Información del artículo
La investigación realizada sobre la infección por el virus de la inmunodeficiencia humana (VIH) es un paradigma de cómo el conocimiento obtenido mediante la investigación básica se traslada al tratamiento de los pacientes. Gracias al estudio del ciclo viral y de la caracterización estructural y funcional de las proteínas del VIH disponemos en el momento actual de más de 20 fármacos para el tratamiento de los pacientes infectados. En este artículo se realiza una revisión del ciclo biológico del VIH y se destacan los pasos que representan dianas preferentes para la intervención farmacológica. En la segunda parte del trabajo se resumen las características de las principales familias que forman el esqueleto del tratamiento antirretroviral clásico y se revisan los fármacos recientemente introducidos que van dirigidos frente a nuevas dianas. Por último se realiza una aproximación a los nuevos prototipos que se encuentran en fase de desarrollo preclínico y que engrosarán en el futuro el arsenal terapéutico contra la infección por el VIH.
Palabras clave:
Antirretrovirales
Factores celulares
Proteínas virales
Entrada
Replicación
Research carried out on human immunodeficiency virus (HIV) infection illustrates the speed in the transfer of knowledge obtained from basic research to the treatment of patients. Due to studying the viral life cycle and structure and function of HIV proteins, there are currently more than 20 drugs available to treat infected patients. In this article a review is carried out on the biological cycle of HIV, highlighting those steps that represent preferential targets for pharmacological intervention. In the second part of the article, the characteristics of the main antiretroviral families that form the basis of classic antiretroviral treatment are summarised as well as reviewing the recently introduced drugs which are directed at new targets. Finally, an assessment is made of the new prototypes that are in the pre-clinical development phase and which will strengthen the future therapeutic arsenal against HIV infection.
Key words:
Antiretrovirals
Cell factors
Viral proteins
Entrance
Replication
El Texto completo está disponible en PDF
Bibliografía
[1.]
J.A. Levy.
Pathogenesis of human immunodeficiency virus infection.
Microbiol Rev, 57 (1993), pp. 183-289
[2.]
W.C. Green.
The molecular biology of human immunodeficiency virus type 1 infection.
N Engl J Med, 324 (1991), pp. 308-317
[3.]
Y. Van Kooyk, T.B. Geijtenbeek.
DC-SIGN: escape mechanism for pathogens.
Nat Rev Immunol, 3 (2003), pp. 697-709
[4.]
T.B. Geijtenbeek, R. Torensma, S.J. Van Vliet, G.C. Van Duijnhoven, G.J. Adema, Y. Van Kooyk, et al.
Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses.
Cell, 100 (2000), pp. 575-585
[5.]
T.B. Geijtenbeek, D.S. Kwon, R. Torensma, S.J. Van Vliet, G.C. Van Duijnhoven, J. Middel, et al.
DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells.
Cell, 100 (2000), pp. 587-597
[6.]
D. Klatzmann, E. Champagne, S. Chamaret, J. Gruest, D. Guetard, T. Hercend, et al.
T-lymphocyte T4 molecule behaves as a receptor for human retrovirus LAV.
Nature, 312 (1984), pp. 767-771
[7.]
Y. Feng, C.C. Broder, P.E. Kennedy, E.A. Berger.
HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane G-protein-coupled receptor.
Science, 272 (1996), pp. 872-877
[8.]
T. Dragic, V. Litwin, G.P. Allaway, S.R. Martin, Y. Huang, K.A. Nagashima, et al.
HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CCCKR-5.
Nature, 381 (1987), pp. 667-673
[9.]
E.J. Kunkel, E.C. Butcher.
Chemokines and the tissue-specific migration of lymphocytes.
Immunity, 16 (2002), pp. 1-4
[10.]
P. Loetscher, B. Moser, M. Baggiolini.
Chemokines and their receptors in lymphocyte traffic and HIV infection.
Adv Immunol, 74 (2000), pp. 127-180
[11.]
J.M. Frade, M. Llorente, M. Mellado, J. Alcamí, J.C. Gutiérrez-Ramos, A. Zaballos, et al.
The amino-terminal domain of the CCR2 chemokine receptor acts as coreceptor for HIV-1 infection.
J Clin Invest, 100 (1997), pp. 497-502
[12.]
H. Choe, M. Farzan, Y. Sun, N. Sullivan, B. Rollins, P.D. Ponath, et al.
The beta chemokine receptors CCR5 and CCR3 facilitate infection by primary HIV1 isolates.
