Abstracts Vol. 1 [International Conference on AIDS (11th: 1996: Vancouver, Canada)]

Tuesday, July 9, 1996

Tu.B.194 -Tu.B.292

from seven centres through the Canadian Pediatric AIDS Research (CPAR) Group. Plasma
was obtained from heparinized samples and stored in 1.0 ml aliquots at-70~ C. Plasma viral
load determinations were performed using the NASBA assay (Organon Teknica). Peripheral
blood mononuclear cells (PBMCs) were isolated and viral stocks generated from qualitative
co-cultures.These stocks were used for viral phenotype and standard ZDV resistance testing (ACTG consensus protocol). Quantitative micrococultures were set up in duplicate serial dilutions. 5 pM ZDV was added to one of the duplicates, with reduction in viral titres in
the presence of drug taken as a measure of drug susceptibilityThe drug-free control culture
was used to calculate cell- associated viral load.
Results: Data are available for 8 I children. Of 72 on which viral phenotype and drug resistance assays have been performed, there were 2 I (28%) with the SI phenotype and I 8
(25%) with high level ZDV resistance. Median cell-associated viral load was 125 TCID/106
PBMCs (range 0-1 5625). 12/62 (I 9%) children had titres > 125. Median plasma viremia was
25 000 copies/ml (range II 00-2400000) with 17/81 (21%) with loads above 100000
copies /ml. A strong correlation was observed between cell and plasma associated viral load
(r-0.4 I, p=0.002). No such correlation was present between any other measured parameters in multple pairwvise comparisons.
Conclusion: Our data suggests that, when constructing a composite virologic parameter of
clinical progression, plasma and cell-associated viral load should not be considered as independent variables. However, there is evidence to recommend including viral phenotype,
resistance and load as independent variables in this model. Our model will be further
refined in ongoing cross-sectional and prospective studies.
Christine Marshall, B.C. Centre for Excellence in HIV/AIDS 667-1081 Burrard St.,Vancouver,
BC V6Z I Y6, Canada Tel [phone] ext. 3179; Fax: [phone];
E-mail: [email protected]
Tu.B. 194
HIV EXPOSURE CATEGORY AND AGE IN THE PROGRESSION TO AIDS IN A STUDY
OF 1199 INDIVIDUALS WITH KNOWN SEROCONVERSION DATES.
Pezzotti p I, Phillips AN2, Dorrucci M, Cozzi Lepri A I, Galai N3,Vlahov D4, Rezza G. the
HIV ISS group. I Istituto Superiore di Sanita; 2Royal Free Hospital; 3The Hebrew University;
4The Johns Hopkins University.
Objective: To assess whether there are differences in the rate of development of AIDS
according to exposure category and whether the more rapid progression to AIDS for older
people holds for each exposure group.
Methods: Multicenter ( 6 major HIV treatment centers across Italy) longitudinal study of
1199 HIV-seroconverted individuals with a negative anti- HIV test less than two years prior
to the first positiv e test, who seroconverted between 1980 and 1 994 and were infected
through inj ecting drug use (695), homosexual (298), and heterosexual sex (206).The outcome measures were AIDS as defined by the 1987 CDC definition (including and excluding
neoplasms), and 1993 European definition.
Results: Two hundred twenty five individuals ( 8.8%) progressed to AIDS (CDC 1987 definition) after a mediran fol low-up of 5.8 years (range: 0.3- 14.3).The univariate analyses estimated a more rapid progression to AIDS for older individuals compared with younger individuals and for homosexual men compared with those in other exposure categories.The
age effect was of similar magnitude in each exposure group rand in men and women. In a
brari ate model with age and exposure groups included as covariates simultaneously differences by exposure groups disappeared [relative hazards (RH) 1.02 (95%Cl: 0.71-I.45), and
1.07 (95%CI: 0.70-1.64), respectively for injection drug users and heterosexuals compared
to homosexual men], while the age effect was still present (RH 1.55, 95%CI: 1.32-1.83 for
ten years increase). Analyses using the other AIDS definitions did not change the results
appreciably.
Conclusions: There is no evidence of differences in the rate of development of AIDS
between those in different exposure groups, while the strong tendency for more rapid progression in older people is similar across all three groups.This is consistent with the view
that external co-fictors do not play a major role in AIDS pathogenesis but that age is of
fundamental significance in the process.
