Nef functions in BLT mice to enhance HIV-1 replication and deplete CD4+CD8+ thymocytes

Retrovirology

Volumn 9, Issue , 2012, Pages

  Zou, Wei ^a   Denton, Paul W ^a   Watkins, Richard L ^a   Krisko, John F ^a   Nochi, Tomonori ^a   Foster, John L ^a   Garcia, J V ^a  

^a UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

HIV 1; Humanized mouse; Nef; Pathogenicity; Replication

Indexed keywords

CD38 ANTIGEN; CD4 ANTIGEN; CD8 ANTIGEN; HLA DR ANTIGEN; NEF PROTEIN; VIRUS RNA;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CD4+ T LYMPHOCYTE; CD4+CD8+ THYMOCYTE; CELL LOSS; CONTROLLED STUDY; GENE DELETION; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; MOUSE; NEF GENE; NONHUMAN; PERIPHERAL LYMPHOCYTE; PROTEIN FUNCTION; REPRODUCIBILITY; THYMOCYTE; VIRUS GENE; VIRUS LOAD; VIRUS REPLICATION;

ACQUIRED IMMUNODEFICIENCY SYNDROME; AMINO ACID SEQUENCE; ANIMALS; ANTIGENS, CD34; ANTIGENS, CD4; ANTIGENS, CD8; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; HEK293 CELLS; HIV-1; HUMANS; LYMPHOCYTE ACTIVATION; MICE; MICE, INBRED NOD; MICE, SCID; MOLECULAR SEQUENCE DATA; NEF GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; RECEPTORS, CXCR4; RNA, VIRAL; THYMOCYTES; TIME FACTORS; VIRAL LOAD; VIRUS REPLICATION;

HUMAN IMMUNODEFICIENCY VIRUS 1; MUS;

EID: 84861419814     PISSN: None     EISSN: 17424690     Source Type: Journal    
DOI: 10.1186/1742-4690-9-44     Document Type: Article

References (71)

