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Human Immunodeficiency Virus (HIV) has the capability to enter a latent stage of infection where it exists as a dormant provirus in CD4+ T-cells. Most latently infected cells are resting memory T cells,[1] however a small fraction of latently infected cells isolated from HIV patients are naive CD4 T cells.[2]

Molecular Control of HIV Latency

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HIV transcription is controlled by the 5' Long Terminal Repeat (LTR) region of the provirus, which serves as the key promoter.[3]

LTR Structure

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The LTR promoter has multiple upstream DNA regulatory elements: there are three SP1-binding sites, a TATA element, and an initiator sequence.[4] The LTR has two NF-кB binding motifs that are capable of binding both NF-кB transcription factors as well as NFATs.[4] The LTR promoter is very noisy[5] and prone to large bursts of transcription.[6] While signaling through the NF-кB enhancers has been shown to be necessary for re-activation of latent proviruses, mutations in these sites do not completely inhibit viral growth in cell line experiments.[7]

Tat Control of HIV Transcription

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The LTR of HIV is positively auto regulated by the Tat (transcription activator) protein, which is found towards the 3' end of the HIV genome. Without Tat activity, HIV transcription is restricted and often results in abortive transcripts.[8] Tat activates the LTR through interactions with the elongation factor P-TEFb;[9] Tat binds to cyclin T1, which is a unit of P-TEFb.[9][10] Tat:P-TEFb directs RNA polymerases to the provirus genome by binding the HIV transactivation response (TAR) element, an RNA stem-loop structure.[4][11]

Latency Regulation

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The mechanisms underpinning HIV latency and proviral induction are not thoroughly understood, and two competing models attempt to explain how latency is controlled.

Cell-dependent control

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In the cell-dependent model of latency regulation, host cell processes control provirus latency and induction. Generally, this model proposes that the relaxation of active CD4+ T-cells to a resting or quiescent state as memory T cells restricts proviral transcription and leads to latency.[12]

Multiple host-cell processes have been experimentally linked to HIV latency regulation. Observations both in patient samples and in vitro experiments with T cell lines have correlated latency with the relaxation of activated T cells to a resting-memory state.[1][13] Latency was initially thought to be due to HIV proviral genome integration into heterochromatin, but later it was found that latent proviral transcripts were still preferentially integrated into active genes.[14] The main changes in cell state observed are epigenetic silencing of the HIV LTR as well as cytosolic sequestration of NF-кB and NFAST, which can activate HIV transcription if present in the nucleus.[1] The LTRs of latent proviruses acquire heterochromatic structures instead of integrating into previously heterochromatic areas,[4] and show high levels of deacetylated and methylated histones,[15][16] which reinforces the role of chromatin restriction in latency regulation.[17] Histone deacetylases (HDACs) are recruited to the proviral genome during latency establishment and methylate key Histone H3 Lysines, indicating a role of HDACs in latency regulation.[1]

In addition to cytosolic sequestration of transcription factors, the P-TEFb complex is restricted in quiescent T cells through incorporation into an RNP complex.[18] In latently infected cells, NF-кB induction and TNF-α have been shown to be necessary but not sufficient for viral induction.[1][19] T-cell Receptor (TCR) activation has been shown to activate proviral transcription in latently-infected memory T cells, indicating some correlation between proviral induction and T cell state.[1]

Cell-autonomous control

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In contrast to the cell-dependent model, the cell-autonomous model proposes that HIV latency decisions are largely driven by the Tat-positive feedback loop and latency is therefore a probabilistic response due to intrinsically generated phenotypic heterogeneity rather than host-cell-determined.[12]

Multiple studies have found that proviral induction is dependent on the Tat autoregulation response.[12][11] In a study focused on understanding the diversity of roles of Sp1 and NF-кB binding elements in the LTR, authors noted that the Tat autoregulatory circuit resulted in a phenotypic bifurcation of genetically identical cells where viral gene expression was either off or highly induced.[11] Additionally, primate studies of HIV latency have shown that latent cells emerge before the adaptive immune response is established, indicating that latency cannot entirely be dependent on T-cell relaxation after peak adaptive immune response.[20] Latency is also established in cell-culture models with up to a 50% probability of establishment.[12][21][22]

Some research has shown that the Tat positive-feedback loop in isolation has the ability to establish latency via stochastic noise,[23] and that T-cell relaxation is not sufficient to drive latency.[12] This model proposes to explain why many latent proviruses are not reactivated along with T-cell reactivation: instead of a deterministic mechanism, cellular activation or relaxation would probabilistically affect HIV latency decisions,[12] which is consistent with other work showing that LTR regulatory sites have some influence on the frequency of phenotypic bifurcation of HIV transcription.[11]

