Immunotherapy for Infectious Diseases

Immune Reconstitution with Antiretroviral Chemotherapy 167
Significant controversy exists over the origins of the increases in CD4� T-cell counts
that occur in the setting of HAART. Multiple mechanisms for reconstitution of peripheral
blood CD4� T-cell numbers have been proposed, including preservation of cells
from HIV-1 infection and death, diminished activation-induced death of uninfected cells,
increased thymic output, peripheral expansion of preexisting cells, and redistribution of
CD4� T-cells to the periphery from lymphoid tissues. When the remarkable peripheral
blood first phase increases induced by protease inhibitor therapies were initially observed, it
was assumed that they reflected preservation of CD4� T-cells that previously would have
been infected by HIV-1 and destroyed either by viral lysis or immune clearance (90–92).
However, studies of lymphoid tissues, which contain more than 95% of the body’s
T-lymphocytes, as well as the vast majority of HIV-1 replication, revealed that 10-fold fewer
lymphoid cells were productively infected than would have been predicted by this model
(93). Although HAART was demonstrated to result in significant declines in measures of
immune activation (82,83,87,94,95) and apoptosis (96) in both lymphoid tissues and peripheral
blood, the fact that the peripheral blood first-phase increases were not observed in lymphoid
tissues (97) argued against this mechanism as the major source of peripheral blood
CD4� T-cell reconstitution. Studies of peripheral blood CD4� T-cell turnover during the
first 12 weeks of HAART (using a novel method of measuring lymphocyte half-life
through incorporation of deuterated glucose) indicated that T-cell half-life is reduced, not
increased by HAART (98), arguing against either diminished apoptosis or decreased viral
infection and death as the major causes of increased CD4� T-cell counts.
The observation that levels of expression of lymphocyte adhesion molecules in lymphoid
tissues of untreated HIV-1-infected individuals were high, and diminished substantially
in the setting of HAART, led to the interpretation that most of the first-phase
increase may be caused by redistribution of cells from the lymphoid tissues to the
peripheral blood, rather than a true increase in total body CD4� T-cells (95). The fact
that the T-cell receptor (TCR) repertoire after the first phase resembles that of the pretreatment
repertoire, which is often aberrant (87,99–101), further supports this interpretation.
In addition, the observation that CD8� lymphocytes as well as B-lymphocytes
also increase during the first 12 weeks of HAART (77–83) suggests that other lymphocyte
populations may be redistributed from lymphoid tissues during the first 12
weeks of HAART as well. Thus, although there is not complete consensus, multiple
lines of evidence suggest that the major source of the first-phase increases in peripheral
blood CD4� T-cells is redistribution of these cells from lymphoid tissues.
The origins of the second-phase increase in peripheral blood CD4� T-cell counts
are also unclear, but most likely these increases do not represent redistribution from
lymphoid tissues. The second-phase increase, which primarily consists of cells with a
naive phenotype, is similar in tempo to what has been observed in cancer patients
treated with chemotherapy (102). Phenotypically naive cells are not necessarily newly
synthesized, as reversion of cells from a memory to a naive phenotype has been
reported (103,104). Studies of lymphoid tissues, however, have demonstrated CD4�
T-cell increases during the second phase, suggesting that these represent true increases
in total body CD4� T-cells (97). The TCR repertoires of the second phase increases
have been less extensively studied, but several studies suggest that they may be trending
toward a more normal repertoire than that prior to HAART (100,101), further bolstering
the theory that HAART results in new CD4� T-cell synthesis.