1. Okulicz JF, Marconi VC, Landrum ML, Wegner S, Weintrob A, Ganesan A, Hale B, Crum-Cianflone N, Delmar J, Barthel V, et al. Clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the US Department of Defense HIV natural history study. J Infect Dis 2009, 200:1714-1723. 10.1086/646609, 19852669.
2. Stevenson M. HIV-1 pathogenesis. Nat Med 2003, 9:853-860. 10.1038/nm0703-853, 12835705.
3. Braibant M, Xie J, Samri A, Agut H, Autran B, Barin F. Disease progression due to dual infection in an HLA-B57-positive asymptomatic long-term nonprogressor infected with a nef-defective HIV-1 strain. Virology 2010, 405:81-92. 10.1016/j.virol.2010.05.026, 20561662.
4. Churchill MJ, Rhodes DI, Learmont JC, Sullivan JS, Wesselingh SL, Cooke IR, Deacon NJ, Gorry PR. Longitudinal analysis of human immunodeficiency virus type 1 nef/long terminal repeat sequences in a cohort of long-term survivors infected from a single source. J Virol 2006, 80:1047-1052. 10.1128/JVI.80.2.1047-1052.2006, 1346882, 16379007.
5. Gorry PR, McPhee DA, Verity E, Dyer WB, Wesselingh SL, Learmont J, Sullivan JS, Roche M, Zaunders JJ, Gabuzda D, et al. Pathogenicity and immunogenicity of attenuated, nef-deleted HIV-1 strains in vivo. Retrovirology 2007, 4:66. 10.1186/1742-4690-4-66, 2075523, 17888184.
6. Greenough TC, Sullivan JL, Desrosiers RC. Declining CD4 T-cell counts in a person infected with nef-deleted HIV-1. N Engl J Med 1999, 340:236-237. 10.1056/NEJM199901213400314, 9917232.
7. Kondo M, Shima T, Nishizawa M, Sudo K, Iwamuro S, Okabe T, Takebe Y, Imai M. Identification of attenuated variants of HIV-1 circulating recombinant form 01_AE that are associated with slow disease progression due to gross genetic alterations in the nef/long terminal repeat sequences. J Infect Dis 2005, 192:56-61. 10.1086/430739, 15942894.
8. Rhodes DI, Ashton L, Solomon A, Carr A, Cooper D, Kaldor J, Deacon N. Characterization of three nef-defective human immunodeficiency virus type 1 strains associated with long-term nonprogression. Australian Long-Term Nonprogressor Study Group. J Virol 2000, 74:10581-10588. 10.1128/JVI.74.22.10581-10588.2000, 110932, 11044102.
9. Salvi R, Garbuglia AR, Di Caro A, Pulciani S, Montella F, Benedetto A. Grossly defective nef gene sequences in a human immunodeficiency virus type 1-seropositive long-term nonprogressor. J Virol 1998, 72:3646-3657. 109585, 9557645.
10. Hofmann-Lehmann R, Vlasak J, Williams AL, Chenine AL, McClure HM, Anderson DC, O'Neil S, Ruprecht RM. Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation. AIDS 2003, 17:157-166. 10.1097/00002030-200301240-00004, 12545074.
11. Kestler HW, Ringler DJ, Mori K, Panicali DL, Sehgal PK, Daniel MD, Desrosiers RC. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 1991, 65:651-662. 10.1016/0092-8674(91)90097-I, 2032289.
12. Hanna Z, Kay DG, Rebai N, Guimond A, Jothy S, Jolicoeur P. Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice. Cell 1998, 95:163-175. 10.1016/S0092-8674(00)81748-1, 9790524.
13. Rahim MM, Chrobak P, Hu C, Hanna Z, Jolicoeur P. Adult AIDS-like disease in a novel inducible human immunodeficiency virus type 1 Nef transgenic mouse model: CD4+ T-cell activation is Nef dependent and can occur in the absence of lymphophenia. J Virol 2009, 83:11830-11846. 10.1128/JVI.01466-09, 2772706, 19740990.
14. Skowronski J, Parks D, Mariani R. Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene. EMBO J 1993, 12:703-713. 413256, 8095017.
15. Glushakova S, Grivel JC, Suryanarayana K, Meylan P, Lifson JD, Desrosiers R, Margolis L. Nef enhances human immunodeficiency virus replication and responsiveness to interleukin-2 in human lymphoid tissue ex vivo. J Virol 1999, 73:3968-3974. 104175, 10196292.
16. Glushakova S, Munch J, Carl S, Greenough TC, Sullivan JL, Margolis L, Kirchhoff F. CD4 down-modulation by human immunodeficiency virus type 1 Nef correlates with the efficiency of viral replication and with CD4(+) T-cell depletion in human lymphoid tissue ex vivo. J Virol 2001, 75:10113-10117. 10.1128/JVI.75.21.10113-10117.2001, 114585, 11581379.
17. Homann S, Tibroni N, Baumann I, Sertel S, Keppler OT, Fackler OT. Determinants in HIV-1 Nef for enhancement of virus replication and depletion of CD4+ T lymphocytes in human lymphoid tissue ex vivo. Retrovirology 2009, 6:6. 10.1186/1742-4690-6-6, 2630989, 19146681.
