GENEVA--Highly active antiretroviral therapy (HAART), usually
including a protease inhibitor, can suppress human immunodeficiency
virus (HIV) so much that the immune system actually begins to heal,
according to work presented at the 12th World Conference on AIDS. In
patients who respond well to HAART, CD4+ and CD8+ cell counts move
toward normal, and the risk of opportunistic infections decreases
(see Oncology News International, August, 1998, pp 1 and 20).
The missing piece of this picture is the most important one: Even
when HAART knocks the virus back to undetectable levels, the
HIV-specific T-cell response does not recover.
Whether the new circulating T cells are completely functional is also
unclear, but immune reconstitution includes some normalization of the
distribution of naïve and memory T cells and some improvements
in T-cell functions.
It does not, unfortunately, include an upsurge in cellular immunity
directed against HIV, such as an increase in cytotoxic T lymphocytes
(CTLs), and although many adult patients have a resurgence of
naïve CD4+ T cells with use of HAART, there is no clear evidence
that enough of these cells are being made for true immune restoration.
One optimistic note at this conference was a report that HAART can
enable production of new naïve T cells in children with HIV,
apparently related to the presence of a functional thymus.
Researchers have been examining two possible scenarios in immune
reconstitution after effective suppression of HIV. One is that
HIV-specific T-cell responses would decrease because patients with
low viral loads would also have less HIV antigen to stimulate
immunity. The other is that HIV-specific immune responses might
increase because the immune suppression caused by the virus would
decrease as the viral load dropped. There is evidence that both may
happen, at different times and in different patients.
T-cell receptors on CD4+ and CD8+ T cells can be expressed in many
ways, which enables T cells to recognize many different antigens in
normal subjects. The T-cell repertoire in HIV-positive patients
becomes skewed. This is caused by expansion of T cells expressing
particular T-cell receptors. AIDS specialists have hoped that
aggressive treatment with HAART would stop this process and help
maintain the more diverse T-cell receptor repertoire needed for
adequate immune function.
Hugo Soudeyns, PhD, of the Laboratory of AIDS Immunopathogenesis,
Lausanne, Switzerland, reported that this immune stabilization may
indeed be occurring, at least with CD8+ T cells. Dr. Soudeyns used a
heteroduplex mobility assay to measure oligoclonal expansions of
various T-cell receptor V beta families in two patients treated with
HAART. This was done using imaging densitometry of gels of the T-cell
receptor beta chain.
After 28 and 35 weeks of follow-up, respectively, in the two
patients, both of whom had responded to HAART, Dr. Soudeyns observed
that the number of expanded oligoclonal populations was reduced. This
reduction would be expected to result in a more normal spread of
T-cell responsiveness. "The main issue is, what are these clones
recognizing in terms of antigen?" he said. "The rapid
stabilization of the T-cell receptor repertoire seen in treated
patients may prevent the clonal exhaustion of HIV-specific CTL clones
observed in untreated subjects."
In related work, Guy Gorochov, MD, of Hôpital de la Pitie,
Paris, also observed that effective HAART suppression of viral
activity could cause "impressive stabilization of the CD8
repertoire during the second 6 months of treatment," and a
return to near-normal polyclonal CD8 T-cell receptors with continued therapy.
However, Dr. Gorochov also warned that if HIV replication is not
fully controlled, the pretreatment oligoclonal state persists,
apparently because active replication is the driving force behind the
dramatic clonal expansion of CD8 cells seen in untreated HIV infection.
Charles Rinaldo, PhD, of the University of Pittsburgh, looked
specifically at what happens to memory CTLs after HAART. He studied
27 late-stage adult patients with CD4 counts under 200
cells/mm3 and plasma loads over 220,000 copies/mL at baseline. Dr.
Rinaldo said that prolonged suppression of HIV with indinavir
(Crixivan)/zidovudine (AZT, Retrovir)/lamiduvine (3TC, Epivir)
produces a "profound but incomplete enhancement" of
anti-HIV CTL activity.
Enhancing CTL Precursors
He found that CTL precursors of memory T cells increased over the
full first year of treatment but still had only a minimal response to
the HIV gag protein. The numbers of these important precursor cells
dropped back to baseline after 2 years.
Dr. Rinaldo suggested that this unfortunate change "may be a
normal homeostatic response to low viral load." He is now trying
an end run around this homeostatic mechanism by providing ongoing but
benign stimulation with an HIV protein. He is enhancing the
production of HIV-specific CTL precursors by growing large numbers of
dendritic cells in vitro, stuffing them with cationic liposomes
containing an HIV protein, and adding them to cultures of T cells.
He has found that the CTL response can be recovered by repeated
treatment with the HIV-protein-containing dendritic cells,
particularly if IL-12 is also added to the culture. This is all in
vitro work so far, but does suggest a possible strategy for filling
in the most important piece missing from immune recovery after
HAART--the generation of CTLs able to kill HIV-infected cells.
Ann-Charlotte Leandersson, BSc, at the Swedish Institute for
Infectious Disease Control, Stockholm, presented elegant but
depressing data confirming that "successful HAART therapy does
not induce recovery of HIV-specific CD4+ responses" once they
have been lost in adult patients. "No or very low increases in
HIV-specific T-cell responses were seen even though viral load was
reduced and CD4 levels increased," she reported.
Dr. Leanderssons group attempted to restore HIV-specific
immunity by vaccinating patients with a recombinant gp160 vaccine
prior to treatment with HAART, and did observe "a tendency
toward higher response in patients who had received vaccination prior
to HAART." This again suggests that some type of vaccination
strategy may be needed for immune restoration.
Hopeful News in Children
The situation in children may be different, since they still have
functional thymus glands. Allessandra Vigano, MD, of the University
of Milan, reported that the all-important naïve CD4+ T cells do
increase after HAART treatment, even in children with advanced disease.
Thymus volume also increased, and there was a positive correlation
between thymus volume (as measured by MRI) and the increase in CD4
cells, the ratio of naïve to memory cells, and the expansion of
the T-cell receptor beta repertoire. Most patients also had increased
ability to respond to recall antigens.