Mapk P38

Journal of General Virology (2008), 89, 1661–1671

DOI 10.1099/vir.0.82971-0

Implication of p38 mitogen-activated protein kinase
isoforms (a, b, c and d) in CD4+ T-cell infection
with human immunodeficiency virus type I
Dolores Gutierrez-Sanmartin,1 Eduardo Varela-Ledo,1 Antonio Aguilera,1
Susana Romero-Yuste,2 Patricia Romero-Jung,1 Antonio Gomez-Tato3
and Benito J. Regueiro1Correspondence
Benito J. Regueiro
mpbjrg@usc.es

1

Clinical Microbiology, Hospital de Conxo, Complejo Hospitalario Universitario de Santiago (CHUS),
15706 Santiago de Compostela, Spain

2

Rheumatology, Hospital Provincial, Complejo Hospitalario de Pontevedra (CHOP), Pontevedra,
Spain

3

Facultad de Matematicas, Universidad de Santiago (Campus Sur), Santiago de Compostela, SpainReceived 6 March 2007
Accepted 1 March 2008

The CD4+ T-cell reduction characteristic of human immunodeficiency virus type 1 (HIV-1)
infection is thought to result, in addition to infected T-cell death, mainly from uninfected bystander
T-cell apoptosis. Nevertheless, the immunological and virological mechanisms leading to T-cell
death during HIV-1 infection are not yet fully understood. In thepresent study, we analysed the
individual implication of the p38 mitogen-activated protein kinase (MAPK) isoforms (p38a, p38b,
p38c and p38d) during apoptosis induced by HIV-1, taking into account that HIV-1 replication is
known to be blocked by p38 inhibitors. For this purpose, we used the SupT1 cell line, where
death induced by HIV-1 mainly occurs by uninfected bystander cell apoptosis. Avariety of SupT1based cell lines were constructed constitutively expressing, under the control of cytomegalovirus
promoter (PCMV), each dominant-negative (dn) p38 isoform and each wild-type p38 isoform as a
control. An enhanced green fluorescent protein marker gene, under the control of the HIV-1
promoter, was inserted in all of them. These cell lines were infected with HIV-1 and analysed by
flowcytometry. We found that survival in SupT1-based cell lines infected by HIV-1 was increased
by the p38adn, p38cdn and p38ddn isoforms, but not by the p38bdn isoform. HIV-1 replication
was delayed most by p38ddn and to a lesser extent by p38adn and p38cdn. Moreover, these
three isoforms, p38adn, p38cdn and p38ddn, reduced apoptosis induced by HIV-1. These results
suggest that, in SupT1-basedcell lines, p38a, p38c and p38d, but not p38b, are implicated in
both HIV-1 induced replication and apoptosis in infected and uninfected bystander cells.

INTRODUCTION
Human immunodeficiency virus type 1 (HIV-1) infection
is characterized by the progressive depletion of CD4+ T
lymphocytes, especially through apoptosis, leading to
immunodeficiency and AIDS (McCune, 2001). Most of
theapoptotic CD4+ T cells in the peripheral blood and
lymph nodes of HIV-1-infected patients do not have
integrated virus (Finkel et al., 1995; Katsikis et al., 1995;
Cloyd et al., 2001). This suggests that apoptosis of these
uninfected bystander cells plays an important role in AIDS
pathogenesis.

A table showing the set of primers used in the construction of retroviral
vectors is available with theonline version of this paper.

0008-2971 G 2008 SGM

Printed in Great Britain

A variety of HIV-1 proteins are implicated in T-cell death.
Some proteins are involved in direct cytopathic effects, such
as protease, others in bystander cell death, such as gp120/gp41
and HIV-1-negative factor (Nef), and others in both
processes, such as Vpr, Vpu and Tat (Casella et al., 1999;
Bartz &Emerman, 1999; Silvestris et al., 1999; Azad, 2000; Nie
et al., 2002; Algeciras-Schimnich et al., 2002; Brenner &
Kroemer, 2003; Yang et al., 2003; Castedo et al., 2003).
Infected and bystander CD4+ T-cell death can be caused by
several mechanisms; namely, the toxic effect of viral proteins,
proapoptotic signalling as a result of interactions between the
HIV-1 envelope glycoproteins and their...