Patrizio Pezzotti, Istituto Superiore di $anita,Viale Regina Elena 299, 00161 Rome, Italy
10 0 tel: (39) (6) 4990 2337; fix: (39) (6) 445 6741I e-mail: [email protected]
c Tu.B.195
> MAJOR HISTOCOMPATIBILITY GENE FREQUENCIES IN LONG TERM
3 ASYMPTOMATIC (LTA) HIV PATIENTS IN FRANCE.
0
S Theodorou loanisi-, Autran BI, Costagliola D2, Raffoux C3, Charron D3, Debre pI, the
Immunoco study group, the ALT study group. I aboratoire Central d'Immunologie H6pital
ryt
> de la Pitie Paris France; 2Centre Cooperateur de Donnees Epidemiologiques sur
lImmunodeficience Humaine INSERM SC4 Paris France; 3Laboratoire d'Immunologie
'O Hopital Saint Louis Paris France
Objective: To determine groups of Antigen Presenting Molecules that favor outcome of
< HIV infection.
r- Materials and Methods: The LTA cohort costaias 32 Freach patients with a ser opositv.ty
O duration of more than 8 years, ar CD4+ count of more than 600 per mm3 and positive or
(:u null slope for that CD4+ for- the last three years without atietroviral treatment.The
r- Inmuraoco cohort contrined 152 French patients enrolled in 1991 independently of retaa
r - retroviral therapy and seroposrtivity duiration in order to dertemrne Cytotoxic T lymphocyte
a- anti-HIV responses is corraltiron to abisolirta CD4~ cornts.The sax ratio the mean age
O ad risk factors between the Immunoco and the LTA group were similar All patients were
1, typed for HLA A, B, red DR naolecules with standard serological or molecular methods.
- Statisticarl conaparisons of gene Si equencres between the LTA and Immunoco cohort were
o- performned iccor ding so Penara's test..O Results: Among thae LTA prtients the A3 and 827 H-LA clsa I molecules wara more Lier 3oquntly ohservad compared to the lrmamsroco group (2 1,8% varsus 9,2% p--0.00 19 and
c-_ I Iversus 3, Ip-.006 aespectrvey). For HLA clall aI molecules DR Iwas more Ir-e-,(,+, quest in the LEA conapired so the Immunoco group (17,2% versus 7% p--0.0053 rasper-:: tively). Furthermore in the Imunoco group gena fraequencres of the HLA A,B and DR mnolecules were aimilar to tfose observed for the healthy French population suggesting that sosceptibnility to HIV farimornfectiorn a not riluoenced by the HLA phenotype of the individual.
234

Conclusions: A3, B27 and DR I Major Histocompatibility genes were statistically more
frequent in the LTA compared to the Immunoco group.These data suggest that presence
of certain Antigen Presenting Molecules favors the outcome of HIV infection. Linkage disequilibrium studies focusing on haplotype rather than gene frequencies are under
progress and should determine whether isolated genes or complete haplotypes are
responsible for this finding.
I.Theodorou - Laboratoire Central d Immunologie Cellulaire etTissulaire - Hopital Pitie
Salpetriere - Batiment CERVI - 83 Bd de I' Hopital 75013 Paris - France.
Tel: [phone] II, Fax: (33 I) 42 17 74 90, email: [email protected]
Tu.B.290
HOST FACTORS IN THE PATHOGENESIS OF HIV DISEASE
Fauci, Anthony S. National Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD
Following primary HIV infection, a state of chronic, persistent infection fueled by cellular
activation usually ensues and the expression of virus over time is determined by a number
of viral factors as well as by upregulatory and downregulatory host factors. Paramount
among these host factors are endogenous cytokines that tightly control HIV expression in
an autocrine and paracrine manner- For exampleTNF-a, IL-If, and IL-6, which are overexpressed in lymphoid tissue of HIV-infected individuals potently induce HIV replication, and
virus replication can be markedly downregulated by blocking these autocrine pathways. Of
note, a number of faictors including the 3-chemokines RANTES, MIP- I a, and MIP- 1I0 directly
downmodulate virus expression in certain culture systems. These chemokines are secreted
by a variety of cell types including CD4+ T cells, monocytes, B cells, as well as CD8+ T cells.
Suppression of HIV replication by the 13- chemokines is dependent upon the culture system
employed as well as the cellular tropism of the virus. In certain culture systems, CD8 + T
cell factors other than the 13-chemokines are responsible for suppression of HIV replication.
