A major challenge in the development of a cure for human immunodeficiency virus (HIV) has been the incomplete understanding of the basic mechanisms underlying HIV persistence during antiretroviral therapy. synapse and the signaling pathways involved in T-cell activation and gene regulation in the context of HIV persistence. remains unclear. However, the block in HIV production in quiescent memory CD4+ T cells extends beyond transcription, as low levels of cell-associated viral RNA have been found in resting DSP-2230 CD4+ T cells from virally suppressed subjects 39. A defect in nuclear export of RNA transcripts has been suggested to block HIV production in latently infected cells 40. A critical unanswered question pertains to the nature of signals an HIV-infected cell receives to establish and ultimately maintain a latently infected reservoir. The immunological mechanisms involved in the generation and maintenance of memory CD4+ T cells have been suggested to regulate the induction of latency and the persistence of the HIV reservoir 41. Several lines of evidence suggest that the generation of memory T cells from effector T DSP-2230 cells during HIV infection contributes to the establishment of a reservoir of long-lived latently infected cells. Latently infected memory T cells harboring replication-competent HIV can be isolated from viremic donors 16, indicating that the latent HIV reservoir is generated and maintained during the viremic phase of the disease. Negative signals, notably mediated by negative regulators of T-cell receptor (TCR) signaling 42, may initiate the transition from activated to quiescent phenotype by reducing the availability of cellular transcription factors essential for active viral gene expression, thereby establishing viral latency in long-lived memory CD4+ T cells harboring HIV-integrated DNA. Memory CD4+ T cells persist in response to prosurvival signals downstream of common chain (c) cytokines DSP-2230 [such as interleukin-7 (IL-7) and IL-15] and TCR stimulation 43C45. We have demonstrated that these cytokines contribute to the DSP-2230 persistence of HIV in this long-lived cellular compartment 17 by controlling homeostatic proliferation during ART 46, 47. Sequencing of HIV genomes in latently infected cells has revealed significant sequence homogeneity, which would support a model of homeostatic proliferation of a small number of latently infected cells 17. In contrast, a reservoir generated by ongoing viral replication and infection of new cells would be evidenced by an accumulation of mutations in the integrated HIV genomes 46, 47. Several immunological mechanisms could be responsible for proliferation-induced HIV persistence: (i) homeostatic proliferation driven by IL-7 and IL-15 48; (ii) inflammation-induced proliferation driven by proinflammatory cytokines such as IL-1, IL-6, and interferon- (IFN-) (49, discussed in this issue); (iii) antigen-induced proliferation; and (iv) self-renewal of stem cell memory T cells by Wnt/Notch signaling 50, 51. IL-7 or proinflammatory cytokines 52C54 as well as TCR engagement 55 have been shown to induce HIV production in primary CD4+ T cells to increase susceptibility of resting memory T cells to infection and establishment of latency 58, 101. Regulatory molecules of the immunological synapse Costimulatory and negative regulatory molecules can be defined as having a positive or a negative role in the regulation of TCR-mediated signals. Although some of these molecules may also have limited function outside the context of antigen recognition, costimulatory molecules play a critical role in the initiation of T-cell activation following the formation of the immunological synapse. For example, DSP-2230 association of the TCR of a naive T cell with a peptideCMHC complex without interaction of the costimulatory receptor CD28 with its primary ligand CD80 (B7.1) results in an anergic T cell that produces very low amounts of IL-2 102. CD28 is highly enriched in TCR microclusters when engaged by CD80, and these CD28CCD80 complexes are transported to the center of the immunological synapse where they form a stable ring around the cSMAC 103. CD28 has a highly conserved short cytoplasmic tail that has no intrinsic enzymatic activity. However, phosphorylation of the tyrosine residues provides docking sites for SH2 domainCcontaining proteins, whereas the proline-rich ARPC5 motifs can bind SH3 domainCcontaining proteins. The role of CD28 costimulation on IL-2 production appears to have two.