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Lack of Detectable HIV-1 Molecular Evolution during Suppressive Antiretroviral Therapy


Anti-HIV compounds are highly effective for preventing the onset of AIDS but they do not cure infected individuals. Very low levels of virus remain detectable in the blood of most patients despite antiviral treatment and levels surge if treatment is stopped. It is crucial to understand why current treatments are not equipped to cure HIV infection so that new therapies addressing these shortcomings can be developed. By characterizing genetic sequences of HIV in patients before and during antiviral treatment, we found that the low levels of virus detected in the blood of treated patients did not result from newly infected cells but originated from cells, or the daughters of cells, that were already infected when treatment was initiated. This finding demonstrates that HIV present in blood after prolonged antiviral treatment is derived from cells infected prior to treatment which likely expanded over time through cell division. Such long lived, infected cells are likely the critical target for developing strategies to cure HIV infection.


Vyšlo v časopise: Lack of Detectable HIV-1 Molecular Evolution during Suppressive Antiretroviral Therapy. PLoS Pathog 10(3): e32767. doi:10.1371/journal.ppat.1004010
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004010

Souhrn

Anti-HIV compounds are highly effective for preventing the onset of AIDS but they do not cure infected individuals. Very low levels of virus remain detectable in the blood of most patients despite antiviral treatment and levels surge if treatment is stopped. It is crucial to understand why current treatments are not equipped to cure HIV infection so that new therapies addressing these shortcomings can be developed. By characterizing genetic sequences of HIV in patients before and during antiviral treatment, we found that the low levels of virus detected in the blood of treated patients did not result from newly infected cells but originated from cells, or the daughters of cells, that were already infected when treatment was initiated. This finding demonstrates that HIV present in blood after prolonged antiviral treatment is derived from cells infected prior to treatment which likely expanded over time through cell division. Such long lived, infected cells are likely the critical target for developing strategies to cure HIV infection.


Zdroje

1. PalmerS, MaldarelliF, WiegandA, BernsteinB, HannaGJ, et al. (2008) Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 105: 3879–3884.

2. MaldarelliF, PalmerS, KingMS, WiegandA, PolisMA, et al. (2007) ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog 3: e46.

3. CoffinJM (1995) HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267: 483–489.

4. CoffinJM (1996) HIV viral dynamics. Aids 10(Suppl 3): S75–84.

5. PerelsonAS, EssungerP, CaoY, VesanenM, HurleyA, et al. (1997) Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387: 188–191.

6. DinosoJB, KimSY, WiegandAM, PalmerSE, GangeSJ, et al. (2009) Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 106: 9403–9408.

7. GandhiRT, ZhengL, BoschRJ, ChanES, MargolisDM, et al. (2010) The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med 7(8): e1000321.

8. McMahonD, JonesJ, WiegandA, GangeSJ, KearneyM, et al. (2010) Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. Clin Infect Dis 50: 912–919.

9. BaileyJR, SedaghatAR, KiefferT, BrennanT, LeePK, et al. (2006) Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J Virol 80: 6441–6457.

10. WagnerTA, McKernanJL, TobinNH, TapiaKA, MullinsJI, et al. (2013) An increasing proportion of monotypic HIV-1 DNA sequences during antiretroviral treatment suggests proliferation of HIV-infected cells. Journal of Virology 87: 1770–1778.

11. JoosB, FischerM, KusterH, PillaiSK, WongJK, et al. (2008) HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proceedings of the National Academy of Sciences of the United States of America 105: 16725–16730.

12. ShiuC, CunninghamCK, GreenoughT, MuresanP, Sanchez-MerinoV, et al. (2009) Identification of Ongoing HIV-1 Replication in Residual Viremia during Recombinant HIV-1 Poxvirus Immunizations in Patients with Clinically Undetectable Viral Loads on Durable Suppressive HAART. J Virol 83: 9731–42.

13. ChunTW, NickleDC, JustementJS, MeyersJH, RobyG, et al. (2008) Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis 197: 714–720.

14. GunthardHF, WongJK, IgnacioCC, GuatelliJC, RiggsNL, et al. (1998) Human immunodeficiency virus replication and genotypic resistance in blood and lymph nodes after a year of potent antiretroviral therapy. J Virol 72: 2422–2428.

15. BenitoJM, LopezM, LozanoS, MartinezP, Gonzalez-LahozJ, et al. (2004) CD38 expression on CD8 T lymphocytes as a marker of residual virus replication in chronically HIV-infected patients receiving antiretroviral therapy. AIDS Res Hum Retroviruses 20: 227–233.

16. Cohen StuartJW, HazeberghMD, HamannD, OttoSA, BorleffsJC, et al. (2000) The dominant source of CD4+ and CD8+ T-cell activation in HIV infection is antigenic stimulation. J Acquir Immune Defic Syndr 25: 203–211.

17. MartinezE, ArnedoM, GinerV, GilC, CaballeroM, et al. (2001) Lymphoid tissue viral burden and duration of viral suppression in plasma. Aids 15: 1477–1482.

