Immunotherapy for Infectious Diseases

226 Kilby and Bucy
the proinflammatory cytokine cascade that stimulates cycles of HIV replication. When
we administered tapering doses of prednisone to advanced AIDS patients with wasting
syndrome, a decline in markers of immunoactivation (neopterin and TNF receptor II
levels) was followed by a dose-related decline in plasma viral load (74). In a large clinical
study involving less advanced HIV infection, patients receiving corticosteroids had
prolonged moderate elevations in their absolute circulating CD4 counts while on therapy
compared with individuals receiving reverse transcriptase inhibitor therapy alone
(75). A multicenter trial in the United States is now being planned to evaluate the
effects of low-dose prednisone when administered to patients with partial but not complete
viral load suppression on HAART. A pilot study evaluating the effects of lowdose
cytotoxic chemotherapy to limit the availability of susceptible target cells is also
currently nearing completion.
The evidence that inflammatory events adversely affect blood CD4 counts and the
apparent paradox of prednisone increasing circulating lymphocyte numbers in less
advanced HIV-infected patients are quite compatible with evidence regarding the T-cell
redistribution phenomenon between tissues and peripheral blood. Based on blood
analysis alone, Pakker et al. (76) surmised that the initial rise in circulating CD4 cells
following initiation of HAART was due to a redistribution of memory cells from tissues
to the periphery. To explore these issues further, we analyzed blood and lymph
node tissues obtained concurrently from patients before and after the initiation of
HAART (77). Ten weeks after HAART, the number of lymphocytes per excised cervical
lymph node had decreased, whereas the number of blood lymphocytes tended to
increase. The expression levels of several proinflammatory cytokines (interferon-�
[IFN-�], IL-1�, IL-6, and MIP-1�) declined following HAART. After therapy, the
expression of adhesion molecules known to mediate lymphocyte sequestration into
inflamed tissues (vascular cell adhesion molecule [VCAM]-1 and intracellular cell
adhesion molecule [ICAM]-1) was also significantly reduced. These data support the
hypothesis that the abrupt rise in blood CD4 cells immediately after therapy is related
to redistribution and that this redistribution is mediated by a resolution of immunoactivation
that had sequestered T-cells within inflamed tissues. This inverse relationship
between blood and inflamed tissues has also been described for other infectious diseases.
For example, a recent report suggests that the reversal of anergy in patients
receiving therapy for tuberculosis corresponds to the release into the bloodstream of
tuberculosis-specific T-cells previously sequestered in infected tissues (78).
TARGETING T-CELL NUMBERS
Another logical approach to ameliorate the consequences of HIV infection would be
to stimulate increases in absolute CD4 cell counts. The aim of this strategy is to reverse
the best characterized immunodeficiency of AIDS without necessarily getting at the
underlying cause of lymphocyte depletion. Controversy remains about the exact pathogenesis
of CD4 cell depletion in AIDS; it has never been conclusively demonstrated
that CD4 cells are killed by a direct HIV cytopathic effect. The frequency of infected
CD4 T-cells is generally very low, so that even though infected cells are quickly cleared
in active infection (via either a cytopathic effect or direct lysis by immune viralspecific
CTL), this mechanism alone may not account for depletion of the entire population
of CD4 T-cells. CD4 cell decline over the natural history of HIV infection may