Bet-Hedging Hypothesis

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One key hypothesis put forward is that latency allows HIV infection to persist past the initial mucosal stage; latently infected cells could allow HIV to disseminate from mucosal tissue to lymph nodes with much higher populations of the target CD4+ T cells.[24] This hypothesis is supported by observations that HIV infections appear to expand from single founder sequences,[25][26] indicating that the mucosal infection provides a bottleneck.[24] A two-compartment model of HIV dissemination and transmission predicts that the probability of latency for an HIV provirus should be close to 50% to balance dissemination from the mucosal tissue and transmission inoculum.[24]

Clinical Relevance

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Latently infected cells are the key barrier to viral elimination by current antiretroviral therapies. A study focused on determining the frequency of latently infected cells in patients on combination antiretroviral therapy found that latently infected cells created a stable reservoir of virus with a half-life of 43 months.[27] This latent reservoir forces patients to continuously take antiretroviral therapy to avoid viral re-emergence. An additional study found that actively infected cells and viremia re-emerge within weeks of antiretroviral therapy being discontinued.[28]

Some work has been put into a "shock and kill" strategy to circumvent the challenge posed by latently infected reservoirs: before antiretrovirals, there is a "shock" phase that attempts to reactivate most latent proviruses. So far, these "shock" phases focus on drugs that stimulate P-TEFb nuclear mobilization and direct transcriptional activation of HIV.[4] Further work is being done to understand LTR noise and more effectively activate or kill latently infected cells.[29]