18. Munch J, Rajan D, Schindler M, Specht A, Rucker E, Novembre FJ, Nerrienet E, Muller-Trutwin MC, Peeters M, Hahn BH, Kirchhoff F. Nef-mediated enhancement of virion infectivity and stimulation of viral replication are fundamental properties of primate lentiviruses. J Virol 2007, 81:13852-13864. 10.1128/JVI.00904-07, 2168858, 17928336.
19. Duus KM, Miller ED, Smith JA, Kovalev GI, Su L. Separation of human immunodeficiency virus type 1 replication from nef-mediated pathogenesis in the human thymus. J Virol 2001, 75:3916-3924. 10.1128/JVI.75.8.3916-3924.2001, 114882, 11264380.
20. Jamieson BD, Aldrovandi GM, Planelles V, Jowett JB, Gao L, Bloch LM, Chen IS, Zack JA. Requirement of human immunodeficiency virus type 1 nef for in vivo replication and pathogenicity. J Virol 1994, 68:3478-3485. 236850, 8189487.
21. Stoddart CA, Geleziunas R, Ferrell S, Linquist-Stepps V, Moreno ME, Bare C, Xu W, Yonemoto W, Bresnahan PA, McCune JM, Greene WC. Human immunodeficiency virus type 1 Nef-mediated downregulation of CD4 correlates with Nef enhancement of viral pathogenesis. J Virol 2003, 77:2124-2133. 10.1128/JVI.77.3.2124-2133.2003, 140869, 12525647.
22. Aldrovandi GM, Gao L, Bristol G, Zack JA. Regions of human immunodeficiency virus type 1 nef required for function in vivo. J Virol 1998, 72:7032-7039. 109923, 9696795.
23. Aldrovandi GM, Zack JA. Replication and pathogenicity of human immunodeficiency virus type 1 accessory gene mutants in SCID-hu mice. J Virol 1996, 70:1505-1511. 189971, 8627668.
24. Denton PW, Estes JD, Sun Z, Othieno FA, Wei BL, Wege AK, Powell DA, Payne D, Haase AT, Garcia JV. Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 2008, 5:e16. 10.1371/journal.pmed.0050016, 2194746, 18198941.
25. Denton PW, Krisko JF, Powell DA, Mathias M, Kwak YT, Martinez-Torres F, Zou W, Payne DA, Estes JD, Garcia JV. Systemic administration of antiretrovirals prior to exposure prevents rectal and intravenous HIV-1 transmission in humanized BLT mice. PLoS One 2010, 5:e8829. 10.1371/journal.pone.0008829, 2809117, 20098623.
26. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, Wege AK, Haase AT, Garcia JV. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 2006, 12:1316-1322. 10.1038/nm1431, 17057712.
27. Sun Z, Denton PW, Estes JD, Othieno FA, Wei BL, Wege AK, Melkus MW, Padgett-Thomas A, Zupancic M, Haase AT, Garcia JV. Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1. J Exp Med 2007, 204:705-714. 10.1084/jem.20062411, 2118553, 17389241.
28. Denton PW, Garcia JV. Humanized mouse models of HIV infection. AIDS Rev 2011, 13:135-148.
29. Peden K, Emerman M, Montagnier L. Changes in growth properties on passage in tissue culture of viruses derived from infectious molecular clones of HIV-1LAI, HIV-1MAL, and HIV-1ELI. Virology 1991, 185:661-672. 10.1016/0042-6822(91)90537-L, 1683726.
30. Schweighardt B, Roy AM, Meiklejohn DA, Grace EJ, Moretto WJ, Heymann JJ, Nixon DF. R5 human immunodeficiency virus type 1 (HIV-1) replicates more efficiently in primary CD4+ T-cell cultures than X4 HIV-1. J Virol 2004, 78:9164-9173. 10.1128/JVI.78.17.9164-9173.2004, 506961, 15308712.
31. Choudhary SK, Walker RM, Powell DM, Planelles V, Walsh C, Camerini D. CXCR4 tropic human immunodeficiency virus type 1 induces an apoptotic cascade in immature infected thymocytes that resembles thymocyte negative selection. Virology 2006, 352:268-284. 10.1016/j.virol.2006.04.037, 16777169.
32. Dion ML, Bordi R, Zeidan J, Asaad R, Boulassel MR, Routy JP, Lederman MM, Sekaly RP, Cheynier R. Slow disease progression and robust therapy-mediated CD4+ T-cell recovery are associated with efficient thymopoiesis during HIV-1 infection. Blood 2007, 109:2912-2920.
33. Brainard DM, Seung E, Frahm N, Cariappa A, Bailey CC, Hart WK, Shin HS, Brooks SF, Knight HL, Eichbaum Q, et al. Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice. J Virol 2009, 83:7305-7321. 10.1128/JVI.02207-08, 2704767, 19420076.
34. Denton PW, Othieno F, Martinez-Torres F, Zou W, Krisko JF, Fleming E, Zein S, Powell DA, Wahl A, Kwak YT, et al. One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. J Virol 2011, 85:7582-7593. 10.1128/JVI.00537-11, 3147928, 21593172.
