The Role of CD8+ Lymphocytes in the Control of SIV Viremia
NIAID News Release
National Institute of Allergy and Infectious
National Institutes of Health
April 21, 1999
Jeffrey T. Safrit, Ph.D.
Yerkes Research Center &
University School of Medicine
The debate about the pathogenic or protective role of CD8+ T cells in
lentiviral infections may be leaning more and more toward one side of the
argument. Understanding the true role of these cells in vivo is critical
to both our understanding of HIV pathogenesis and for the design of
vaccine candidates. To this end, clinical evidence has been accumulating
for the past few years on the potential of the cellular immune response to
control viral replication in HIV-1 infected individuals. Now, a recent
report by Jörn Schmitz et al. from the laboratories of Drs Keith Reimann
and Norman Letvin has provided direct evidence for the positive role of
CD8+ T cells in controlling virus in SIV-infected macaques (1).
These investigators successfully depleted CD8+ lymphocytes in rhesus
macaques infected with SIV-mac251 and examined the effect of this
depletion on viral load, Gag p27 antigenemia, and SIV-Gag-specific CD8+ T
cells during both the acute and chronic phases of infection, and on
In an experimental setting that mimics primary HIV-1 infection in
humans, rhesus macaques infected with SIVmac251 manifest extremely high
viremias that peak between days 7 and 10 post infection. This high viral
load then rapidly declines over the next few days presumably due to the
onset of the SIV-specific immune response. Others have argued, however, in
favor of an exhaustion of appropriate target cells as a reason for this
decline (2). In the
present study, six acutely infected animals given a humanized anti-CD8
monoclonal antibody were completely depleted of CD8+ lymphocytes for a
variable duration. In three of the animals, CD8+ cells were depleted for
17-21 days while the remaining three animals were depleted of CD8+ cells
from 4 to as much as 9 weeks. Despite the variability in time of
depletion, the results were very consistent. In the CD8 depleted animals,
viral RNA and Gag p27 antigenemia remained higher for longer than in
animals treated with a control antibody. In fact, in the animals that were
depleted of CD8+ lymphocytes for >4 weeks, viral RNA and gag p27
antigen were never controlled and all three developed disease rapidly.
These results are more consistent with the hypothesis that reduction of
acute viremia is due to the SIV-specific CD8+ T cell response than due to
exhaustion of target cells.
Previous attempts at assessing the consequences of in vivo CD8+ cell
depletion on the course of SIV infection have been hampered both by the
variability of the viral loads and the incomplete depletions that were
achieved (3, 4). In a
study of protection provided by attenuated SIV strains, Stebbings et al.
determined that CD8+ cells were not necessary for protection from
subsequent wild type virus infection (3). In
addition, Matano et al. depleted CD8+ cells prior to or during early SHIV
infection (4). They
found ensuing viral loads to be higher while CD4+ cells were lower than
controls, suggesting a role for CD8+ cells in clearance of viremia.
However, the CD8+ cells depletions in both sets of experiments were
partial and thus the results must be interpreted with caution. In
addition, the number of macaques per experiment prevented any
statistically significant results. Both of these hurdles were overcome in
the study by Schmitz et al. (1). The use
of a "humanized" monoclonal may have been the difference as the half-life
and thus effectiveness of the antibody would likely be increased due to
the reduction of any anti-monoclonal immune responses in the macaques. The
previous studies used unmodified murine monoclonal antibodies.
Two recent studies have addressed the role of CD8+ lymphocytes in
controlling virus during chronic SIV infection of macaques. Schmitz et al
extended their findings in the acute infection model to examine the
effects of CD8+ cell depletion in animals infected with SIVmac251 for
greater than nine months (1). Jin et
al. depleted CD8+ lymphocytes in seven macaques (six infected with
SIVmac251 or 239 for 1 to 4 years and one uninfected control) (5). Both
studies achieved transient depletions of CD8 cells lasting from 8-14 days.
