Differential Induction of Interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

Abstract

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...

Differential Induction of Rat Neuronal Excitotoxic Cell Death by Human Immunodeficiency Virus Type 1 Clade B and C Tat Proteins

“…28 Interestingly, the intact C30C31 motif found in clade B Tat was shown to be critical for exciting the NMDAR, whereas the C31S mutation, found in over 90% of clade C Tat proteins, significantly attenuated this neurotoxic response. 24,28 Moreover, clade C Tat has a reduced effect on monocyte chemotaxis and tumor necrosis factor, interleukin-10, chemokine (C-C motif) ligand 2 (CCL2), and indoleamine-2,3-dioxygenase (IDO) production from monocytes 29,30 and astrocytes, 24,26 possibly as a result of the C31S mutation. In this study, we compared the ability of clade C Tat and the full length form of Tat most commonly used to chelate zinc and whether these interactions affected the neurotoxic potential of the Tat proteins.…”

tatExon 1 Exhibits Functional Diversity during HIV-1 Subtype C Primary Infection

“…DNA binding and transcriptional activity of the NF-B p65 subunit is enhanced through direct binding to Tat via this cysteine-rich region and is complemented by a corresponding association between the arginine-rich motif of Tat, which sequesters the NF-B inhibitor, IB␣, allowing the transcription factor to relocalize to the nucleus. (83), which is reported to be important for monocyte chemotaxis and subsequent interleukin 10 (IL-10) induction (84). Abrogated binding of the CS motif in subtype C to chemokine (CC motif) receptor 2b (CCR2b) prevents downstream signaling that culminates in cytokine induction and the upregulation of chemokine (CXC motif) receptor 4 (CXCR4) on CD4 ϩ T cells (83).…”

Of Mice and Monkeys: Can Animal Models Be Utilized to Study Neurological Consequences of Pediatric HIV-1 Infection?

“…64,67,68 Clade-specific induction and severity of neuropathogensis have been reported. 64,67–69 Specifically, clade B has a higher neurotoxic potential than clade C and may account for the higher incidence of HIV-1 associated neurological disorders in adults in Western countries. 67–70 The scarce reports of neurological manifestations of HIV-1 infection in children of developing countries suggest a similar neurological profile to infected children in Western countries where clade B HIV-1 is prevalent.…”