35. Calugi G, Montella F, Favalli C, Benedetto A. Entire genome of a strain of human immunodeficiency virus type 1 with a deletion of nef that was recovered 20 years after primary infection: large pool of proviruses with deletions of env. J Virol 2006, 80:11892-11896. 10.1128/JVI.00932-06, 1642615, 16987968.
36. Kirchhoff F, Greenough TC, Brettler DB, Sullivan JL, Desrosiers RC. Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med 1995, 332:228-232. 10.1056/NEJM199501263320405, 7808489.
37. Miller MD, Warmerdam MT, Gaston I, Greene WC, Feinberg MB. The human immunodeficiency virus-1 nef gene product: a positive factor for viral infection and replication in primary lymphocytes and macrophages. J Exp Med 1994, 179:101-113. 10.1084/jem.179.1.101, 2191317, 8270859.
38. Pizzato M, Helander A, Popova E, Calistri A, Zamborlini A, Palu G, Gottlinger HG. Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef. Proc Natl Acad Sci U S A 2007, 104:6812-6817. 10.1073/pnas.0607622104, 1871867, 17412836.
39. Baenziger S, Tussiwand R, Schlaepfer E, Mazzucchelli L, Heikenwalder M, Kurrer MO, Behnke S, Frey J, Oxenius A, Joller H, et al. Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-gamma c-/- mice. Proc Natl Acad Sci U S A 2006, 103:15951-15956. 10.1073/pnas.0604493103, 1635108, 17038503.
40. Douek DC, Betts MR, Hill BJ, Little SJ, Lempicki R, Metcalf JA, Casazza J, Yoder C, Adelsberger JW, Stevens RA, et al. Evidence for increased T cell turnover and decreased thymic output in HIV infection. J Immunol 2001, 167:6663-6668.
41. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998, 396:690-695. 10.1038/25374, 9872319.
42. Cummins NW, Badley AD. Mechanisms of HIV-associated lymphocyte apoptosis: 2010. Cell Death Dis 2010, 1:e99. 10.1038/cddis.2010.77, 3032328, 21368875.
43. Garg H, Joshi A, Ye C, Shankar P, Manjunath N. Single amino acid change in gp41 region of HIV-1 alters bystander apoptosis and CD4 decline in humanized mice. Virol J 2011, 8:34. 10.1186/1743-422X-8-34, 3034703, 21255440.
44. Zhao RY, Li G, Bukrinsky MI. Vpr-host interactions during HIV-1 viral life cycle. J Neuroimmune Pharmacol 2011, 6:216-229. 10.1007/s11481-011-9261-z, 21318276.
45. Sato K, Misawa N, Fukuhara M, Iwami S, An DS, Ito M, Koyanagi Y. Vpu augments the initial burst phase of HIV-1 propagation and downregulates BST2 and CD4 in humanized mice. J Virol 2012, 86:5000-5013. 10.1128/JVI.07062-11, 22357275.
46. Hunt PW, Landay AL, Sinclair E, Martinson JA, Hatano H, Emu B, Norris PJ, Busch MP, Martin JN, Brooks C, et al. A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. PLoS One 2011, 6:e15924. 10.1371/journal.pone.0015924, 3031543, 21305005.
47. Long BR, Stoddart CA. Alpha interferon and HIV Infection Cause Activation of Human T Cells in NSG-BLT Mice. J Virol 2012, 86:3327-3336. 10.1128/JVI.06676-11, 3302309, 22238321.
48. Dion ML, Poulin JF, Bordi R, Sylvestre M, Corsini R, Kettaf N, Dalloul A, Boulassel MR, Debre P, Routy JP, et al. HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation. Immunity 2004, 21:757-768. 10.1016/j.immuni.2004.10.013, 15589165.
49. Gaulton GN, Scobie JV, Rosenzweig M. HIV-1 and the thymus. AIDS 1997, 11:403-414. 10.1097/00002030-199704000-00002, 9084786.
50. Dyer WB, Zaunders JJ, Yuan FF, Wang B, Learmont JC, Geczy AF, Saksena NK, McPhee DA, Gorry PR, Sullivan JS. Mechanisms of HIV non-progression; robust and sustained CD4+ T-cell proliferative responses to p24 antigen correlate with control of viraemia and lack of disease progression after long-term transfusion-acquired HIV-1 infection. Retrovirology 2008, 5:112. 10.1186/1742-4690-5-112, 2633348, 19077215.
51. Zaunders J, Dyer WB, Churchill M. The Sydney Blood Bank Cohort: implications for viral fitness as a cause of elite control. Curr Opin HIV AIDS 2011, 6:151-156. 10.1097/COH.0b013e3283454d5b, 21378562.
52. Greenough TC, Brettler DB, Kirchhoff F, Alexander L, Desrosiers RC, O'Brien SJ, Somasundaran M, Luzuriaga K, Sullivan JL. Long-term nonprogressive infection with human immunodeficiency virus type 1 in a hemophilia cohort. J Infect Dis 1999, 180:1790-1802. 10.1086/315128, 10558933.
53. Mangasarian A, Piguet V, Wang JK, Chen YL, Trono D. Nef-induced CD4 and major histocompatibility complex class I (MHC-I) down-regulation are governed by distinct determinants: N-terminal alpha helix and proline repeat of Nef selectively regulate MHC-I trafficking. J Virol 1999, 73:1964-1973. 104438, 9971776.