References

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  1. ^ a b c d e f Tyagi, Mudit; Pearson, Richard John; Karn, Jonathan (July 2010). "Establishment of HIV Latency in Primary CD4 + Cells Is due to Epigenetic Transcriptional Silencing and P-TEFb Restriction". Journal of Virology. 84 (13): 6425–6437. doi:10.1128/JVI.01519-09. ISSN 0022-538X. PMC 2903277. PMID 20410271.
  2. ^ Brenchley, Jason M.; Hill, Brenna J.; Ambrozak, David R.; Price, David A.; Guenaga, Francisco J.; Casazza, Joseph P.; Kuruppu, Janaki; Yazdani, Javaidia; Migueles, Stephen A.; Connors, Mark; Roederer, Mario; Douek, Daniel C.; Koup, Richard A. (February 2004). "T-Cell Subsets That Harbor Human Immunodeficiency Virus (HIV) In Vivo: Implications for HIV Pathogenesis". Journal of Virology. 78 (3): 1160–1168. doi:10.1128/JVI.78.3.1160-1168.2004. ISSN 0022-538X. PMC 321406. PMID 14722271.
  3. ^ German Advisory Committee Blood (Arbeitskreis Blut), Subgroup 'Assessment of Pathogens Transmissible by Blood' (2016). "Human Immunodeficiency Virus (HIV)". Transfusion Medicine and Hemotherapy. 43 (3): 203–222. doi:10.1159/000445852. ISSN 1660-3796. PMC 4924471. PMID 27403093.
  4. ^ a b c d e Karn, Jonathan (January 2011). "The molecular biology of HIV latency: breaking and restoring the Tat-dependent transcriptional circuit". Current Opinion in HIV and AIDS. 6 (1): 4–11. doi:10.1097/COH.0b013e328340ffbb. ISSN 1746-630X. PMC 3032057. PMID 21242887.
  5. ^ Singh, Abhyudai; Razooky, Brandon; Cox, Chris D.; Simpson, Michael L.; Weinberger, Leor S. (April 2010). "Transcriptional Bursting from the HIV-1 Promoter Is a Significant Source of Stochastic Noise in HIV-1 Gene Expression". Biophysical Journal. 98 (8): L32–L34. Bibcode:2010BpJ....98L..32S. doi:10.1016/j.bpj.2010.03.001. ISSN 0006-3495. PMC 2856162. PMID 20409455.
  6. ^ Singh, Abhyudai; Razooky, Brandon S; Dar, Roy D; Weinberger, Leor S (January 2012). "Dynamics of protein noise can distinguish between alternate sources of gene-expression variability". Molecular Systems Biology. 8 (1): 607. doi:10.1038/msb.2012.38. ISSN 1744-4292. PMC 3435505. PMID 22929617.
  7. ^ Chen, B K; Feinberg, M B; Baltimore, D (July 1997). "The kappaB sites in the human immunodeficiency virus type 1 long terminal repeat enhance virus replication yet are not absolutely required for viral growth". Journal of Virology. 71 (7): 5495–5504. doi:10.1128/jvi.71.7.5495-5504.1997. ISSN 0022-538X. PMC 191791. PMID 9188623.
  8. ^ Williams, Samuel A; Chen, Lin-Feng; Kwon, Hakju; Ruiz-Jarabo, Carmen M; Verdin, Eric; Greene, Warner C (2006-01-11). "NF-κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation". The EMBO Journal. 25 (1): 139–149. doi:10.1038/sj.emboj.7600900. ISSN 0261-4189. PMC 1356344. PMID 16319923.
  9. ^ a b Wei, Ping; Garber, Mitchell E; Fang, Shi-Min; Fischer, Wolfgang H; Jones, Katherine A (February 1998). "A Novel CDK9-Associated C-Type Cyclin Interacts Directly with HIV-1 Tat and Mediates Its High-Affinity, Loop-Specific Binding to TAR RNA". Cell. 92 (4): 451–462. doi:10.1016/s0092-8674(00)80939-3. ISSN 0092-8674. PMID 9491887.
  10. ^ Fujinaga, Koh; Cujec, Thomas P.; Peng, Junmin; Garriga, Judit; Price, David H.; Graña, Xavier; Peterlin, B. Matija (September 1998). "The Ability of Positive Transcription Elongation Factor b To Transactivate Human Immunodeficiency Virus Transcription Depends on a Functional Kinase Domain, Cyclin T1, and Tat". Journal of Virology. 72 (9): 7154–7159. doi:10.1128/jvi.72.9.7154-7159.1998. ISSN 0022-538X. PMC 109937. PMID 9696809.
  11. ^ a b c d Burnett, John C.; Miller-Jensen, Kathryn; Shah, Priya S.; Arkin, Adam P.; Schaffer, David V. (2009-01-09). Bieniasz, Paul D. (ed.). "Control of Stochastic Gene Expression by Host Factors at the HIV Promoter". PLOS Pathogens. 5 (1): e1000260. doi:10.1371/journal.ppat.1000260. ISSN 1553-7374. PMC 2607019. PMID 19132086.
  12. ^ a b c d e f Razooky, Brandon S.; Pai, Anand; Aull, Katherine; Rouzine, Igor M.; Weinberger, Leor S. (February 2015). "A Hardwired HIV Latency Program". Cell. 160 (5): 990–1001. doi:10.1016/j.cell.2015.02.009. PMC 4395878. PMID 25723172.
  13. ^ Pearson, Richard; Kim, Young Kyeung; Hokello, Joseph; Lassen, Kara; Friedman, Julia; Tyagi, Mudit; Karn, Jonathan (2008-12-15). "Epigenetic Silencing of Human Immunodeficiency Virus (HIV) Transcription by Formation of Restrictive Chromatin Structures at the Viral Long Terminal Repeat Drives the Progressive Entry of HIV into Latency". Journal of Virology. 82 (24): 12291–12303. doi:10.1128/JVI.01383-08. ISSN 0022-538X. PMC 2593349. PMID 18829756.
  14. ^ Lewinski, M. K.; Bisgrove, D.; Shinn, P.; Chen, H.; Hoffmann, C.; Hannenhalli, S.; Verdin, E.; Berry, C. C.; Ecker, J. R.; Bushman, F. D. (June 2005). "Genome-Wide Analysis of Chromosomal Features Repressing Human Immunodeficiency Virus Transcription". Journal of Virology. 79 (11): 6610–6619. doi:10.1128/jvi.79.11.6610-6619.2005. ISSN 0022-538X. PMC 1112149. PMID 15890899.
