The use of combination antiretroviral therapy (ART) for the treatment of HIV has resulted in a significant reduction in morbidity and mortality, however HIV infection cannot be eradicated with ART alone. The major barrier to eradication of HIV is persistent long lived latently infected resting CD4+ T-cells. Developing strategies to blockthe establishment of latent infection could be used in addition to ART to eliminate or accelerate the decay of latently infected CD4+ T-cells. Our overall hypothesis is that specific chemokines, molecules involved in controlling T cell migration and recirculation, are critical for facilitatinglatent infection in resting CD4+ T-cells. Our overall aim is to identify novel interventions to blok infection of resting CD4+ T-cells by targeting host and not viral factors. To address this, we willuse a robust model we have recently developed to establish latency in vitro. In this model, resting CD4+ T-cells are incubated with chemokines that bind to chemokine receptors highly expressed on resting cells. After incubation with the relevant chemokines, cells are infected with HIV and high levels of integration and no virus production is observed, consistent with latent infection. Using this model of chemokine-induced latency, we will first determine whether the establishment of latency can be inhibited by either chemokine receptor or chemokine antagonists. Chemokine antagonists are chemokines with progressive truncation of the N-terminus end which acquire antagonist rather than agonist activity. We will specifically target chemokine receptors that we have shown are critical for HIV infection of resting CD4+ T-cells. These include CXCR3, CCR6 and CCR7. The chemokine receptor and chemokine antagonists will be evaluated alone and in combination in vitro. We will then define the mechanisms of how chemokines mediate efficient nuclear localization and integration in resting CD4+ T-cells. We will first identify the critical cytoskeletal pathways required for migration of the virus to the nucleus in a resting CD4+ T-cell. Using fluorescent microscopy we will identify whether the key pathways involve the actin or microtubule cytoskeleton. We will identify whether changes in the cytoskeleton facilitate nuclear localization in resting CD4+ T-cells and whether this is activated by a specific signaling event or simply by T-cell migration alone. Finally, we will explore the rol of the phophoinosito-3-kinase (PI3K) pathway in mediating efficient HIV integration in resting CD4+ T-cells. We will determine the relevant downstream proteins and specific nuclear factors that are important for facilitating integration. We will also define the sites of HIV integration i this model of latency and determine the relationship between integration and transcription factor binding sites. Overall, these studies may ultimately identify novel antiviral targets, specific forblocking latent infection of resting CD4+ T-cells.

Public Health Relevance

This proposal will directly address the specific aims of the FOA to develop new ideas and approaches in understanding HIV persistence. Our overall goal is to identify the role of a family of proteins called chemokines in establishing HIV latent infecton in resting CD4+ T-cells using a novel in vitro model. We will explore strategies aimed at blocking HIV infection of resting CD4+ T-cells by inhibition of chemokine function.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Lawrence, Diane M
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Monash University
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Khoury, Gabriela; Anderson, Jenny L; Fromentin, RĂ©mi et al. (2016) Persistence of integrated HIV DNA in CXCR3?+?CCR6?+?memory CD4+ T cells in HIV-infected individuals on antiretroviral therapy. AIDS 30:1511-20
Saleh, Suha; Lu, Hao K; Evans, Vanessa et al. (2016) HIV integration and the establishment of latency in CCL19-treated resting CD4(+) T cells require activation of NF-?B. Retrovirology 13:49
Gorry, Paul R; Francella, Nicholas; Lewin, Sharon R et al. (2014) HIV-1 envelope-receptor interactions required for macrophage infection and implications for current HIV-1 cure strategies. J Leukoc Biol 95:71-81
Anderson, Jenny L; Cheong, Karey; Lee, Amas K H et al. (2014) Entry of HIV in primary human resting CD4(+) T cells pretreated with the chemokine CCL19. AIDS Res Hum Retroviruses 30:207-8
Solomon, Ajantha; Tennakoon, Surekha; Leeansyah, Edwin et al. (2014) No difference in the rate of change in telomere length or telomerase activity in HIV-infected patients after three years of darunavir/ritonavir with and without nucleoside analogues in the MONET trial. PLoS One 9:e109718
Evans, Vanessa A; Kumar, Nitasha; Filali, Ali et al. (2013) Myeloid dendritic cells induce HIV-1 latency in non-proliferating CD4+ T cells. PLoS Pathog 9:e1003799
Rajasuriar, Reena; Khoury, Gabriela; Kamarulzaman, Adeeba et al. (2013) Persistent immune activation in chronic HIV infection: do any interventions work? AIDS 27:1199-208
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Spina, Celsa A; Anderson, Jenny; Archin, Nancie M et al. (2013) An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog 9:e1003834

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