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Broad CTL Response is Required to Clear Latent HIV-1 Due To Dominance of Escape Mutations
Summary of Study
The goal of the study was to ascertain if the reversal of the latent reservoir in resting CD4 + T cells was successful in killing infected cells. Notably, HIV-1 infections persist in CD4+ T cells in their resting memory stage (Søgaard et al. 9; Archin et al. 730). Accordingly, Deng et al. conducted a cohort study at Johns Hopkins University in California that involved three cohort groups: 10 chronic-treatment patients, ten acute-treatment patients (3 months of infections), and seven non-infected patients (5). The research method involved the retrieval of plasma blood from the infected patients with HIV-1 and isolating CD4 + T cells, CD8 + T cells, and CD34 + T cells (Deng et al. 5). The cells were then cultured then sequencing was done on the proviral HIV-1 DNA in resting CD4 + T cells. The aim was to determine whether the cytotoxic T lymphocyte response was active in infected CD4 + T cells (Deng et al. 1). The researchers indicate that CTL responses were not effective since HIV-1 developed variants that could escape CTL action, rendering re-infection in patients. From this, the CD 4 + T cells were cultured along with CD 8 + T cells to stimulate them. The target was to identify if CD4 + T cells would be able to fight against HIV-1, and it was successful (Deng et al. 7). The researchers concluded success in a reverse latent reservoir in CD4 + T cells infected with HIV-1 for the improved fight against the virus (7).
Implications of the Study
The study’s implications are on the advancement of antiretroviral therapy. Currently, the basic element of ART against HIV-1 is on reducing the morbidity and mortality through the fight against the virus in CD4 + T cells in their active form (Siliciano et al. 230). However, Deng et al. have opened avenues through which ART can be improved for further action in a latent reservoir in CD4 + T cells (3).
The research has also increased the number of mutations required on the inhibition of HIV-1 replication in CD4 + T cells (Deng et al. 2; Jones et al. 1). The discovery of the CTL response variant mutations in HIV-1 will prove ideal for a further pharmacological address in developing improved ART.
Additionally, the study has also presented a new wave in HIV-1 replication in the latent reservoir. The findings have provided a differential outlook between acute-treatment patients and chronic-patients, with the latter being more affected during the resting stage of the CD4 + T cells (Deng et al. 1; Elliot et al. 1).
Finally, Deng at al. (1) have also presented original pharmacological knowledge on new drug target. The experiment has dictated that the chances of re-infection can occur when HIV-1 is present in CD4 + T cells, particularly in the resting stage (Deng et al. 1; Archin et al. 730). The information is critical to acknowledge that there is a new drug target for pharmaceutical exploration.
Pathogenesis, Treatment, and Prevention
In active state, the CD4+ T cells act as reservoirs for replication and infection of HIV-1 in the lymphoid glands (Sung 258). During this time, the cell count reduces to a point when a latent reservoir of the cells remains (Shan et al. 491; Søgaard et al. 2). At the resting stage, the CD4 + T cells are able to restrict continued replication of the HIV-1 but, the virus has mutational properties that allow it to bypass the restrictions and possibility of re-infection occurs (Jones et al. 1).
Research by Bullen et al. (425) and Rasmussen et al. (e32) have shown that early restriction of HIV-1 in resting CD4 + T cells could be a possible pharmacological drug therapy for ARTs. The drug therapy would target the inhibition of reverse transcription of the HIV-1 virus.
As for the prevention, Rasmussen et al. (e31) propose the use of enzymatic action of the SAMHD1- a host cell restriction factor- known to have actions against the virus during replication in resting CD4 + T cells.
Works Cited
Archin, Nancy M., et al. “HIV-1 Expression within Resting CD4+ T Cells After Multiple Doses Of Vorinostat.” The Journal of Infectious Diseases vol. 210, no. 5, 2014, pp. 728-735.
Bullen, C. Korin, et al. “New Ex Vivo Approaches Distinguish Effective and Ineffective Single Agents for Reversing HIV-1 Latency in Vivo.” Nature medicine 20.4 (2014): 425.
Crooks, Amanda M., et al. “Precise Quantitation of The Latent HIV-1 Reservoir: Implications For Eradication Strategies.” The Journal of Infectious Diseases vol. 212, no. 9, 2015, pp. 1361-1365.
Deng, Kai, et al. “Broad CTL Response is Required to Clear Latent HIV-1 Due to Dominance Of Escape Mutations.” Nature vol. 517, no. 7534, 2015, pp. 381-385.
Elliott, Julian H., et al. “Activation of HIV Transcription With Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy.” PLoS Pathogens vol. 10, no. 11, 2014.
Jones, Richard Brad, et al. “Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes.” PLoS Pathogens vol. 10, no. 8, 2014.
Rasmussen, Thomas A., et al. “Panobinostat, A Histone Deacetylase Inhibitor, For Latent-Virus Reactivation In HIV-Infected Patients on Suppressive Antiretroviral Therapy: A Phase 1/2, Single Group, Clinical Trial.” The Lancet HIV vol. 1, no. 1, 2014, pp. e13-e21.
Siliciano, Robert, Kai Deng, and Liang Shan. “Method and Compositions for the Prevention And Treatment of an HIV infection.” U.S. Patent Application No. 15/528,230.
Shan, Liang, et al. “Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates the Elimination of Latent Viral Reservoir After Virus Reactivation.” Immunity vol. 36, no. 3, 2012, pp. 491-501.
Søgaard, Ole S., et al. “The Depsipeptide Romidepsin Reverses HIV-1 Latency in Vivo.” PLoS Pathogens vol. 11, no. 9, 2015.
Sung, Julia A., et al. “Expanded Cytotoxic T-Cell Lymphocytes Target The Latent HIV Reservoir.” The Journal of Infectious Diseases vol. 212, no. 2, 2015, pp. 258-263.