My research aims to understand the cellular and molecular mechanisms involved in the establishment and maintenance of HIV latent infection. A major barrier to HIV cure is the persistence of a reservoir of latently infected CD4 T cells that harbors transcriptionally silent proviral HIV and persists despite effective antiretroviral therapy. Upon treatment interruption, these latently infected cells are induced to produce replicating virus making HIV infection an incurable chronic condition. These latently infected cells mostly consist of resting memory CD4 T cells, which paradoxically, are relatively resistant to direct HIV infection. It is generally accepted that latently infected cells are generated largely by a population of productively infected activated T cells that return to a resting memory phenotype. However, work conducted during my doctoral training confirmed that direct infection of resting CD4 T cells likely also contributes to the generation of this reservoir. My recent research revealed that direct infection of resting CD4 T cells is more efficient through cell-cell contact. This process of HIV cell-to-cell transmission between T cells generated latent infection that appears to be difficult to revert into producing infectious particles. This observation suggests that unknown mechanisms of transcriptional regulation are at work when latent infection is generated through cell-to-cell transmission. This mechanism for the generation of latent infection could be a very important barrier to the eradication of HIV in vivo.
Resting CD4 T cells repress HIV through multiple mechanisms including proviral epigenetic regulation, intrinsic transcriptional repressors and limiting key transcriptional activators. In a collaborative project, we used a yeast-one-hybrid screen and identified novel transcription factors that recognize signal sequences within the proviral promoter. Some of these novel factors reveal new pathways for the transcriptional regulation of proviral HIV and are linked to T cell differentiation and maturation. Understanding how latently infected cells are established and maintained and the molecular mechanisms that allow HIV to remain latent, are essential for developing new therapies aimed at curing infected individuals.
- University of Pennsylvania, PhD
- Pennsylvania State University, BS
- Published on 8/21/2018
Agosto LM, Herring MB, Mothes W, Henderson AJ. HIV-1-Infected CD4+ T Cells Facilitate Latent Infection of Resting CD4+ T Cells through Cell-Cell Contact. Cell Rep. 2018 Aug 21; 24(8):2088-2100. PMID: 30134170.
- Published on 7/9/2018
Agosto LM, Henderson AJ. CD4+ T Cell Subsets and Pathways to HIV Latency. AIDS Res Hum Retroviruses. 2018 09; 34(9):780-789. PMID: 29869531.
- Published on 7/9/2018
Pena-Cruz V, Agosto LM, Akiyama H, Olson A, Moreau Y, Larrieux JR, Henderson A, Gummuluru S, Sagar M. HIV-1 replicates and persists in vaginal epithelial dendritic cells. J Clin Invest. 2018 Aug 01; 128(8):3439-3444. PMID: 29723162.
- Published on 6/9/2017
Miller CM, Akiyama H, Agosto LM, Emery A, Ettinger CR, Swanstrom RI, Henderson AJ, Gummuluru S. Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells. J Virol. 2017 Jul 01; 91(13). PMID: 28424288.
- Published on 9/16/2016
Agosto LM, Hirnet JB, Michaels DH, Shaik-Dasthagirisaheb YB, Gibson FC, Viglianti G, Henderson AJ. Porphyromonas gingivalis-mediated signaling through TLR4 mediates persistent HIV infection of primary macrophages. Virology. 2016 Dec; 499:72-81. PMID: 27639573.
- Published on 11/4/2015
DeMaster LK, Liu X, VanBelzen DJ, Trinité B, Zheng L, Agosto LM, Migueles SA, Connors M, Sambucetti L, Levy DN, Pasternak AO, O'Doherty U. A Subset of CD4/CD8 Double-Negative T Cells Expresses HIV Proteins in Patients on Antiretroviral Therapy. J Virol. 2015 Nov 04; 90(5):2165-79. PMID: 26537682.
- Published on 9/30/2015
Agosto LM, Gagne M, Henderson AJ. Impact of Chromatin on HIV Replication. Genes (Basel). 2015; 6(4):957-76. PMID: 26437430.
- Published on 3/9/2015
Agosto LM, Uchil PD, Mothes W. HIV cell-to-cell transmission: effects on pathogenesis and antiretroviral therapy. Trends Microbiol. 2015 May; 23(5):289-95. PMID: 25766144.
- Published on 2/27/2014
Agosto LM, Zhong P, Munro J, Mothes W. Highly active antiretroviral therapies are effective against HIV-1 cell-to-cell transmission. PLoS Pathog. 2014 Feb; 10(2):e1003982. PMID: 24586176.
- Published on 8/16/2013
Sherrill-Mix S, Lewinski MK, Famiglietti M, Bosque A, Malani N, Ocwieja KE, Berry CC, Looney D, Shan L, Agosto LM, Pace MJ, Siliciano RF, O'Doherty U, Guatelli J, Planelles V, Bushman FD. HIV latency and integration site placement in five cell-based models. Retrovirology. 2013 Aug 16; 10:90. PMID: 23953889.
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