  15. ^ Verdin, E.; Paras, P.; Van Lint, C. (August 1993). "Chromatin disruption in the promoter of human immunodeficiency virus type 1 during transcriptional activation". The EMBO Journal. 12 (8): 3249–3259. doi:10.1002/j.1460-2075.1993.tb05994.x. ISSN 0261-4189. PMC 413592. PMID 8344262.
  16. ^ Williams, Samuel A; Chen, Lin-Feng; Kwon, Hakju; Ruiz-Jarabo, Carmen M; Verdin, Eric; Greene, Warner C (2005-12-01). "NF-κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation". The EMBO Journal. 25 (1): 139–149. doi:10.1038/sj.emboj.7600900. ISSN 0261-4189. PMC 1356344. PMID 16319923.
  17. ^ Ylisastigui, Loyda; Archin, Nancie M; Lehrman, Ginger; Bosch, Ronald J; Margolis, David M (May 2004). "Coaxing HIV-1 from resting CD4 T cells". AIDS. 18 (8): 1101–1108. doi:10.1097/00002030-200405210-00003. ISSN 0269-9370. PMID 15166525.
  18. ^ Nguyen, Van Trung; Kiss, Tamás; Michels, Annemieke A.; Bensaude, Olivier (November 2001). "7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes". Nature. 414 (6861): 322–325. Bibcode:2001Natur.414..322N. doi:10.1038/35104581. ISSN 0028-0836. PMID 11713533. S2CID 4341651.
  19. ^ Brooks, David G.; Kitchen, Scott G.; Kitchen, Christina M. R.; Scripture-Adams, Deirdre D.; Zack, Jerome A. (April 2001). "Generation of HIV latency during thymopoiesis". Nature Medicine. 7 (4): 459–464. doi:10.1038/86531. ISSN 1078-8956. PMID 11283673. S2CID 12685909.
  20. ^ Whitney, James B.; Hill, Alison L.; Sanisetty, Srisowmya; Penaloza-MacMaster, Pablo; Liu, Jinyan; Shetty, Mayuri; Parenteau, Lily; Cabral, Crystal; Shields, Jennifer; Blackmore, Stephen; Smith, Jeffrey Y.; Brinkman, Amanda L.; Peter, Lauren E.; Mathew, Sheeba I.; Smith, Kaitlin M. (August 2014). "Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys". Nature. 512 (7512): 74–77. Bibcode:2014Natur.512...74W. doi:10.1038/nature13594. ISSN 0028-0836. PMC 4126858. PMID 25042999.
  21. ^ Calvanese, Vincenzo; Chavez, Leonard; Laurent, Timothy; Ding, Sheng; Verdin, Eric (November 2013). "Dual-color HIV reporters trace a population of latently infected cells and enable their purification". Virology. 446 (1–2): 283–292. doi:10.1016/j.virol.2013.07.037. PMC 4019006. PMID 24074592.
  22. ^ Dahabieh, Matthew S.; Ooms, Marcel; Simon, Viviana; Sadowski, Ivan (2013-04-15). "A Doubly Fluorescent HIV-1 Reporter Shows that the Majority of Integrated HIV-1 Is Latent Shortly after Infection". Journal of Virology. 87 (8): 4716–4727. doi:10.1128/JVI.03478-12. ISSN 0022-538X. PMC 3624398. PMID 23408629.
  23. ^ Weinberger, Leor S.; Burnett, John C.; Toettcher, Jared E.; Arkin, Adam P.; Schaffer, David V. (July 2005). "Stochastic Gene Expression in a Lentiviral Positive-Feedback Loop: HIV-1 Tat Fluctuations Drive Phenotypic Diversity". Cell. 122 (2): 169–182. arXiv:q-bio/0608002. doi:10.1016/j.cell.2005.06.006. PMID 16051143.
  24. ^ a b c Rouzine, Igor M.; Weinberger, Ariel D.; Weinberger, Leor S. (February 2015). "An Evolutionary Role for HIV Latency in Enhancing Viral Transmission". Cell. 160 (5): 1002–1012. doi:10.1016/j.cell.2015.02.017. PMC 4488136. PMID 25723173.
  25. ^ Kearney, M.; Maldarelli, F.; Shao, W.; Margolick, J. B.; Daar, E. S.; Mellors, J. W.; Rao, V.; Coffin, J. M.; Palmer, S. (2009-03-15). "Human Immunodeficiency Virus Type 1 Population Genetics and Adaptation in Newly Infected Individuals". Journal of Virology. 83 (6): 2715–2727. doi:10.1128/jvi.01960-08. ISSN 0022-538X. PMC 2648286. PMID 19116249.
  26. ^ Keele, Brandon F.; Giorgi, Elena E.; Salazar-Gonzalez, Jesus F.; Decker, Julie M.; Pham, Kimmy T.; Salazar, Maria G.; Sun, Chuanxi; Grayson, Truman; Wang, Shuyi; Li, Hui; Wei, Xiping; Jiang, Chunlai; Kirchherr, Jennifer L.; Gao, Feng; Anderson, Jeffery A. (2008-05-27). "Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection". Proceedings of the National Academy of Sciences. 105 (21): 7552–7557. Bibcode:2008PNAS..105.7552K. doi:10.1073/pnas.0802203105. ISSN 0027-8424. PMC 2387184. PMID 18490657.
  27. ^ Finzi, Diana; Blankson, Joel; Siliciano, Janet D.; Margolick, Joseph B.; Chadwick, Karen; Pierson, Theodore; Smith, Kendall; Lisziewicz, Julianna; Lori, Franco; Flexner, Charles; Quinn, Thomas C.; Chaisson, Richard E.; Rosenberg, Eric; Walker, Bruce; Gange, Stephen (May 1999). "Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy". Nature Medicine. 5 (5): 512–517. doi:10.1038/8394. ISSN 1078-8956. PMID 10229227. S2CID 30573138.
  28. ^ Chun, Tae-Wook; Davey, Richard T.; Engel, Delphine; Lane, H. Clifford; Fauci, Anthony S. (October 1999). "Re-emergence of HIV after stopping therapy". Nature. 401 (6756): 874–875. doi:10.1038/44755. ISSN 0028-0836. PMID 10553903. S2CID 4347459.
  29. ^ Weinberger, Leor S (December 2015). "A minimal fate-selection switch". Current Opinion in Cell Biology. 37: 111–118. doi:10.1016/j.ceb.2015.10.005. PMID 26611210.
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