Interleukin 10 Responses Are Associated With Sustained CD4 T-Cell Counts in Treated HIV Infection

Loss of CD4 T lymphocytes is central to the pathogenesis of HIV infection. Without intervention, helper T-cell function declines, followed by broad alterations in immune responses. HIV replication is efficiently controlled in most subjects by use of highly active antiretroviral therapy (HAART), which frequently results in undetectable HIV RNA and recovery of CD4 T-cell counts. However, a substantial proportion of treated subjects appear to have a higher risk for non–AIDS-defining illnesses and a life span that is estimated to be 10 years shorter, compared with HIV-negative populations [1–5]. Low CD4 T-cell counts during HAART are associated with increased risk of cancer, liver disease, and cardiovascular disease [6–8]. Persistent activation of CD4 and CD8 T cells, detected by expression of CD38 and HLA-DR, appears to be associated with limited recovery of CD4 T-cell counts [9]; current hypotheses suggest that disease progression may be more closely associated with immune activation levels than with HIV replication levels [10–12]. The trend for a higher risk of non–AIDS-related illnesses has also been observed among participants in the Women's Interagency HIV Study (WIHS), even in the presence of virologic control and initial recovery of CD4 T-cell counts [13–16]. Interleukin 10 (IL-10) is a type II cytokine initially characterized as an inhibitor of helper T-cell subtype 1 cytokines [17]. A major immunoregulatory effect of IL-10 is inhibition of antigen presentation, acting primarily on dendritic cells and monocytes [18, 19]. IL-10 may also decrease apoptosis of B and T lymphocytes [20–22]. As a consequence, several clinical studies have investigated treatment with recombinant IL-10 for subjects with inflammatory conditions such as psoriasis, Crohn disease, or rheumatoid arthritis [23]. Toll-like receptors (TLRs) are critical components of innate immunity and play a key role in pathogen defense [24]. TLR3, the receptor for double-stranded RNA, and TLR4, the receptor for bacterial lipopolysaccharide (LPS), have recognized roles in antiviral and antibacterial immunity [25, 26]. Bacterial products leaking from the intestinal mucosa [27] and residual HIV replication [28] may contribute to chronic inflammation in treated HIV infection. We investigated the ex vivo capacity of peripheral blood mononuclear cells (PBMCs) from HIV-infected women to respond to TLR3 and TLR4 ligands, representing innate responses to pathogens of intracellular or extracellular origin, respectively. Dysregulated inflammatory cytokine responses in HIV-infected women have been reported in the WIHS [29, 30]. We observed that spontaneous release of inflammatory cytokines in vitro was demonstrable in >60% of HIV-infected women but that responses to TLR3 and TLR4 stimulation were reduced in women with HIV/hepatitis C virus (HCV) coinfection, compared with women with HIV monoinfection [29]. In contrast, IL-10 responses to TLR4 stimulation were enhanced in women with HIV monoinfection, compared with women with HIV/HCV coinfection or noninfected controls. High production of IL-10 in untreated HIV infection has been considered detrimental for virus control because of IL-10 inhibition of the antiviral activity of helper T-cell subtype 1 cytokines [31]. However, the implications of altered cytokine responses, including IL-10 production, in HAART recipients are incompletely understood. The aim of this analysis was to investigate the possible influence of cytokines produced by cells of the innate immune compartment on levels of CD4 T cells over time in treated HIV infection.