HIV latency

Last updated

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]

Contents

Molecular Control of HIV Latency

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

LTR Structure

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

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

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

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

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

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

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]

Related Research Articles

<span class="mw-page-title-main">HIV</span> Human retrovirus, cause of AIDS

The human immunodeficiency viruses (HIV) are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype.

<span class="mw-page-title-main">Retrovirus</span> Family of viruses

A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. Many retroviruses cause serious diseases in humans, other mammals, and birds.

Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus like the HTL viruses, HI viruses, and BLV. It belongs to the genus Betaretrovirus. MMTV was formerly known as Bittner virus, and previously the "milk factor", referring to the extra-chromosomal vertical transmission of murine breast cancer by adoptive nursing, demonstrated in 1936, by John Joseph Bittner while working at the Jackson Laboratory in Bar Harbor, Maine. Bittner established the theory that a cancerous agent, or "milk factor", could be transmitted by cancerous mothers to young mice from a virus in their mother's milk. The majority of mammary tumors in mice are caused by mouse mammary tumor virus.

Following infection with HIV-1, the rate of clinical disease progression varies between individuals. Factors such as host susceptibility, genetics and immune function, health care and co-infections as well as viral genetic variability may affect the rate of progression to the point of needing to take medication in order not to develop AIDS.

The genome and proteins of HIV (human immunodeficiency virus) have been the subject of extensive research since the discovery of the virus in 1983. "In the search for the causative agent, it was initially believed that the virus was a form of the Human T-cell leukemia virus (HTLV), which was known at the time to affect the human immune system and cause certain leukemias. However, researchers at the Pasteur Institute in Paris isolated a previously unknown and genetically distinct retrovirus in patients with AIDS which was later named HIV." Each virion comprises a viral envelope and associated matrix enclosing a capsid, which itself encloses two copies of the single-stranded RNA genome and several enzymes. The discovery of the virus itself occurred two years following the report of the first major cases of AIDS-associated illnesses.

<span class="mw-page-title-main">Envelope glycoprotein GP120</span> Glycoprotein exposed on the surface of the HIV virus

Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1984. The 120 in its name comes from its molecular weight of 120 kDa. Gp120 is essential for virus entry into cells as it plays a vital role in attachment to specific cell surface receptors. These receptors are DC-SIGN, Heparan Sulfate Proteoglycan and a specific interaction with the CD4 receptor, particularly on helper T-cells. Binding to CD4 induces the start of a cascade of conformational changes in gp120 and gp41 that lead to the fusion of the viral membrane with the host cell membrane. Binding to CD4 is mainly electrostatic although there are van der Waals interactions and hydrogen bonds.

<span class="mw-page-title-main">APOBEC3G</span> Protein and coding gene in humans

APOBEC3G is a human enzyme encoded by the APOBEC3G gene that belongs to the APOBEC superfamily of proteins. This family of proteins has been suggested to play an important role in innate anti-viral immunity. APOBEC3G belongs to the family of cytidine deaminases that catalyze the deamination of cytidine to uridine in the single stranded DNA substrate. The C-terminal domain of A3G renders catalytic activity, several NMR and crystal structures explain the substrate specificity and catalytic activity.

Simian foamy virus (SFV) is a species of the genus Spumavirus that belongs to the family of Retroviridae. It has been identified in a wide variety of primates, including prosimians, New World and Old World monkeys, as well as apes, and each species has been shown to harbor a unique (species-specific) strain of SFV, including African green monkeys, baboons, macaques, and chimpanzees. As it is related to the more well-known retrovirus human immunodeficiency virus (HIV), its discovery in primates has led to some speculation that HIV may have been spread to the human species in Africa through contact with blood from apes, monkeys, and other primates, most likely through bushmeat-hunting practices.

<span class="mw-page-title-main">Long terminal repeat</span> DNA sequence

A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus or a retroviral provirus. All retroviral genomes are flanked by LTRs, while there are some retrotransposons without LTRs. Typically, an element flanked by a pair of LTRs will encode a reverse transcriptase and an integrase, allowing the element to be copied and inserted at a different location of the genome. Copies of such an LTR-flanked element can often be found hundreds or thousands of times in a genome. LTR retrotransposons comprise about 8% of the human genome.

