CD8 T cells w/o perforin in HIV+ children/adolescents & 11/7/03 AIDS

At the 7/03 2nd IAS Conference on HIV Pathogenesis and Treatment in
Abstract 174, Kinter et al. (Fauci is senior author) stated:

"In addition, CD25+, but not CD25-, CD4+ T cells suppressed perforin
expression in CD8+ T cells proliferating in response to autologous HIV
super-infected CD4+ T cells."

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In the 11/7/03 AIDS article titled "Discordant expression of perforin
and granzyme A in total and HIV-specific CD8 T lymphocytes of HIV
infected children and adolescents," Haridas et al. state:

"It is important to note that both perforin and granzyme are required
for HIV-1 specific cytotoxic activity."

"Taken together, the data points to an accumulation of CD27+ CD8 cells
that express granzyme without the co-expression of perforin in the
context of virus replication in this patient population. This feature
was noted in the HIV antigen-specific cells and total CD8 T cells. These
findings support the concept of arrested maturation of CD8 T cells
wherein CD8 T cells are activated and differentiate into a pre-effector
stage in which granzyme expression occurs but without acquisition of the
full effector cell cytolytic capabilities. This scenario would not
contradict the recent data in HIV infected adults [Nature Med 2002,
8:379-385] in which diminished perforin expression was associated with
ineffective CD8 T-cell responses and was attributed to cell cycle
dysregulation."

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Haridas V, McCloskey TW, Pahwa R, Pahwa S. Discordant expression of
perforin and granzyme A in total and HIV-specific CD8 T lymphocytes of
HIV infected children and adolescents. AIDS. 2003 Nov 7;17(16):2313-22.

North Shore-Long Island Jewish Research Institute,New York University
School of Medicine,Manhasset,New York,USA.

Abstract: OBJECTIVE Perforin and granzyme are cytotoxic effector
molecules that are believed to play essential roles in cytotoxic T cell
(CTL) activity. We tested the hypothesis that dysregulation of these
effector molecules contributes to defects of CD8 antiviral immune
responses in pediatric subjects in chronic stages of perinatal HIV
infection.DESIGN/METHOD Studies of CD8 T cells were conducted in 33
treatment experienced HIV+ patients (median age, 10.6 years) and in 14
age-matched healthy controls. CD8 T cells specific for HIV Gag and Pol
peptides were identified in HLA-A2+ patients by tetramer binding assays.
HIV-specific and total CD8 T cells were examined for perforin, granzyme
and expression of CD27, a marker that is lost in terminally
differentiated cells.RESULTS Three populations of CD8 T cells were
identified: granzyme+ perforin+; granzyme+ perforin- and cells negative
for both perforin and granzyme. In HIV infected patients, granzyme+
cells were increased in total CD8 T cells (39% versus 13% in controls)
and were highest in HIV Gag-specific CD8 cells (42%). Perforin+ CD8 T
cells were approximately fivefold fewer than granzyme+ CD8 T cells and
were enriched in CD27 negative cells. Most HIV-specific CD8 cells were
CD27+. Granzyme expression in CD8 T cells correlated negatively with CD4
percentage and positively with virus load.CONCLUSION A disproportionate
and generalized increase in CD27+, granzyme+, CD8 T cells is a hallmark
of established pediatric HIV infection. These findings support the
concept of skewed maturation, with failure of CD8 T cells to mature into
perforin-enriched, CD27-negative, effector cells.

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Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg
GS, King A, Lechner F, Spina CA, Little S, Havlir DV, Richman DD,
Gruener N, Pape G, Waters A, Easterbrook P, Salio M, Cerundolo V,
McMichael AJ, Rowland-Jones SL. Memory CD8+ T cells vary in
differentiation phenotype in different persistent virus infections.
Nat Med. 2002 Apr;8(4):379-85.

MRC Human Immunology Unit, Institute of Molecular Medicine, John
Radcliffe Hospital, Oxford, UK. [EMAIL PROTECTED]

Abstract: The viruses HIV-1, Epstein-Barr virus (EBV), cytomegalovirus
(CMV) and hepatitis C virus (HCV) are characterized by the establishment
of lifelong infection in the human host, where their replication is
thought to be tightly controlled by virus-specific CD8+ T cells. Here we
present detailed studies of the differentiation phenotype of these
cells, which can be separated into three distinct subsets based on
expression of the costimulatory receptors CD28 and CD27. Whereas CD8+ T
cells specific for HIV, EBV and HCV exhibit similar characteristics
during primary infection, there are significant enrichments at different
stages of cellular differentiation in the chronic phase of persistent
infection according to the viral specificity, which suggests that
distinct memory T-cell populations are established in different virus
infections. These findings challenge the current definitions of memory
and effector subsets in humans, and suggest that ascribing effector and
memory functions to subsets with different differentiation phenotypes is
no longer appropriate.

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THE 2nd IAS CONFERENCE ON HIV PATHOGENESIS AND TREATMENT

July 13-16, 2003

Le Palais des Congres de Paris

174. CD4+CD25+ T CELLS SUPPRESS HIV-SPECIFIC CD4+ AND CD8+ T CELL IMMUNE
RESPONSES IN VITRO

A. Kinter, S. Kern, Y. Lin, M. Hennessey, M. Daucher, R. Jackson,
A.S. Fauci

Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
Email: [EMAIL PROTECTED]

CD25+CD4+ regulatory T cells, first described in murine models of
certain autoimmune disorders, have been found to play a role in
maintaining peripheral tolerance to self antigens, to suppress CD4+ and
CD8+ foreign antigen-specific responses both in vitro and in mice with
certain parasitic and bacterial infections, and to suppress tumor
immunity. To date, the potential role of CD25+CD4+ regulatory cells in
HIV pathogenesis has not been investigated. The frequency of CD45RA-CD4+
T cells expressing CD25 in the peripheral blood of HIV-infected
individuals was lower than that found in uninfected subjects.
CD25+CD45RA-CD4+ T cells isolated from most asymptomatic HIV-infected
individuals were found to suppress CD4+ memory T cell proliferation and
IL-2 production in response to HIV p24 in vitro; these effects were not
reversed by treatment with neutralizing anti-IL-10 or TGF-beta
antibodies. Depletion of CD25+CD4+ T cells from PBMC resulted in
enhanced HIV Gag-stimulated IFN-gamma production from CD8+ T cells from
most donors and enhanced constitutive IFN-gamma production by CD8+
T cells from HIV viremic individuals. In addition, CD25+, but not
CD25-, CD4+ T cells suppressed perforin expression in CD8+ T cells
proliferating in response to autologous HIV super-infected CD4+ T cells.
Finally, under polyclonal stimulating conditions, the presence of
pre-activated, paraformaldehyde fixed CD25+CD4+ T cells during
CD8+ T cell activation was found to suppress the production of soluble
HIV-inhibitory factors by CD8+ T cells without significantly impacting
CD8+ T cell activation. These in vitro data suggest that CD25+CD4+
T cells may suppress HIV-specific immune response of both CD4+ and CD8+
T cells in vivo.