Comparison of the Frequency of Interleukin (IL)–2–, Interferon-g–, and IL-
4–Producing T Cells in 2 Diseases, Human Immunodeficiency Virus Types 1
and 2, with Distinct Clinical Outcomes
Ana E. Sousa, Ana F. Chaves, Ana Loureiro,
and Rui M. M. Victorino
Cellular Immunology Unit, Center for Biology and Molecular
Pathology, Department of Medicine 2, University Hospital of Santa
Maria, Faculty of Medicine of Lisbon, Lisbon, Portugal
Human immunodeficiency virus (HIV) type 2 infection is associated with a better clinical
outcome, slower rates of CD4 T cell decline, and lower viremia than is HIV-1. This study
compares HIV-1 and HIV-2 in regard to the percentages of interleukin (IL)–2–, interferon
(IFN)–g–, and IL-4–producing cells at the single-cell level, as determined by flow cytometry.
At a given degree of CD4 T cell depletion, the frequency of T cells able to produce IL-2 is
better preserved in HIV-2 than in HIV-1 infection, particularly within the CD4 T cell subset.
As described for HIV-1 immunodeficiency, HIV-2–positive patients exhibit a marked expan-
sion of terminally differentiated effector CD8 T cells (CD28?CD27?IFN-g+). However, the
proportion of CD8 T cells able to simultaneously produce IL-2 and IFN-g is higher in HIV-
2 disease. Considering the central role of IL-2 as a lymphocyte proliferative and survival
factor, these findings provide a possible immunologic basis for the distinct course of HIV-2
One of the strategies to investigate human immunodeficiency
virus (HIV) immunopathogenesis has been to use natural mod-
els of HIV-1 infection with unusual clinical outcomes, such as
exposed but uninfected subjects  and long-term nonprogres-
sors . Recently, the immunodeficiency associated with HIV
type 2 (HIV-2), the second AIDS-associated virus, has emerged
as a unique model of human-attenuated HIV disease [3, 4].
Clinical studies have shown that HIV-2 disease progression is
slower than that of HIV-1, with limited impact on the survival
of most infected adults [5–7]. Although the routes of trans-
missibility are the same as those of HIV-1 infection, both hori-
zontal and vertical transmission are much lower [8, 9].Methods
confirmed that the levels of viremia were very low [10, 11], a
finding that was expected in view of the reduced frequency of
successful virus isolation from HIV-2–infected patients . Of
interest, the quantitative assessment of HIV-2 provirus load
Received 12 February 2001;revised16April2001;electronicallypublished
31 July 2001.
Presented in part: 2000 International Meeting of the Institute of Human
Virology, Baltimore, September 2000 (abstract 281).
The study was approved by the Ethical Board of the Faculty of Medicine
Financial support: Ministe ´rio da Cie ˆncia e Tecnologia–Praxis XXI;Com-
issa ˜o Nacional de Luta Contra a SIDA (CNLCS)–Ministe ´rio da Sau ´de (to
R.M.M.V.); Praxis (scholarships to A.E.S. and A.L.); CNLCS (scholarship
Reprints or correspondence: Dr. Ana E. Sousa, Dept. of Medicine 2,
Faculty of Medicine of Lisbon/University Hospital of Santa Maria,Av.Prof
Egas Moniz, 1649-028 Lisbon, Portugal (email@example.com).
The Journal of Infectious Diseases
? 2001 by the Infectious Diseases Society of America. All rights reserved.
documented levels similar to those observed in HIV-1–infected
individuals [13, 14]. On the basis of the scanty immunologic
data available, some authors have suggested that the control
of viremia could be attributed to a more effective immune re-
sponse against HIV-2 by broadly reactive neutralizing anti-
bodies and strong cytotoxic responses [15, 16], although pu-
tative particularities of the virus biology could equally be
responsible [4, 17].
of a reduced viremia, irrespective of the stage of CD4 T cell
depletion [6, 11], HIV-2–associated immunodeficiency repre-
sents an important model to validate some of the hypotheses
of HIV-1 immunopathogenesis, particularly the ones involving
T cell homeostasis disturbances  and the influence of cy-
tokine production imbalances . The potential of the HIV-
2 model has not been fully explored, because, in part, of the
geographic confinement of the infection to West Africa [3, 4].
Portugal represents the only developed country with a signifi-
cant prevalence of HIV-2 infection (5% of the reported AIDS
cases) as a result of the strong connectionstoitsformercolonies
in West Africa . We designed a cross-sectional study tocom-
pare HIV-2– and HIV-1–infected patients living in Portugal
with respect to their differences in T cell populations, defined
functionally by their ability to produce interleukin (IL)–2, in-
terferon (IFN)–g, and IL-4. The patients were stratified ac-
cording to their peripheral blood CD4 T cell counts.
26 HIV-1–infected patients currently living in Portugal and at-
tending outpatient clinics in Lisbon. None of the patients had any
The study involved 27 HIV-2–infected and
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