Cell, 83 (1996), pp. 1135-1148
[13.]
C. Harrowe, C. Cheng-Mayer.
Amino acid substitution in the V3 loop are responsible for adaptation to growth in transformed T-cell lines to a primary HIV-1.
Virology, 210 (1995), pp. 490-511
[14.]
F. Cocchi, A.L. DeVico, A. Garzino-Demo, S.K. Arya, R.C. Gallo, P. Lusso.
Identification of Rantes, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factros produced by CD8+ T cells.
Science, 270 (1995), pp. 1811-1815
[15.]
E. Oberlin, A. Amara, F. Bachelerie, C. Bessia, J.L. Virelizier, F. Arenzana-Seisdedos, et al.
The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1.
Nature, 382 (1996), pp. 833-835
[16.]
A. Amara, S.L. Gall, O. Schwartz, J. Salamero, M. Montes, P. Loetscher, et al.
HIV coreceptor down-regulation as antiviral principle: SDF-1alpha-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication.
J Exp Med, 186 (1997), pp. 139-146
[17.]
W.W. Agace, A. Amara, A.I. Roberts, J.L. Pablos, S. Thelen, M. Uguccioni, et al.
Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation.
Curr Biol, 10 (2000), pp. 325-328
[18.]
W.C. Greene.
Redistricting the retroviral restriction factors.
Nat Med, 10 (2004), pp. 778-780
[19.]
S.P. Goff.
Genetic control of retrovirus susceptibility in mammalian cells.
Annu Rev Genet, 38 (2004), pp. 61-85
[20.]
M. Stremlau, M. Perron, S. Welikala, J. Sodroski.
Species-specific variation in the B30.2(SPRY) domain of TRIM5alpha determines the potency of human immunodeficiency virus restriction.
J Virol, 79 (2005), pp. 3139-3145
[21.]
M. Stremlau, C.M. Owens, M.J. Perron, M. Kiessling, P. Autissier, J. Sodroski.
The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys.
Nature, 427 (2004), pp. 848-853
[22.]
R. Gaynor.
Cellular factors involved in the regulation of HIV-1 expression.
AIDS, 6 (1992), pp. 347-363
[23.]
O. Schwartz, V. Marechal, O. Danos, J.M. Heard.
Human immunodeficiency virus type 1 Nef increases the efficiency of reverse transcription in the infected cell.
J Virol, 69 (1995), pp. 4053-4059
[24.]
A. ZackJ, S.J. Arrigo, S.R. Weitsman, A.S. Go, A. Haislip, I.S. Chen.
HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure.
Cell, 61 (1990), pp. 213-222
[25.]
M.I. Bubrinsky, T.L. Stanwick, M.P. Dempsey, M. Stevenson.
Quiescent T lymphocytes as an inducible virus reservoir of HIV-1 infection.
Science, 254 (1991), pp. 423-427
[26.]
T.W. Chun, L. Stuyver, S.B. Mizell, L.A. Ehler, J.A. Mican, M. Baseler, et al.
Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy.
Proc Natl Acad Sci U S A, 94 (1997), pp. 13193-13197
[27.]
J. Alcamí, T. Laín de Lera, L. Folgueira, M.A. Pedraza, J.M. Jacqué, F. Bachelerie, et al.
Absolute dependence on kB responsive elements for initiation and Tat-mediated amplification of HIV transcription in blood CD4 T lymphocytes.
EMBO Journal, 14 (1995), pp. 1552-1560
[28.]
M. Emerman, M.H. Malim.
HIV-1 regulatory/accesory genes: keys to unraveling viral and host cell biology.
Science, 280 (1998), pp. 1880-1884
[29.]
B.R. Cullen.
HIV-1 auxiliary proteins: making connections in a dying cell.
Cell, 93 (1998), pp. 685-692
[30.]
A.M. Sheehy, N.C. Gaddis, J.D. Choi, M.H. Malim.
Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein.
Nature, 418 (2002), pp. 646-650
[31.]
M. Marin, K.M. Rose, S.L. Kozak, D. Kabat.
HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation.
Nat Med, 9 (2003), pp. 1398-1403
[32.]
B. Mangeat, P. Turelli, G. Caron, M. Friedli, L. Perrin, D. Trono.
Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts.
Nature, 424 (2003), pp. 99-103
[33.]
Y.L. Chiu, V.B. Soros, J.F. Kreisberg, K. Stopak, W. Yonemoto, W.C. Greene.
Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells.
Nature, 435 (2005), pp. 108-114
[34.]
C. Esnault, O. Heidmann, F. Delebecque, M. Dewannieux, D. Ribet, A.J. Hance, et al.
APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses.
Nature, 433 (2005), pp. 430-433
[35.]
R.J. Pomerantz, D. Horn.
Twenty years of therapy for HIV-1 infection.
Nat Med, 9 (2003), pp. 867-873
[36.]
Panel de expertos de Gesida y Plan Nacional sobre el Sida. Recomendaciones de Gesida/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana [actualizado Ene 2008]. Disponible en: http://www.gesida.seimc.org/pcientifica/dcconsensos.asp?apnv0=pcientifica≈
[37.]
J.P. Lalezari, K. Henry, M. O’Hearn, J.S. Montaner, P.J. Piliero, B. Trottier, et al.
Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia.
N Engl J Med, 348 (2003), pp. 2186-2195
[38.]
M. Westby, C. Smith-Burchnell, J. Mori, M. Lewis, M. Mosley, M. Stockdale, et al.
Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry.
J Virol, 81 (2007), pp. 2359-2371
[39.]
D. Hardy, J. Reynes, I. Konourina, D. Wheeler, S. Moreno, E. Van der Ryst, et al.
Efficacy and safety of maraviroc plus optimized background therapy in treatment-experienced patients infected with CCR5-Tropic HIV-1: 48-week combined analysis of the MOTIVATE Studies.
Boston: 15th Conference on Retroviruses and Opportunistic Infections,
[40.]
S. Rusconi, A. Scozzafava, A. Mastrolorenzo, C.T. Supuran.
An update in the development of HIV entry inhibitors.
Curr Top Med Chem, 7 (2007), pp. 1273-1289
[41.]
K.O. Tanaka, R. Tanaka, S. Kumakura, A. Shimoyamada, K. Hirose, M. Yanaka, et al.
Development of novel orally bioavailable CXCR4 antagonists, KRH-3955 and KRH-3140: Binding specificity, pharmacokinetics and anti-HIV-1 activity in vivo and in vitro.
Denver: 13th Conference on Retroviruses and Opportunistic Infections,
[42.]
O. Hartley, H. Gaertner, J. Wilken, D. Thompson, R. Fish, A. Ramos, et al.
Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors.
Proc Natl Acad Sci U S A, 101 (2004), pp. 16460-16465
[43.]
J.D. Murga, M. Franti, D.C. Pevear, P.J. Maddon, W.C. Olson.
Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1.
Antimicrob Agents Chemother, 50 (2006), pp. 3289-3296
[44.]
F. Giguel, L. Beebe, T.S. Migone, D. Kuritzkes.
The anti-CCR5 mAb004 inhibits HIV-1 replication synergistically in combination with other antiretroviral agents but does not select for resistance during in vitro passage.
Denver: 13th Conference on Retroviruses and Opportunistic Infections,
[45.]
J. Alcami.
HIV persistence during therapy. Third international workshop.
Idrugs, 11 (2008), pp. 87-89
[46.]
W. John, T. Fisher, M. Embrey, M. Egbertson, J. Vacca, D. Hazuda, et al.
Next generation of inhibitors of HIV-1 integrase strand transfer inhibitor: Structural diversity and resistance profiles.
Boston: 15th Conference on Retroviruses and Opportunistic Infections,
[47.]
K. Salzwedel, D.E. Martin, M. Sakalian.
Maturation inhibitors: a new therapeutic class targets the virus structure.
AIDS Rev, 9 (2007), pp. 162-172
[48.]
A.M. Sheehy, N.C. Gaddis, J.D. Choi, M.H. Malim.
Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein.
Nature, 418 (2002), pp. 646-650
[49.]
M. Stremlau, C.M. Owens, M.J. Perron, M. Kiessling, P. Autissier, J. Sodroski.
The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys.
Nature, 427 (2004), pp. 848-853
[50.]
A.L. Brass, D.M. Dykxhoorn, Y. Benita, N. Yan, A. Engelman, R.J. Xavier, et al.
Identification of host proteins required for HIV infection through a functional genomic screen.
Science, 319 (2008), pp. 921-926
[51.]
R. Harris.
The potential for exploiting host restriction factors for therapy.
Boston: 15th Conference on Retroviruses and Opportunistic Infections,
Copyright © 2008. Elsevier España S.L.. Todos los derechos reservados