54. Muthumani K, Choo AY, Hwang DS, Premkumar A, Dayes NS, Harris C, Green DR, Wadsworth SA, Siekierka JJ, Weiner DB. HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. Blood 2005, 106:2059-2068. 10.1182/blood-2005-03-0932, 1895138, 15928037.
55. Muthumani K, Choo AY, Shedlock DJ, Laddy DJ, Sundaram SG, Hirao L, Wu L, Thieu KP, Chung CW, Lankaraman KM, et al. Human immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism. J Virol 2008, 82:11536-11544. 10.1128/JVI.00485-08, 2583658, 18799583.
56. Lu TC, He JC, Wang ZH, Feng X, Fukumi-Tominaga T, Chen N, Xu J, Iyengar R, Klotman PE. HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein. J Biol Chem 2008, 283:8173-8182. 10.1074/jbc.M708920200, 2276381, 18234668.
57. Franco JM, Rubio A, Martinez-Moya M, Leal M, Merchante E, Sanchez-Quijano A, Lissen E. T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood 2002, 99:3702-3706. 10.1182/blood.V99.10.3702, 11986226.
58. Kim SS, Peer D, Kumar P, Subramanya S, Wu H, Asthana D, Habiro K, Yang YG, Manjunath N, Shimaoka M, Shankar P. RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice. Mol Ther 2010, 18:370-376. 10.1038/mt.2009.271, 2839291, 19997090.
59. Lan P, Tonomura N, Shimizu A, Wang S, Yang YG. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood 2006, 108:487-492. 10.1182/blood-2005-11-4388, 16410443.
60. Rajesh D, Zhou Y, Jankowska-Gan E, Roenneburg DA, Dart ML, Torrealba J, Burlingham WJ. Th1 and Th17 immunocompetence in humanized NOD/SCID/IL2rgammanull mice. Hum Immunol 2010, 71:551-559. 10.1016/j.humimm.2010.02.019, 2875879, 20298731.
61. Gibbs JS, Regier DA, Desrosiers RC. Construction and in vitro properties of HIV-1 mutants with deletions in " nonessential" genes. AIDS Res Hum Retroviruses 1994, 10:343-350. 10.1089/aid.1994.10.343, 8068414.
62. Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol 2000, 74:11081-11087. 10.1128/JVI.74.23.11081-11087.2000, 113188, 11070003.
63. Wei BL, Denton PW, O'Neill E, Luo T, Foster JL, Garcia JV. Inhibition of lysosome and proteasome function enhances human immunodeficiency virus type 1 infection. J Virol 2005, 79:5705-5712. 10.1128/JVI.79.9.5705-5712.2005, 1082736, 15827185.
64. Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M, Dewar RL, Planta A, Liu S, Metcalf JA, et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 2003, 41:4531-4536. 10.1128/JCM.41.10.4531-4536.2003, 254331, 14532178.
65. Estable MC, Bell B, Merzouki A, Montaner JS, O'Shaughnessy MV, Sadowski IJ. Human immunodeficiency virus type 1 long terminal repeat variants from 42 patients representing all stages of infection display a wide range of sequence polymorphism and transcription activity. J Virol 1996, 70:4053-4062. 190286, 8648743.
66. Lu YC, Touzjian N, Stenzel M, Dorfman T, Sodroski JG, Haseltine WA. Identification of cis-acting repressive sequences within the negative regulatory element of human immunodeficiency virus type 1. J Virol 1990, 64:5226-5229. 248024, 2398545.
67. Chen J, Malcolm T, Estable MC, Roeder RG, Sadowski I. TFII-I regulates induction of chromosomally integrated human immunodeficiency virus type 1 long terminal repeat in cooperation with USF. J Virol 2005, 79:4396-4406. 10.1128/JVI.79.7.4396-4406.2005, 1061576, 15767439.
68. Bates DL, Barthel KK, Wu Y, Kalhor R, Stroud JC, Giffin MJ, Chen L. Crystal structure of NFAT bound to the HIV-1 LTR tandem kappaB enhancer element. Structure 2008, 16:684-694. 10.1016/j.str.2008.01.020, 2697820, 18462673.
69. Markovitz DM, Smith MJ, Hilfinger J, Hannibal MC, Petryniak B, Nabel GJ. Activation of the human immunodeficiency virus type 2 enhancer is dependent on purine box and kappa B regulatory elements. J Virol 1992, 66:5479-5484. 289105, 1501284.
70. Cooney AJ, Tsai SY, O'Malley BW, Tsai MJ. Chicken ovalbumin upstream promoter transcription factor binds to a negative regulatory region in the human immunodeficiency virus type 1 long terminal repeat. J Virol 1991, 65:2853-2860. 240909, 2033658.
71. O'Neill E, Kuo LS, Krisko JF, Tomchick DR, Garcia JV, Foster JL. Dynamic evolution of the human immunodeficiency virus type 1 pathogenic factor, Nef. J Virol 2006, 80:1311-1320. 10.1128/JVI.80.3.1311-1320.2006, 1346962, 16415008.