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

12th World AIDS Conference

Abstracts 21101-21105 259

277*/21101 HIV-1 subtypes differ in time to AIDS
Phyllis Kanki1, D. Hamel1, J.L. Sankale1, I. Thior1, R.G. Marlink1, M. Essex1,
S. Mboup2. Harvard AIDS Institute, 651 Huntington Ave Boston MA 02115, USA;
Cheikh Anta Diop University Dakar, Senegal
Background: The recognition of the different HIV-1 subtypes, have led many to
question whether properties of HIV-1 can be generalized among different subtypes. Much of our knowledge of HIV-1 pathogenesis comes from the developed
world, where HIV infection is almost exclusively due to subtype B. The vast
majority of new HIV infections worldwide are due to non-B subtypes.
Objective: To study the introduction and spread of HIV-1 subtypes infecting a
high risk population followed for 10 years. To evaluate time to AIDS in different
HIV-1 subtypes.
Methods: From 1985 to 1995, a prospective study of registered female sex
workers in Dakar, Senegal allowed the identification of HIV-1 seroconverters.
Uncultured PBMC DNA was subjected to PCR of the C2-V3 env region and
automated sequence analysis. Subtype assignment was based on phylogenetic
tree analysis with 1000 bootstrap resamplings.
Results: Over the 10 year period, 54 of 81 HIV-1 seroincident infections were
subtyped; 37 subtype A, 5 subtype C, 5 subtype D, 6 subtype G, and 1 recombinant A/G. In clinical follow-up, the AIDS-free survival curves were distinct by HIV
subtype (p value = 0.03). Subtype A was the predominant subtype (68%) with an
87% probability of AIDS-free time at 5 years post infection. Women infected with
a non-A subtype were -8 times more likely to develop AIDS compared to those
infected with subtype A (HR = 8.23; p = 0.009).
Conclusions: We have provided the first evidence that HIV-1 subtypes may
differ in their progression time to AIDS. Although subtype A may be the most
predominant and potentially most transmissible subtype in this region, it clearly
has a reduced ability to induce disease relative to non-A subtypes.
276*/21102 Control of HIV-1 proliferation and pathogenesis
with host factors in the hu-PBL-SCID mouse
system
Yuetsu Tanaka1, R. Tanaka2, Y. Kumazama2, Y. Koyanagi3, N. Yamamoto3.
ISchool Of Science, Kitasato Univ., Kanagawa; 2Kitasato Univ., Crest,
Sagamihara; 3 Tokyo Medical and Dental Univ., Tokyo, Japan
Objectives: To examine possible host factors involved in regulation of HIV-1
proliferation and pathogenesis in the hu-PBL-SCID mouse system
Design: prospective, controlled study.
Methods: C.B.-17 scid/scid mice depleted of NK cells were engrafted with
either normal human peripheral blood mononuclear cells (PBMC) or PBMC depleted of CD14' monocytes. After one week, they were infected i.p. with 1000
infectious units of either macrophage tropic- (M-) or T-cell line-tropic (TCL-) HIV-1,
and were sacrificed on day 7 after infection. HIV-1 proliferation was determined
by quantitation of plasma p24 and provirus copies in the mononuclear cells in the
peritoneal lavage (MPL). HIV-1 pathogenesis, the depletion of CD4+ T cells, was
determined by a flow cytometry of the MPL stained with specific mAbs.
Results: Depletion of CD14~ monocytes from the engrafted PBMC did not
affect the efficiency of engraftment of CD4+ T cells, but resulted in decrease
of the M-HIV-1 proliferation and pathogenesis. Administration of human IL-4 (1
ug/animal) and human IFN-y-neutralizing mAb (1 mg/animal) prior to HIV-1 infection enhanced the TCL-HIV-1 proliferation. Administration of 1 ml of 10-fold
concentrated culture supernatants of an HTLV-l-transformed CD4+ Th type-1 cell
line (#4) on days 1 and 3 after infection inhibited the proliferation and pathogenesis
of the M-tropic HIV-1 in three of five mice.
Conclusions: The present results indicate that CD14+ monocytes are required
for productive infection of M-HIV-1 in the hu-PBL-SCID mouse system. Host
factors including the Th type-regulating cytokines may play an important role in
determining proliferation and pathogenesis of the two types of HIV-1 in vivo. This
hu-PBL-SCID mouse system will be useful for in vivo evaluation of soluble factors
suppressing HIV-1.
S270*/21103 Limited CD4+ T-cell renewal as a mechanism for
CD4 lymphocyte depletion in HIV-1 infection
Sylvain Fleury1, R.J. de Boer2, G.P. Rizzardi1, K.C. Wolthers3, S.A. Otto3,
F. Miedema3, G. Pantaleo1. 1Lab. of AIDS Immunopathogenesis, Hdpital
Beaumont, 29 Avenue de Beaumont, Lausanne, Switzerland; 2Theoretical
Biology, Univ. of Utrecht, Utrecht; 3Dept. of Clinical Viro-lmmunology,
Amsterdam, The Netherlands
Objectives: To investigate the turnover of CD4+ and CD8+ T lymphocytes, the
number of cycling T cells freshly isolated from both blood and lymph nodes was
determined. It has been postulated that the turnover of CD4' T lymphocytes
(about 109 cells/day) is highly increased in HIV-infected subjects. However, this
result was extrapolated from T cell counts in the blood, which represent only 2%
of the total body lymphocytes.
Design: Analysis of T lymphocytes turnover in blood and lymph nodes of

