MicroRNAs (miRNAs) are small noncoding RNAs that may target more than one-third of human genes, yet the mechanisms used by miRNAs to repress translation of target mRNAs are obscure. Using a recently described cell-free assay of miRNA function, we observe that miRNA-targeted mRNAs are enriched for 40S but not 60S ribosome components. Additionally, toeprinting analysis of miRNA-targeted mRNAs demonstrates that Ϸ18 nt 3 relative to the initiating AUG are protected, consistent with 40S ribosome subunits positioned at the AUG codon. Our results suggest that miRNAs repress translation initiation by preventing 60S subunit joining to miRNA-targeted mRNAs.argonaute ͉ translation ͉ ribosome

As the AIDS epidemic unfolded, the appearance of opportunistic infections in at-risk persons provided clues to the underlying problem: a dramatic defect in cell-mediated immunity associated with infection and depletion of CD4+ T lymphocytes. Moreover, the emergence of HIV-associated malignancies in these same individuals was a clear indication of the significant role effective cellular immunity plays in combating cancers. As research in the HIV field progressed, advances included the first demonstration of the role of PD-1 in human T cell exhaustion, and the development of gene-modified T cell therapies, including chimeric antigen receptor (CAR) T cells. In the intervening years, the oncology field has capitalized on these advances, effectively mobilizing the cellular immune response to achieve immune-mediated remission or cure of previously intractable cancers. Although similar therapeutic advances have not yet been achieved in the HIV field, spontaneous CD8+ T cell mediated remission or functional cure of HIV infection does occur in very small subset of individuals in the absence of anti-retroviral therapy (ART). This has many similarities to the CD8+ T cell mediated functional control or elimination of cancers, and indicates that immunotherapy for HIV is a rational goal. In HIV infection, one major barrier to successful immunotherapy is the small, persistent population of infected CD4+ T cells, the viral reservoir, which evades pharmacological and immune-mediated clearance, and is largely maintained in secondary lymphoid tissues at sites where CD8+ T cells have limited access and/or function. The reservoir-enriched lymphoid microenvironment bears a striking resemblance to the tumor microenvironment of many solid tumors–namely high levels of anti-inflammatory cytokines, expression of co-inhibitory receptors, and physical exclusion of immune effector cells. Here, we review the parallels between CD8+ T cell-mediated immune control of HIV and cancer, and how advances in cancer immunotherapy may provide insights to direct the development of effective HIV cure strategies. Specifically, understanding the impact of the tissue microenvironment on T cell function and development of CAR T cells and therapeutic vaccines deserve robust attention on the path toward a CD8+ T cell mediated cure of HIV infection.

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Small molecules and antisense oligonucleotides that inhibit the translation initiation factors eIF4A1 and eIF4E have been explored as broad-based therapeutic agents for cancer treatment, based on the frequent upregulation of these two subunits of the eIF4F cap-binding complex in many cancer cells. Here we provide support for these therapeutic approaches with mechanistic studies of eIF4F-driven tumor progression in a preclinical model of melanoma. Silencing eIF4A1 or eIF4E decreases melanoma proliferation and invasion. There were common effects on the level of cell cycle proteins which could explain the antiproliferative effects in vitro. Using clinical specimens, we correlate the common cell cycle targets of eIF4A1 and eIF4E with patient survival. Finally, comparative proteomic and transcriptomic analyses reveal extensive mechanistic divergence in response to eIF4A1 or eIF4E silencing. Current models indicate that eIF4A1 and eIF4E function together through the 5′UTR to increase translation of oncogenes. In contrast, our data demonstrate that the common effects of eIF4A1 and eIF4E on translation are mediated by the coding region and 3′UTR. Moreover, their divergent effects occur through the 5′UTR. Overall, our work shows that it will be important to evaluate subunit-specific inhibitors of eIF4F in different disease contexts to fully understand their anticancer actions.