gression. Moreover, induction of anti-CD4bd Abs by vaccines may not be beneficial but rather detrimental to the induction of immune responses that these
vaccines are designed to elicit.
Presenting author: Peter Chien, 423 E 23rd St, Rm 18-124N, New York,
NY 10010, United States, Tel.: [phone], Fax: [phone], E-mail:
chienp01 @med.nyu.edu

ThPeA7109 IT-cell Phenotypes and Thymic Volumes in older
and younger HIV-infected and uninfected persons
to explore mechanisms of accelerated HIV-disease
progression with age: Baseline analysis of ACTG
5015 and 5113
R. Kalayjian', A. Landay2, B. Gross3, R. Pollard', A. Sevin5, M. Pu5,
M. Chernoff5, A. Namkung6, L. Fox7, J. Janik8, K. Waterman9, S. Fiscus10,
A. Wu1, E. Lawrence12, S. Slater3, D. Longo3, D. Taub3, F Rousseau4
M.M. Lederman'. 1CWRU, Division ofInfectious Diseases, Cleveland, OH,
United States; 2Rush-Presbyterian-St. Lukes, Chicago, United States; 3U
Michigan, Ann Arbor, United States; 4UC Davis, Sacramento, United States;
5Harvard U, Boston, United States; 6ACTG Operations Ctr, Rockville, United
States; 7Division of AIDS, NIAID, Bethesda, United States; 8Frontier Science,
Amherst, United States; 9 U Texas, Galveston, United States; 10UNC, Chapel Hill,
United States; 1'Johns Hopkins U, Baltimore, United States; 12AACTG-CCG,
Redbud, United States; 13NIA, Bethesda, United States; 14Triangle, Durham,
United States
Background: To explore the basis of age-associated, accelerated HIV-disease
progression by examining differences in T-cell phenotypes and thymic volumes in
younger and older subjects.
Methods: ACTG 5015 is a study of immune and virologic differences in response to HAART, between 2 cohorts of HIV-infected (HIVpos) subjects, <30yrs
(Y) and >45yrs (0), with < 600 CD4 cells/p L and who were naive to therapy.
Age-matched, HIV-uninfected (HIVneg), healthy volunteers were controls (ACTG
5113). Differences in T-cell phenotypes and CT scans of thymus (graded 0-5)
were analyzed by two-sided Wilcoxon rank sum tests.
Results: Sample size and med age for each cohort, respectively, were HIVpos/O: 27, 50yrs; HIVpos/Y: 28, 26 yrs; HIVneg/O: 24, 49yrs; HIVneg/Y:24, 25yrs.
Among HIVpos subjects, older age was significantly associated with lower %naive
and higher %memory phenotypes, higher %CD95 and lower %CD28 expression
on both CD4 and CD8 cells. Age was not significantly associated with %HLADR/CD38 expression on CD4 or CD8 cells. Among HIVneg subjects, similar but
non-significant age-associated differences were observed in %naive and %memory phenotypes and in %CD95 expression on both CD4 and CD8 cells and
%CD28 expression on CD8 cells.
HIVpos/O HIVpos/Y HIVneg/O HIVneg/O
CD4 tot 15 23 51 44
CD4 naive 21 36 44 49
CD4/CD95 88 72 60 55
CD4/CD28 83 93 100 99
CD8 tot 59 51 22 26
CD8 naive 18 27 46 56
CD8/CD95 95 87 68 56
CD8/CD28 21 32 55 66
Thymic volumes were significantly greater in HIVneg/Y than in HIVpos/Y and between Y and O in both HIVpos and HIVneg cohorts, but were comparable in older
HIVneg and HIV/pos.
Conclusion: HIV infection may heighten the immunologic phenotypic perturbations seen in older healthy persons and this may include accelerated thymic involution in younger subjects.
Presenting author: Robert Kalayjian, Division of Infectious Diseases, 2500
MetroHealth Dr, Cleveland, OH, 44109-1998, United States, Tel.: [phone], Fax: [phone], E-mail: rkalayjian @ metrohealth.org
ThPeA7110 Analysis of CTL responses in HIV-1 clade C
infected and exposed uninfected individuals from
Lusaka, Zambia
M.M. Addol, M. Altfeld', C. Fitzpatrick', A. Rathod', X.G. Yu', D.M. Brainard',
4Department of Pathology and Microbiology, University Teaching Hospital,
Lusaka, Zambia; 5 Departments of Medicine and Microbiology School of
Medicine, University of Alabama at Birmingham, Birmingham, United States
Background: HIV-1 clade C is the most prevalent subtype in sub-Saharan Africa,
which remains the most-affected region by the HIV pandemic. The aim of this
study was to investigate HIV-1 clade C specific cellular immune responses in
HIV-1 infected individuals and their exposed uninfected partners in a completely
blinded study.
Methods: 61 individuals (including HIV-infected individuals, their exposed, but
uninfected partners and negative control subjects) were recruited from the Zambia/University of Alabama Research project in Lusaka. Fresh PBMC from these
individuals were screened by IFN-g-Elispot assay for HIV-specific T cell re
sponses directed against HIV-1 clade C p17, p24, Rev, Tat and Nef in blinded
experiments. Results were confirmed by repeat Elispot and/or flow-based intracellular cytokine staining (ICS) both on the same sample and from a different time
point. In a subset of individuals ICS was performed both on fresh PBMC and after
a 10-day expansion with peptide pools. All experiments were completed before
unblinding.
Results: After unblinding of the study strong and broad CTL responses were
found in 18 of 18 HIV-1 infected individuals and none of 43 HIV-1 negative in