For almost two decades, thousands of immunologists and virologists
involved in AIDS research at a cost running into the billions of
dollars, have attempted to explain the qualitative dysfunctions of PBMCs
subsequent to resolution of primary HIV-1 infection.
The most important of these dysfunctions has been the impairment of
proliferative responses to mitogens, specific antigens, and recall
antigens.
Therefore, AIDS research has been focused on how the HIV-1 proteins
(nef, tat, rev, env (gp160, gp120, gp41), vpr, vif, gag) can cause these
dysfunctions that are not seen in HIV-negative controls.
Intriguingly, in the 8/00 Clinical Immunology, researchers at the
University of Massachusetts Medical School determined that, after
vaccinia immunization of healthy laboratory workers, these same
qualitative dysfunctions were found--transiently--immediately after
the immunizations.
Mathew et al. (2000) state: "This is the first report of in vitro
immunosuppression following uncomplicated vaccinia immunization. We
found that proliferative responses of PBMC to mitogens, specific
antigens, and recall antigens were decreased after immunization with
vaccinia virus in four of five volunteers studies."
These decreased proliferative responses were to PHA, anti-CD3, tetanus
toxoid antigens, influenza viral antigens, and vaccinia viral antigens.
Immunizations cause normal immune system activation in the secondary
lymphoid tissues (spleen, lymph nodes, Peyer's patches). After
resolution, activated lymphocytes are desequestered to the peripheral
blood. HIV-1 infection of humans causes chronic immune system
activation, which is not resolved.
As shown with HAART therapy, desequestration consists primarily of
activated lymphocytes (e.g., anergic suppressor CD4 T cells expressing
CD4+CD25+) (J Immunol 2000, 165:1692-1704; J Clin Invest 1999,
103:1391-1398).
Anergic cells do not respond to mitogens, specific antigens, or recall
antigens.
Interestingly, in the vaccinia immunized laboratory workers, PBMC
proliferative responses to PHA were restored with the addition of IL-2
or irradiated autologous healthy PBMC.
For more information on anergic suppressor CD4+CD25+ T cells, the
brilliant studies by NIAID's Thornton and Shevach should be read
(J Immunol 2000, 164:183-190; J Exp Med 1998, 188:287-296; J Immunol
1998, 160:1212-8).
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Mathew A, Ennis FA, Rothman AL. Transient Decreases in Human T Cell
Proliferative Responses Following Vaccinia Immunization. Clin Immunol
2000 Aug;96(2):100-107.
Center for Infectious Disease and Vaccine Research, University of
Massachusetts Medical School, Worcester, Massachusetts, 01655
Email: Alan.Rothman@umassmed.edu
Abstract: To further study the immunosuppression associated with virus
infections, we analyzed the proliferative responses of serial PBMC
samples obtained following vaccinia virus immunization. In four of five
volunteers, responses to PHA, anti-CD3, vaccinia virus, and recall
antigens were markedly decreased at at least one time point between days
5 and 29 after vaccination. Responses to PHA were restored by the
addition of IL-2 or irradiated autologous healthy PBMC in the two
volunteers tested, suggesting that the proliferation defect is
attributable to accessory cell dysfunction. In one donor, immobilized
anti-CD3 failed to induce proliferation, but addition of immobilized
anti-CD28 partially restored proliferation. These results indicate that
vaccinia virus infection can transiently suppress proliferative
responses of PBMC, in part by causing accessory cell dysfunction. Our
findings extend the list of viral infections associated with systemic
immunologic effects and demonstrate that suppression of proliferation
can occur with localized virus infections.