The net expression of virus is determined at least in part by the balance of these opposing
factors. The real and potential mechanisms of these regulatory phenomena are complex
and diverse, and will be discussed.
AS Fauci, Building 31, Room 7A03, 31 Center Dr. MSC 2520, Bethesda, MD, 20892-2520
USA Tel: [phone] Fax: [phone]
Tu.B.29 I
CHALLENGES OF HIV RESEARCH AS WE APPROACH THE 21ST CENTURY
Levy, ay A. Dept. of Medicine and Cancer Research Institute, University of Califbr nia, San
Francisco, CA, USA
The human rimmunodeficiency vir us (HIV) has shown noteworthy heterogeneity in its ability
to infect normal CD4+ cells as well as a variety of human and primate cell inesat. HIV diverasity is noted in the induction of cytopathic changes in cells, and virus sensitivity to various
immune responses including antiviral antibodes and both cellu-medited and cytokine-directed activities. India cd viduals infected wth the virus can show rapid, slow or non-progression to
AIDS. The latter group, known as Long-Term Survivors (LTS), have pr ovided important
information on viral characteristics and host immune responses that affect HIV pathogenesis. In addition, some people practicing high-risk behavior show no evidence of HIV infection but have cell-mediated anti-HIV responses suggesting exposure to the virus. This group
represents an excellent population for studying natural resistance an d potential protective
correlates relevant to vaccine development. A major reason for long-term survival from
HIV infection can be the presence of a strong CD8+ cell antiviral response mediated in
part by a secreted CD8+ cell antiviral factor (CAF). The activated HLA-DR+ CD28+ subset of CD8+ cells seems primarily responsible or this activity. CAF has physio-chemical
features, antigenic pr operties, and biologic functions which distinguish it from other known
cytokines, including chemokines. This CD8+ cell antiviral response, prominent in asymptomatic individuals, is also present in some high-risk uninfected people, and appears to mediate protection from productive HIV superinfection in animal models, such as HIV-2 infection
of baboons. It blocks HIV replication in CD4+ cells without any apparent effect on cell
phenotype or function. The antiviral activity may explain the low viral load typically seen in
LTS and the normal architecture observed in lymph nodes from these individuals as compared to Progressors. A major emphasis in future HIV research should be to define CAF
and determine a means by which we can maintain or even enhance this natural antivir-al
activity of CD8+ cells. The effects of cytokines and antigen-presenting cells in helping to
sustain this CD8+ cell activity should be appreciated. Through a strong cell-mediated
immune response, resistance to HIV infection could be induced with vaccines and a persistent asymptomatic state could be provided for all infectedrindividuals.
JA Levy, San Francisco, CA, 94143--0128, USA Tel: [phone] Fax: [phone]
E-mail: jalevylitsa.ucsfedu
Tu.B.292
AIDS CARE IN THE NEW WORLD
Volbarding. Paul A. nivarsity of California, San Francisco, San Francisco General Hospital. USA
AIDS is changing and so mutt we and our health da atstem. Increasingly we canf-ont a
new world of AIDS characterized by new knowledge. new treatments, new patient populatrues and at least in the Gaited States, by a new system of health rare. As with ill chrnges,
those in AIDS Srirag both risks and oppor tunitias.
The new developments in fHIV medicine are ohsiout red exciting. Given the increasragly
refined tools ol vil load measurements red molecular tectiques, we are morn closer to
understanding the viral and immunologic pathogenesa of LIlV disease. We apprecia the
enormous regenar atrve cipabilrties of the immsrae system as it attempts to tsurvise the cantinuous onslaught of ac true 3IV aepi cation. We als abetter understand the complexity of
the virus and its nutaubilty driver by its brief recplrcartrve cycle. These developments. in torn,
have expanded our secse oftheraspeutic possiblity. Anti uirnl treatments of a potency only
imaginted a few years igo ire becoming routine, and serrous scientists are asking whether
viral enradication ay be posasible is at least sonse putrents.
Gnfortunatela these development a l osa their- mpac because o cotervaenng
changes, thus a a our patient population. red in our iare systenet. AIDS in the Gaited
States is rapidly becoming r poor person's disease, of those whom our- society can more or
less ignore. Even gay men, draproportionately affected enrly in the epidemic, hid a political
voice. Much leas a heard hiow ouin current grou oltf yrong rchn isen ad women, often