18. RuizL, van LunzenJ, ArnoA, StellbrinkHJ, SchneiderC, et al. (1999) Protease inhibitor-containing regimens compared with nucleoside analogues alone in the suppression of persistent HIV-1 replication in lymphoid tissue. Aids 13: F1–8.

19. MartinezMA, CabanaM, IbanezA, ClotetB, ArnoA, et al. (1999) Human immunodeficiency virus type 1 genetic evolution in patients with prolonged suppression of plasma viremia. Virology 256: 180–187.

20. LlewellynN, ZioniR, ZhuH, AndrusT, XuY, et al. (2006) Continued evolution of HIV-1 circulating in blood monocytes with antiretroviral therapy: genetic analysis of HIV-1 in monocytes and CD4+ T cells of patients with discontinued therapy. J Leukoc Biol 80: 1118–1126.

21. ShiB, KitchenC, WeiserB, MayersD, FoleyB, et al. Evolution and recombination of genes encoding HIV-1 drug resistance and tropism during antiretroviral therapy. Virology 404: 5–20.

22. ChunTW, DaveyRTJr, OstrowskiM, Shawn JustementJ, EngelD, et al. (2000) Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy. Nat Med 6: 757–761.

23. BuzonMJ, MassanellaM, LlibreJM, EsteveA, DahlV, et al. (2010) HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nature Medicine 16: 460–465.

24. HatanoH, HayesTL, DahlV, SinclairE, LeeTH, et al. (2011) A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. The Journal of infectious diseases 203: 960–968.

25. LlibreJM, BuzonMJ, MassanellaM, EsteveA, DahlV, et al. (2012) Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: a randomized 48-week study. Antiviral therapy 17: 355–364.

26. PolisMA, SidorovIA, YoderC, JankelevichS, MetcalfJ, et al. (2001) Correlation between reduction in plasma HIV-1 RNA concentration 1 week after start of antiretroviral treatment and longer-term efficacy. Lancet 358: 1760–1765.

27. MaldarelliF, KearneyM, PalmerS, StephensR, MicanJ, et al. (2013) HIV Populations are Large and Accumulate High Genetic Diversity in Nonlinear Fashion. Journal of Virology 87(18): 10313–23.

28. MensH, KearneyM, WiegandA, ShaoW, SchonningK, et al. (2010) HIV-1 continues to replicate and evolve in patients with natural control of HIV infection. Journal of Virology 84: 12971–12981.

29. ElbeikT, AlvordWG, TrichavarojR, de SouzaM, DewarR, et al. (2002) Comparative analysis of HIV-1 viral load assays on subtype quantification: Bayer Versant HIV-1 RNA 3.0 versus Roche Amplicor HIV-1 Monitor version 1.5. J Acquir Immune Defic Syndr 29: 330–339.

30. PalmerS, KearneyM, MaldarelliF, HalvasEK, BixbyCJ, et al. (2005) Multiple, linked human immunodeficiency virus type 1 drug resistance mutations in treatment-experienced patients are missed by standard genotype analysis. J Clin Microbiol 43: 406–413.

31. KearneyM, PalmerS, MaldarelliF, ShaoW, PolisMA, et al. (2008) Frequent Polymorphism at Drug Resistance Sites in HIV-1 Protease and Reverse Transcriptase. AIDS 22(4): 497–501.

32. KearneyM, MaldarelliF, ShaoW, MargolickJB, DaarES, et al. (2009) Human immunodeficiency virus type 1 population genetics and adaptation in newly infected individuals. J Virol 83: 2715–2727.

33. TamuraK, PetersonD, PetersonN, StecherG, NeiM, et al. (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Molecular Biology and Evolution 28: 2731–2739.

34. AchazG, PalmerS, KearneyM, MaldarelliF, MellorsJW, et al. (2004) A robust measure of HIV-1 population turnover within chronically infected individuals. Mol Biol Evol 21: 1902–1912.

35. RouzineIM, CoffinJM (2010) Multi-site adaptation in the presence of infrequent recombination. Theoretical Population Biology 77: 189–204.

36. HudsonRR, BoosDD, KaplanNL (1992) A statistical test for detecting geographic subdivision. Mol Biol Evol 9: 138–151.

37. Swofford DL (2003) PAUP: Phylogenetic analysis using parsimony, version 4. Sunderland (Massachusetts): Sinauer.

38. CornuetJM, LuikartG (1996) Description and power analysis of two tests for detecting recent population bottlenec.ks from allele frequency data. Genetics 144: 2001–2014.

39. ZhangQ, WangP, KimY, Haste-AndersenP, BeaverJ, et al. (2008) Immune epitope database analysis resource (IEDB-AR). Nucleic Acids Research 36: W513–518.

40. BrennanTP, WoodsJO, SedaghatAR, SilicianoJD, SilicianoRF, et al. (2009) Analysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy. Journal of Virology 83: 8470–8481.

41. NettlesRE, KiefferTL, KwonP, MonieD, HanY, et al. (2005) Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA : the journal of the American Medical Association 293: 817–829.

42. YuklSA, GianellaS, SinclairE, EplingL, LiQ, et al. (2010) Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. The Journal of infectious diseases 202: 1553–1561.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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