Visna-maedi virus from the genus Lentivirus and subfamily Orthoretrovirinae, is a retrovirus that causes encephalitis and chronic pneumonitis in sheep. It is known as visna when found in the brain, and maedi when infecting the lungs. Lifelong, persistent infections in sheep occur in the lungs, lymph nodes, spleen, joints, central nervous system, and mammary glands; The condition is sometimes known as ovine progressive pneumonia (OPP), particularly in the United States, or Montana sheep disease. White blood cells of the monocyte/macrophage lineage are the main target of the virus.

CD4 immunoadhesin is a recombinant fusion protein consisting of a combination of CD4 and the fragment crystallizable region, similarly known as immunoglobulin. It belongs to the antibody (Ig) gene family. CD4 is a surface receptor for human immunodeficiency virus (HIV). The CD4 immunoadhesin molecular fusion allow the protein to possess key functions from each independent subunit. The CD4 specific properties include the gp120-binding and HIV-blocking capabilities. Properties specific to immunoglobulin are the long plasma half-life and Fc receptor binding. The properties of the protein means that it has potential to be used in AIDS therapy as of 2017. Specifically, CD4 immunoadhesin plays a role in antibody-dependent cell-mediated cytotoxicity (ADCC) towards HIV-infected cells. While natural anti-gp120 antibodies exhibit a response towards uninfected CD4-expressing cells that have a soluble gp120 bound to the CD4 on the cell surface, CD4 immunoadhesin, however, will not exhibit a response. One of the most relevant of these possibilities is its ability to cross the placenta.

<span class="mw-page-title-main">RELB</span> Protein-coding gene in the species Homo sapiens

Transcription factor RelB is a protein that in humans is encoded by the RELB gene.

<span class="mw-page-title-main">HTATSF1</span> Protein-coding gene in the species Homo sapiens

HIV Tat-specific factor 1 is a protein that in humans is encoded by the HTATSF1 gene.

Tat (HIV)

In molecular biology, Tat is a protein that is encoded for by the tat gene in HIV-1. Tat is a regulatory protein that drastically enhances the efficiency of viral transcription. Tat stands for "Trans-Activator of Transcription". The protein consists of between 86 and 101 amino acids depending on the subtype. Tat vastly increases the level of transcription of the HIV dsDNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to cellular factors and mediates their phosphorylation, resulting in increased transcription of all HIV genes, providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response.

<span class="mw-page-title-main">Vpr</span> Group of transport proteins

Vpr is a Human immunodeficiency virus gene and protein product. Vpr stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication and enhanced gene expression from provirus in dividing or non-dividing cells such as T cells or macrophages. Vpr also induces G2 cell cycle arrest and apoptosis in proliferating cells, which can result in immune dysfunction.

2F5 is a broadly neutralizing human monoclonal antibody (mAb) that has been shown to bind to and neutralize HIV-1 in vitro, making it a potential candidate for use in vaccine synthesis. 2F5 recognizes an epitope in the membrane-proximal external region (MPER) of HIV-1 gp41. 2F5 then binds to this epitope and its constant region interacts with the viral lipid membrane, which neutralizes the virus.

Bovine immunodeficiency virus (BIV) is a retrovirus belonging to the genus Lentivirus. It is similar to the human immunodeficiency virus (HIV) and infects cattle. The cells primarily infected are lymphocytes and monocytes/macrophages.

<span class="mw-page-title-main">IFNA16</span> Protein-coding gene in the species Homo sapiens

Interferon alpha-16, also known as IFN-alpha-16, is a protein that in humans is encoded by theIFNA16 gene.

<span class="mw-page-title-main">Sharon Lewin</span> Australian infectious disease physician and researcher

Sharon Ruth Lewin, FRACP, FAHMS is an Australian physician who is the inaugural Director of The Peter Doherty Institute for Infection and Immunity. She is also a Professor of Medicine at The University of Melbourne, a National Health and Medical Research Council (NHMRC) Practitioner Fellow, Director of the Cumming Global Centre for Pandemic Therapeutics, and President of the International AIDS Society (IAS).

Bryan Richard Cullen is a James B. Duke Professor of Molecular Genetics and Microbiology at Duke University Medical Center in Durham, North Carolina. Cullen was the Founding Director of the Duke University Center for Virology.

References

  1. 1 2 3 4 5 6 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. 1 2 3 4 5 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. 1 2 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. 1 2 3 4 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. 1 2 3 4 5 6 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. 1 2 3 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.