The clade B human immunodeficiency virus, type 1 (HIV-1) Tat (trans-acting regulatory protein) induces interleukin-10 (IL-10) production in monocytes. IL-10, an anti-inflammatory cytokine, down-regulates proinflammatory cytokines and suppresses the immune response, leading to a rapid progression from HIV-1 infection to AIDS. Nine clades of HIV-1 are responsible for the majority of infections worldwide. Recent studies demonstrate that different HIV-1 clades have biological differences in relation to transmission, replication, and disease progression. In this study, we show that the cysteine to serine mutation at position 31, found in >90% of HIV-1 clade C Tat proteins, results in a marked decrease in IL-10 production in monocytes compared with clade B Tat. Additionally, the C31S mutation found in C Tat is responsible for the inability of these Tat proteins to produce high IL-10 levels in monocytes due to its inability to induce intracellular calcium flux through L-type calcium channels. Moreover, we show that p38␣/p38␤ and phosphoinositide 3-kinase are crucial to Tat-induced IL-10 production. These findings provide further evidence that HIV-1 clades differ in their biological properties that may impact HIV-1 pathogenesis and disease progression.The human immunodeficiency virus type 1 (HIV-1) 3 transacting regulatory protein (Tat) is an 86 -101-residue protein involved in initiating viral transcription and RNA chain elongation. In addition to its primary role as a transcriptional activator of viral gene expression, Tat is actively released from unruptured, HIV-1-infected cells and is detectable in ex vivo culture supernatants and in the serum of HIV-1 infected individuals (1, 2). Most exogenous Tat studies use a truncated 86-residue HIV-1 clade B Tat with few studies examining the functions of other clades or isotypes (3). However, these studies have shown that exogenous B Tat induces the production of cytokines, such as tumor necrosis factor, chemokine (C-C motif) ligand 2 (CCL2), interleukin-6 (IL-6), and interleukin-10 (IL-10) from monocytes and macrophages (4 -9).The expression of IL-10-specific mRNA and the production of IL-10 are both increased in HIV-1-infected individuals (10 -12). IL-10 is an anti-inflammatory cytokine produced by a wide variety of cells including monocytes, macrophages, T cells, natural killer cells, and B cells (13) that down-regulates major histocompatibility complex class II (13) and inhibits T cell proliferation while reducing the production of proinflammatory cytokines. Elevated IL-10 levels are found in individuals with rapid progression to AIDS (14 -16), and individuals with higher plasma levels of IL-10 have more severely compromised T helper cell function (14 -16) combined with lower T helper cell counts (17). Interestingly, in samples from patients chronically infected with HIV, blocking the IL-10/IL-10 receptor pathway in vitro using specific antibodies enhanced CD4 ϩ T cell responses (14 -16). Therefore, maintaining low levels of IL-10 may slow HIV-1 disease progression.Recen...

We previously reported that 2,3-dideoxyinosine (didanosine, or ddI) significantly altered mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells in human immunodeficiency virus type 1 (HIV-1)-infected children who had undetectable plasma HIV-1 RNA for more than 2 years while receiving highly active antiretroviral therapy. This research examines the in vitro effects of nucleoside reverse transcriptase inhibitors (NRTIs) on mitochondria of human skeletal muscle cells (HSMCs), including myoblasts and differentiated myotubes. mtDNA, mitochondrial RNA (mtRNA), and mRNA levels for nuclear mitochondrial regulatory factors were quantified in vitro using HSMCs, including myoblasts and differentiated myotubes, treated with NRTIs singly and in combination. After 5 days of treatment, mtDNA was significantly decreased in myoblasts and myotubes treated with ddI (P < 0.001 and P ‫؍‬ 0.01, respectively) and ddI-containing regimens (P < 0.001 and P < 0.001, respectively) compared to levels in untreated cells. mtRNA (MTCYB) was also significantly decreased in the myoblasts and myotubes treated with ddI (P ‫؍‬ 0.004) and ddI-containing regimens (P < 0.001). Regardless of the NRTI regimens examined, NRTI combinations significantly decreased mtRNA (MTCO3) in myoblasts and myotubes (P ‫؍‬ 0.02 and P ‫؍‬ 0.01, respectively). No significant differences were observed for nuclear mitochondrial regulatory factor mRNA in myoblasts or myotubes when treated with NRTIs (P > 0.07). ddI and ddI-containing regimens significantly decrease mtDNA and mtRNA in HSMCs, most notably in myoblasts. These findings may be of particular importance in developing countries, where ddI is widely used for first-line treatment of HIV-infected children.