VANCOUVER, BC--CD8+ T cells appear to play a central role in the body's strategy for fighting HIV, particularly in those patients known as long-term non-progressors or long-term survivors who remain well for many years despite being infected with HIV.
VANCOUVER, BC--CD8+ T cells appear to play a central role in thebody's strategy for fighting HIV, particularly in those patientsknown as long-term non-progressors or long-term survivors whoremain well for many years despite being infected with HIV.
New research presented at the 11th International Conference onAIDS suggests two separate mechanisms by which CD8+ cells suppressHIV, but the specific suppressive factor (or factors) secretedby CD8 has not yet been identified.
Work by Drew Weissman, MD, PhD, and his colleagues at the NIHshow that CD8+ T cells function differently in HIV-infected subjectsthan in uninfected controls. These researchers developed an invitro system that models the paracortical region of the lymphnode by using dendritic cells to activate CD4+ T cells (withoutadditional mitogen). This mimics the situation in the lymph nodeswhere most HIV replication and spread are now thought to occur.
Dr. Weissman tested CD8+ cell activity in two systems. One useddendritic cells and CD4+ T cells from uninfected people. TheirT cells were pulsed with HIV as an "acute infection"model. The other approach used dendritic cells and CD4+ T cellsfrom HIV-infected subjects as an "endogenous infection"model. In both models, CD8+ T cells were added at the initiationof culture.
The CD8+ cells produced two forms of suppressive activity. Onefactor suppressed HIV replication in chronically infected CD4+T cells. This factor was produced by CD8+ T cells from both infectedand uninfected subjects, but the ability to produce it appearsto be lost as HIV infection progresses.
The second factor suppressed HIV replication during acute infection.It was produced only by CD8+ from HIV- infected subjects. Thissuppressive activity was seen even in CD8+ cells from patientswith advanced HIV disease.
CD8+ cells from uninfected subjects actually enhanced viral replication.Pretreatment of CD8+ cells with gamma irradiation wiped out thesuppressive factor that blocks acute HIV infection but not theone that blocks HIV replication in chronically infected cells.
The chemokines MIP-1-alpha, MIP-1-beta, and RANTES have been identifiedin supernatants of stimulated CD8+ cells from HIV-infected individualsand are candidates for the role of suppressive factors, althoughseveral studies presented at the meeting cast doubt on this hypothesis.
Roberto Paganelli, MD, of the University La Sapienza, Rome, reportedthat CD8+ T cell clones from long-term non-progressors secretehigher amounts of MIP-1-alpha, MIP-1-beta, and RANTES than doclones from patients who have progressed to AIDS.
However, Andrea Rubbert, MD, of the NIH, reported that none ofthese che-mokines had any inhibitory effect on viral replicationin CD4+ T cells co-cultured with autologous dendritic cells.
Carl Mackewicz, PhD, of the University of California, San Francisco,reported that CD8+ cells from HIV-infected individuals produceMIP-1-alpha, MIP-1-beta, and RANTES after activation but thatthe levels of these chemokines present in cell supernatants didnot correlate with their anti-HIV activity. With some HIV strains,viral suppression required levels in amounts up to 10-fold greaterthan those produced by CD8+ T cells.
Guido Poli, MD, of Milan, Italy, studied the effects of chemokineson HIV replication in peripheral blood mononuclear cells (PBMCs)from infected individuals. Chemokine concentrations were determinedduring HIV isolation from either total PBMCs of long-term non-progressorsor PBMC cultures that had been depleted of CD8+ T cells.
No distinctive patterns of chemokine concentrations were observedeither with or without CD8+ cells. MCP-1 and RANTES had oppositeeffects when added to cultures: They enhanced viral replicationin some and suppressed it in others, Dr. Poli reported.
The existence of an HIV-suppressive factor generated by CD8+ cellswas first proposed by Jay A. Levy, MD, of the University of California,San Francisco. Despite the excitement at the meeting over newantiviral drug combinations, Dr. Levy maintains that immune systemresearch is the best bet for ultimately beating the disease.
His lab has identified but not characterized the CD8 suppressingfactor, which he calls CD8+ cell antiviral factor (CAF), and heis convinced that it is not one of the alpha or beta chemokines.This is in part because the chemokine concentrations requiredto block HIV are much higher than those normally produced by CD8+cells, as Dr. Mackewicz's study showed.
"Moreover," Dr. Levy pointed out, "CAF productioncorrelates with an asymptomatic state while levels of chemokineproduction by CD8+ cells are similar among infected individualsmanifesting different clinical stages. Furthermore, the antiviralactivity of CD8+ cell fluids containing CAF likewise are not affectedby antibodies to these alpha and beta chemokines."
Dr. Levy also reported that CAF activity from transformed CD8+cell lines (cell lines that have been genetically altered throughincorporation of foreign DNA) did not correlate with levels ofbeta chemokine production.
Further evidence that CAF blocks viral transcription comes fromwork by Dr. Mackewicz and others showing that transformed CD8cells from HIV-infected individuals exhibit significant and broadantiviral activity, and that CAF inhibits activation of HIV-1in a chronically infected cell line.
A study by Arevik Mosoian, PhD, Mary Klotman, MD, and their colleaguesat Mt. Sinai School of Medicine, New York, was done on purifiedCD8+ cells from a cohort of pediatric long-term survivors andrapid progressors. The cells were transformed with herpesvirusSaimiri (HVS), and supernatants were tested for ability to inhibitHIV activation in an acute infection assay and in a chronicallyinfected monocytic cell line.
The investigators found suppressing activity in cells from bothrapid pro-gressors and long-term survivors. There was significantinhibitory activity in both primary and transformed cells andagainst a number of HIV isolates.