Interestingly, the humanized anti-CD8 monoclonal antibody appeared to be
no more efficient than a murine anti-CD8 when used in the chronic
infection setting. Nonetheless, both studies were able to show dramatic
rises in viremia during the window of depletion. As expected, when the
CD8+ cells returned, viremia fell back to the original chronic levels,
consistent with the conclusion that CD8+ lymphocytes are responsible for
controlling levels of virus.
A noted difference among the studies above was the effect of the
depletion and increased viremia on the macaque CD4+ lymphocytes. While
Schmitz et al made no reference to changes in the CD4+ subset in either
the acute or chronic infection experiments, the studies of both Jin et al.
and Matano et al. noted declines in CD4+ lymphocytes coincident with the
rise in viremia. The CD4+ cell levels returned to pre-CD8 depletion levels
as virus was again controlled by the CD8+ cells. The later results seem to
be more in line with what would be expected during even a transient
dramatic increase in viremia. These results are also consistent with the
typical pattern seen in acute HIV infection when the high viral loads
result in declines in CD4 cells that usually return to baseline as virus
is controlled (6).
Role of Antigen Specific CD8+ Lymphocytes
As CD8+ lymphocytes may be able to control virus by a number of
specific and nonspecific mechanisms, it was reasonable to ask to what
extent SIV-specific CD8+ cytotoxic T lymphocytes (CTL) might be involved
in the control of virus in vivo. Schmitz et al followed SIV gag-specific
CTL in Mamu A*01 animals during and after the depletions by flow
cytometric staining with SIV peptide tetramers (p11c, C-M) (1). During
acute infection, the appearance of tetramer positive CTL was delayed by
CD8+ cell depletion but arose coincident with the control of viremia in
the Mamu A*01 animal where depletion lasted < 21 days. In contrast, in
a Mamu A*01 animal that was depleted of CD8+ cells > 28 days, tetramer
positive CTL were never observed and virus was never controlled.
Interestingly, when gag-specific CTL were followed during the chronic
infection experiment, a significant boost of the pre-depletion levels of
tetramer positive cells occurred that was coincident with the control of
viremia following the transient depletion.
These studies emphasize the potential relevance of virus-specific CD8+
lymphocytes in the context of prophylactic HIV vaccines. By their nature,
induced CD8+ cells would serve as a second line of defense in situations
where virus broke through antibody containment and was able to infect
cells in the new host. The above results also suggest that therapeutic
vaccines capable of boosting antigen-specific cellular responses may
productively modulate viral replication in already infected individuals.
Schmitz JE; Kuroda MJ; Santra S; Sasseville VG; Simon MA; Lifton
MA; Racz P; Tenner-Racz K; Dalesandro M; Scallon BJ; Ghrayeb J; Forman
MA; Montefiori DC; Rieber EP; Letvin NL; Reimann KA. 1999. Control of
viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.
Phillips AN. 1996. Reduction of HIV concentration during acute
infection: independence from a specific immune response. Science
Stebbings R; Stott J; Almond N; Hull R; Lines J; Silvera P;
Sangster R; Corcoran T; Rose J; Cobbold S; Gotch F; McMichael A; Walker
B. 1998. Mechanisms of protection induced by attenuated simian
immunodeficiency virus. II. Lymphocyte depletion does not abrogate
protection. AIDS Res Hum Retroviruses 14:1187-1198.
Matano T; Shibata R; Siemon C; Connors M; Lane HC; Martin MA.
1998. Administration of an anti-CD8 monoclonal antibody interferes with
the clearance of chimeric simian/human immunodeficiency virus during
primary infections of rhesus macaques. J Virol 72:164-169.
Jin X; Bauer DE; Tuttleton SE; Lewin S; Gettie A; Blanchard J;
Irwin CE; Safrit JT; Mittler J; Weinberger L; Kostrikis LG; Zhang L;
Perelson AS; Ho DD. 1999. Dramatic Rise in Plasma Viremia after CD8(+) T
Cell Depletion in Simian Immunodeficiency Virus-infected Macaques. J
Exp Med 189:991-998.
Safrit JT; Koup RA. 1995. The immunology of primary HIV
infection: which immune responses control HIV replication? Curr Opin
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