HIV-negative and HIV-infected subjects.
Methods: CD4 and CD8 lymphocytes were freshly isolated from blood and
lymph node of HIV-negative (n = 8) and HIV-infected (n = 22) subjects. The
HIV-infected subjects had CD4 T cell counts above 300/mm3 and were 'naive' to
antiviral therapy. Turnover of CD4 and CD8 lymphocytes was estimated by the
analysis of the expression of the nuclear antigen Ki67 by FACS. Genomic DNA

was extracted from sorted CD4 and CD8 cells from blood and lymph nodes and
telomere length was determined.
Results: We found that the average total number of CD4'Ki67" cells (i.e.
proliferating cells) is reduced by about two-fold in HIV-infected subjects (6.54 x
108 in HIV-infected versus 1.29 x 109 in HIV-negative subjects), whereas the
average total number of CD8+Ki67+ lymphocytes was 6 to 7 fold higher in HIVinfected subjects (7.2 x 108 in HIV-infected versus 1.07 x 108 in HIV-negative
subjects). Furthermore, telomere length of peripheral blood CD4' and CD8' T
cells is shorter compared to those from lymph node.
Conclusion: These results provide strong evidence that the progressive decline of CD4+ T lymphocytes observed in HIV-infected subjects is primarily the
consequence of a limited renewal rather than an increased destruction.
21104 Perturbations in the CD4+ TCR V/ repertoire indicate fast
progression to disease in SIV infection
Raflick-Pierre Sekaly1, M.D. Salha2, A. Yachou2, N. Beausoleil3, J. Fournier3,
E. Rud4. 1110 Pine Avenue, West Montreal, Montreal; 2lmmunology, IRCM,
Montreal, QC; 3Animal Resource Division, Ottawa; 4National Lab HIV
Pathogenesis Health Canada, Ottawa, ON, Canada
Objectives: To investigate whether viral load is important in modulating the TCR
repertoire during primary infection.
Methods: We studied the occurrence of perturbations in the TCR VI repertoire
of CD4 and CD8 T cells in SIV-infected cynomolgus macaques during primary
infection. We used four different strains of SIV: a wild type SIVmac32H(J5) and
a Nef deficient strain SIVmac32H(C8) which confers a low viral load in infected
individuals, SIV-PBj14-6.6sm and SHIV89.6P which both causes a rapid dramatic
drop in CD4+ T cell number and in the case of PBj14 induces disease within 2
weeks of infection. Each group was comprised of four macaques including a non
infected group. The V/ repertoire was typed by flow cytometry, the CD4 absolute
count was determined and the viral load was evaluated by a bDNA assay.
Results: The CD8 compartment of all SIV infected macaques showed
transient yet different expansions in a restricted number of V/ families during
primary infection. In the CD4 compartment transient perturbations affecting a
large panel of TCR V/Is were clearly observed in a J5 as well as PBj14 and
SHIV-infected macaques who quickly progressed to AIDS. The perturbations
occur not only during primary infection but also at late stages of the disease
subsequent to increases in viremia. In contrast, in the J5 or PBj14 macaques with
stable CD4 counts or in C8-infected macaques little if no perturbations in the CD4
compartment were observed. These results suggest that the magnitude of the
viremia has a major impact on the TCR repertoire, as well as host factors since a
heterogeneity in the type of response generated is observed within each group.
Conclusion: Results suggest that both host factors and viral factors are important for the prognosis of the disease. They also indicate that CD4 perturbations
in the CD4 repertoire are a strong indication of disease progression.
21105 Infection with different HIV-1 subtypes (B or C) result in
similar immune activation, progression and response to
treatment
Zvi Bentwich1, A. Kalinkovich1, Z. Weisman', R. Burstein1, M. Podolyako1,
N. Galai2. 'AIDS Centre Kaplan Medical Centre 76100 Rehovot; 2Ben Gurion
University Beer-Sheva, Israel
Objective: Compare the immune profile, viral load, disease progression and
response to treatment, between Ethiopian immigrants in Israel (ETH) infected
with African HIV-1 subtype C and non-Ethiopian Israelis (ISR) infected with HIV-1
subtype B.
Methods: Two open cohorts of ETH (N = 71) and ISR (N = 91), followed in the
same center and stratified for CD4 levels, were studied. Changes in peripheral
blood T-cell subsets were determined over six years and estimated using a two
segment regression model. T-cell activation markers were determined by flow
cytometry. IL-2, IFNy, IL-12, IL-4, IL-10, and sTNF-R secretion were determined
in supernatants of PHA or SAC-stimulated PBMC by ELISA. Chemokine secretion
by CD8 cells stimulated by PHA + PMA, was determined by ELISA. Plasma viral
load was determined by NASBA before and after HAART.
Results: Longitudinal changes of CD4 and CD8 T-cell subsets in the two
cohorts, with analysis done overall or stratified by initial CD4, were similar during follow-up. Progression to AIDS from given CD4 categories was also similar
although the spectrum of diagnoses was different in the two categories. No significant difference was found in the correlation of plasma viral load to CD4 levels.
Response to antiretroviral treatment and HAART was similar, and resulted in
comparable decrease in viral load and rise in CD4 level. In both groups we also
found: 1) similar T-cell activation profile, and cytokine and chemokine secretion;
2) similar increase in CD4+ and CD8+HLA-DR+, and decrease in naive and
CD8+CD28+ cells. Higher levels of IL-4 secretion and serum IgE were found in
the ETH cohort.
Conclusions: Individuals infected with either HIV-1 subtype C or subtype B, do
not differ in their immune activation profile, rate of disease progression, plasma

viral load and response to treatment, once living in the same environment. These
findings suggest that penetration and spread of HIV-1 subtype C into Western
environments is not likely to change the natural course of the infection there.