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Emerging strategies to deplete the HIV reservoir.

ABSTRACT: This review highlights recent studies undertaken to further advance the search for successful approaches to eradicate HIV infection.Small pharmacological compounds such as histone deacetylase inhibitors, inhibitors of bromodomain and extraterminal proteins such as JQ1, and protein kinase C activators such as bryostatin and prostratin are proposed as putative candidates for inducing the expression of latent HIV in a so-called 'shock and kill' or 'kick and kill' strategy for HIV eradication. However, in order to achieve viral clearance, it is thought likely these compounds will have to be administered in concert with strategies that augment clearance of virus-infected cells in patients that have long been aviremic on successful antiretroviral therapy (ART). Several candidate therapies for this purpose are at hand, such as therapeutic HIV vaccines - recently shown to promote robust cytotoxic T cell responses and blunt viral rebound after ART interruption in clinical studies. HIV-infected patients treated during early infection may be ideal candidates for early studies to test these strategies, as early ART has been shown to limit the establishment of an HIV reservoir.HIV latency is multifactorial and thus the eradication of HIV infection may require multiple approaches. Translational efforts employing pharmacological methods to target HIV latency should evaluate in parallel the additional potential benefits of invigorating the immune response of HIV-infected individuals, and limiting the size of the reservoir via early ART.

SUBMITTER: Archin NM

PROVIDER: S-EPMC4031321 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Emerging strategies to deplete the HIV reservoir.

Archin Nancie M NM Margolis David M DM

Current opinion in infectious diseases 20140201 1

<h4>Purpose of review</h4>This review highlights recent studies undertaken to further advance the search for successful approaches to eradicate HIV infection.<h4>Recent findings</h4>Small pharmacological compounds such as histone deacetylase inhibitors, inhibitors of bromodomain and extraterminal proteins such as JQ1, and protein kinase C activators such as bryostatin and prostratin are proposed as putative candidates for inducing the expression of latent HIV in a so-called 'shock and kill' or ' ...[more]

PMID: 24296585

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Project description:The wasps Leptopilina heterotoma parasitize and ingest their Drosophila hosts. They produce extracellular vesicles (EVs) in the venom that are packed with proteins, some of which perform immune suppressive functions. EV interactions with blood cells of host larvae are linked to hematopoietic depletion, immune suppression, and parasite success. But how EVs disperse within the host, enter and kill hematopoietic cells is not well understood. Using an antibody marker for L. heterotoma EVs, we show that these parasite-derived structures are readily distributed within the hosts' hemolymphatic system. EVs converge around the tightly clustered cells of the posterior signaling center (PSC) of the larval lymph gland, a small hematopoietic organ in Drosophila. The PSC serves as a source of developmental signals in naïve animals. In wasp-infected animals, the PSC directs the differentiation of lymph gland progenitors into lamellocytes. These lamellocytes are needed to encapsulate the wasp egg and block parasite development. We found that L. heterotoma infection disassembles the PSC and PSC cells disperse into the disintegrating lymph gland lobes. Genetically manipulated PSC-less lymph glands remain non-responsive and largely intact in the face of L. heterotoma infection. We also show that the larval lymph gland progenitors use the endocytic machinery to internalize EVs. Once inside, L. heterotoma EVs damage the Rab7- and LAMP-positive late endocytic and phagolysosomal compartments. Rab5 maintains hematopoietic and immune quiescence as Rab5 knockdown results in hematopoietic over-proliferation and ectopic lamellocyte differentiation. Thus, both aspects of anti-parasite immunity, i.e., (a) phagocytosis of the wasp's immune-suppressive EVs, and (b) progenitor differentiation for wasp egg encapsulation reside in the lymph gland. These results help explain why the lymph gland is specifically and precisely targeted for destruction. The parasite's simultaneous and multipronged approach to block cellular immunity not only eliminates blood cells, but also tactically blocks the genetic programming needed for supplementary hematopoietic differentiation necessary for host success. In addition to its known functions in hematopoiesis, our results highlight a previously unrecognized phagocytic role of the lymph gland in cellular immunity. EV-mediated virulence strategies described for L. heterotoma are likely to be shared by other parasitoid wasps; their understanding can improve the design and development of novel therapeutics and biopesticides as well as help protect biodiversity.

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Emerging strategies to deplete the HIV reservoir.

Publications

Emerging strategies to deplete the HIV reservoir.

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