The impact of immune regulatory imbalance covers surprising physiological breadth. Although dominance of anti-inflammatory cytokines such as IL-10 is associated with reduced immune responsiveness and susceptibility to persistent infection, conditions such as cardiovascular disease and diabetes are linked to chronic inflammation and lower IL-10 levels. An appropriate threshold for immune activation is critical for optimal protection from infection and conversely, from short- and long-term side-effects of immune effector mechanisms. To assess the possibility that IL-10 plays a role in setting this threshold and that healthy maintenance of immune silence may involve low-level immune suppression, we sought out and characterized human peripheral blood cells constitutively producing the immunosuppressive cytokine IL-10. We determined the surface phenotype of circulating PBMC constitutively producing IL-10 by surface and intracellular flow cytometry and visualized their ultrastructure by electron microscopy. The frequency of IL-10-producing and -secreting cells was estimated by ELISPOT and flow cytometry. Up to 1% of PBMC constitutively produce IL-10. These CD14(-)CD36(+)CD61(+) nonadherent cells expressed general markers of hematopoietic and progenitor cells (CD45 and CD7) but no stem cell, T cell, B cell, NK cell, monocytes or dendritic cell markers. Inflammation-associated TLRs were also absent. The IL-10-producing cells had prominent nuclei, multiple mitochondria, and abundant rough endoplasmic reticulum. Healthy individuals have PBMC constitutively producing IL-10. Although the lineage of these cells remains unclear, their properties and frequency suggest a potential role in homeostatic or innate immune suppression.

The extent to which highly active antiretroviral therapy (HAART) restores human immunodeficiency virus (HIV)-specific immunity in advanced infection is unknown. Therefore, we studied how effective therapy affected HIV-specific CD8+ T cell responses in 4 individuals who had progressed to advanced infection. CD8+ T cell responses were assessed by cytotoxicity and interferon-gamma (IFN-γ) production. Proliferative CD4+ T cell responses against HIV, Candida and mitogen were measured by 3H-thymidine incorporation. Substantial immune reconstitution indicated by increased CD4+ and CD8+ T cell numbers followed suppression of viral replication. This was associated with emergence of HIV-specific cytotoxic T lymphocytes (CTL), but only concurrent with detectable viral replication. Emergent anti-HIV CTL were similar to those at earlier stages of infection in terms of their specificity, function, and CD28 phenotype. However, they were very short-lived in the absence of detectable HIV replication. Antigen-specific CD4+ T cell responses remained severely compromised. Thus, effective antiretroviral therapy restores the capacity for HIV-specific CTL responses after advanced infection. However, the transient nature of these responses suggests failure to generate stable long-lived memory cells in the absence of HIV-specific helper T cell responses.

Virus-specific cytotoxic T lymphocytes (CTL) potentially protect against viral infection, or once infection has occurred, limit viral replication and prevent the development of associated disease. Although there is evidence that generation of anti-HIV CTL allows a small minority of individuals to resist HIV infection, once HIV infection does occur, even potent CTL responses fail to control HIV replication sufficiently for protection from disease progression. Despite this ultimate failure, many investigators believe that an effective anti-HIV CTL response at least temporarily limits HIV replication and delays disease progression. In this review, we describe the salient characteristics of anti-HIV CTL, discuss some of the evidence that anti-HIV CTL modulate viral replication and disease course and present several of the more prominent explanations for their eventual failure. We conclude that strategies for modulating the CTL response in HIV-infected individuals should be applied together with highly active antiretroviral therapy to maintain or elicit anti-HIV CTL responses. If such strategies reduce dependence on antiretroviral therapy for suppression of HIV replication, this will provide direct evidence that anti-HIV CTL influence the rate of HIV replication and disease progression.

Cytotoxic T lymphocytes (CTL) that kill uninfected activated CD4+ T cells can be induced in vitro by stimulating CD8+ T cells with activated autologous CD4+ T cells. Similar CTL have been detected in circulating T cells from human immunodeficiency virus type 1 (HIV)-infected individuals. To define the in vivo correlates of this CTL activity, we studied plasma β-2 microglobulin and HIV RNA levels, T-lymphocyte subset counts, and expression of CD28 on CD8+ T cells concurrently with circulating CTL activity against uninfected CD4+ T cells in 75 HIV-infected individuals at different stages of disease progression. Mean values of each parameter were compared in subsets of this group of 75 segregated on the basis of this CTL activity. The group with CTL against uninfected activated CD4+ T lymphocytes had more CD8+ T cells, a higher percentage of CD28− CD8+ T cells, and higher plasma levels of HIV RNA and β-2 microglobulin. CTL against uninfected activated CD4+ T cells were predominantly CD28− and in HIV-infected individuals were associated with immunological or virological evidence of progressive disease. In HIV infection, circulating CTL activity against uninfected activated CD4+ T lymphocytes is associated with immune activation, CD8+ T cell expansion, accumulation of CD28− CD8+ T cells, and inadequate suppression of HIV replication.

BACKGROUND:HIV-specific cytotoxic T lymphocytes (CTL) can restrict HIV replication in acute and chronic infection, but disease progression occurs in parallel with declining CTL activity. An understanding of why CTL fail to control HIV replication might reveal important mechanisms of disease progression and enhance prospects for developing effective CTL-based immunotherapies. OBJECTIVES:To investigate the functional integrity, T-cell repertoire diversity, and HIV reactivity of CD8 T lymphocytes in individuals with advanced HIV infection. METHODS:Individuals were considered to have progressed to advanced HIV infection if their total T-cell count was < 500 x 10(6) cells/(l) on at least two successive clinic visits. CD8 T cells from these individuals were analyzed for CTL function, HIV reactivity and T-cell receptor (TCR) diversity by chromium release assays and reverse transcriptase polymerase chain reaction. RESULTS:CD8 T cells from all individuals with advanced HIV infection proliferated and differentiated into functional CTL in vitro. Despite extremely low T-cell counts and previous AIDS-defining illnesses, six individuals had inducible anti-HIV CTL responses. In two additional cases, HIV-specific CTL activity became detectable following significant treatment-associated remission of T-cell lymphopenia. Assessment of TCRbetaV gene family representation and betaV gene intrafamily diversity indicated CD8 T-cell repertoire diversity is maintained through advanced HIV infection. CONCLUSIONS:These data suggest that HIV-specific CTL activity can be selectively compromised while the functional and genetic integrity of the CD8 population as a whole remains intact. A substantial fraction of individuals retain inducible anti-HIV CTL activity through advanced HIV infection and, in at least some cases, effective treatment can restore HIV-specific CTL responses even at this late stage of disease.