International AIDS Society Newsletter, no. 21

I AS
INTERNATIONAL
AIDS SOCIETY
Strategies Towards Restoration of Immunity to HIV
Professor Brigitte Autran, MD, PhD
Laboratoire d'Immunologie Cellulaire
Hopital Pitie-Salptrire
Paris - France

The course of infection caused by the Human
Immunodeficiency Virus (HIV) has been
tremendously amended during the past five
years by the introduction of powerful antiretroviral (ARV) therapies that improve the
immune system and protect patients against
the risk of opportunistic infections and AIDS
(1). These successes are, however, severely challenged nowadays. Indeed, ARV cannot eradicate the virus and has to be maintained for life
with major costs and severe side-effects,
involving metabolic complications and mitochondrial dysfunction, as well as clinical consequences such as the lipodystrophy syndrome
and increased risks for cardiovascular diseases.
In addition, lack of compliance to such lifelong treatment leads to relapses of viral replication and induction of virus mutations
responsible for a growing rate of virus resistance to ARV and treatment failures that
require the development of new therapeutic
interventions (2). An innovative strategy is
attracting growing interest that aims at restoring immune control of HIV in order to allow
prolonged interruptions of these toxic, expensive and only partially effective ARV therapies.
Successes and Limitations of the Immune
Reconstitution with Antiretroviral Therapy
The CD4 T-cell responses against opportunistic pathogens such as CMV or Mycobacterium
tuberculosis are rapidly restored after 3
months of Highly Active Antiretroviral
Therapy (HAART) in AIDS patients [1,3 31
Such reconstitution requires a solid and
durable control of HIV replication [31. The net

increases in frequencies of pathogenspecific CD4 T-cells after introduction of
HAART strongly correlates with clinical status, [4]. The restored immune defenses against
opportunistic pathogens allow discontinuation
of primary or secondary prophylaxis against
CMV and/-or Pneumocystis carinii [5,6} and
help facilitate the long-term clinical management of AIDS and HIV infection.
In contrast, a poor restoration of CD4 cell
reactivity against HIV itself is observed in most
patients except in those treated at the earliest
stages of infection [1,7]. Such dissociation
between a strong and protective immunity
rapidly restored against opportunistic
pathogens and a waning immunity against
HIV with HAART reflects the differences in
the host's exposure to antigenic stimuli.
Indeed, the amounts of CMV or Candida antigens are not immediately affected by HAART
and memory CD4 T-cells specific for those
pathogens are rapidly re-stimulated and reexpand. In contrast, the rapid reduction in HIV
antigens with HAART impairs appropriate
stimulation of HIV-specific CD4 cells.
Similarly, a decline of HIV-specific CD8 T-cells
was reported to parallel virus reduction [8-10].
Therefore, a reduced exposure to HIV antigens
during "suppressive" HAART delays the onset
of HIV-specific CTL in primary infection and
reduces the levels of pre-existing CTLs in
chronic infection. The same phenomenon also
prevents restoration of HIV-specific CD4 Tcells in chronic stages while preserving these
immune responses from destruction by the
virus at primary infection. This phenomenon is

the consequence of the reduction of HIV production with successful therapy down to
extremely low levels which are unable to stimulate the restoration of immune defenses against
HIV. Despite persistence of some viral replication, the HIV antigen load might still be insufficient to allow memory T-cell expansion during HAART. Lack of restoration of T-helper
cell activity and CTLs against HIV appears to
be of utmost importance considering the central role played by these cells in the immune
control of virus infection.
Can HIV Boost the Immune System?
These observations have led to the concept of
structured therapeutic interruptions (STI) in
order to re-amplify HIV-specific T cells by reexposing them to virus particles during treatment windows. Various schedules of STI are
currently being explored to limit the toxicity
and the costs of these therapies by limiting the
time on treatment. This strategy might have
some benefit after treatment of primary infection and appears to be successful at restoring
HIV-specific CD4 and CD8 responses that
help to control HIV replication without therapy [11,121. However, in chronically-infected
patients HIV-specific CD4 T-cells are expanded only transiently after re-exposure to pathogenic antigen and are rapidly eliminated
[ 13,14]. The HIV-specific CD8 T-cells are
moderately stimulated but only the pre-existing T-cell clones are boosted that previously
failed to contain virus replication before the
initiation of ARV. Finally, these responses are
certainly stimulated too late after re-emer
4