Abstract
The natural history of HIV-1 infection is characterized by persistent viremia, progressive CD4 lymphopenia, and profound immune suppression resulting in opportunistic infections, neoplasms, and death. Introduction of combination antiretroviral therapy has been effective in suppressing HIV-1 replication, reversing immunodeficiency to a degree, reducing HIV-1-associated complications, and thereby prolonging life. One of the most vexing challenges of prolonged antiretroviral therapy is the development of drug resistance. Antiretroviral therapies fail in a substantial number of cases, often with emergence of HIV-1 variants encoding mutations that confer potent drug resistance to individual agents or entire drug classes. Resistance testing methods have been introduced to evaluate drug resistance, and several studies have reported clinical benefits of genotyping and phenotyping assays in clinical decision-making. However, the genetic variability of HIV-1 to develop resistance exceeds the antiretroviral armamentarium, and the number of patients with drug experience and resistance to all classes of antiretrovirals continues to grow. From a clinical standpoint, it would be useful to have a more comprehensive grasp of pathogenic determinants of HIV-1 in all patients. One proposed in vitro correlate of HIV-1 pathogenic potential is the replication capacity of HIV-1. New techniques to assess HIV-1 replication potential are in development, with a commercial assay now available to analyze clinical samples. In this review we explore the experimental basis for replication capacity measurements and potential clinical applications of this methodology.
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References and Recommended Reading
Clavel F, Race E, Mammano F: HIV-1 drug resistance and viral fitness. Adv Pharmacol 2000, 49:41–66.
Nijhuis M, Deeks S, Boucher C: Implications of antiretroviral resistance on viral fitness. Curr Opin Infect Dis 2001, 14:23–28.
Quiñones-Mateu M, Arts EJ: HIV-1 fitness: implications for drug resistance, disease progression, and global epidemic evolution. In HIV-1 Sequence Compendium 2001. Los Alamos, NM: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory; 2001:134–170. Contains a compendium of mutatins and relative replication capacity assessments for HIV-1 mutations.
Coffin, JM, Hughes SH, Varmus HE: Retroviruses. Plainview, NY: Cold Spring Harbor Laboratory Press; 1997.
Bour S, Strebel K: HIV-1 accessory proteins: multifunctional components of a complex system. Adv Pharmacol 2000, 48:75–120.
Zhang YM, Imamichi H, Imamichi T, et al.: Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J Virol 1997, 71:6662–6670.
Maree AF, Keulen W, Boucher CA, De Boer RJ: Estimating relative fitness in viral competition experiments. J Virol 2000, 74:11067–11072. Description of precise fitness measurements.
Rouzine IM, Rodrigo A, Coffin JM: Transition between stochastic evolution and deterministic evolution in the presence of selection: general theory and application to virology. Microbiol Mol Biol Rev 2001, 65:151–185.
Wodarz D, Nowak MA: Mathematical models of HIV-1pathogenesis and treatment. Bioessays 2002, 24:1178–1187.
Bonhoeffer S, Barbour AD, De Boer RJ: Procedures for reliable estimation of viral fitness from time-series data. Proc R Soc Lond Biol Sci 2002, 269:1887–1893.
Mammano F, Trouplin V, Zennou V, Clavel F: Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug. J Virol 2000, 74:8524–8531.
Kosalaraksa P, Kavlick MF, Maroun V, et al.: Comparative fitness of multi-dideoxynucleoside-resistant human immunodeficiency virus type 1 (HIV-1) in an In vitro competitive HIV-1 replication assay. J Virol 1999, 73:5356–6533.
Maeda Y, Venzon DJ, Mitsuya H: Altered drug sensitivity, fitness, and evolution of human immunodeficiency virus type 1 with pol gene mutations conferring multi-dideoxynucleoside resistance. J Infect Dis 1998, 177:1207–1213.
Kellam P, Larder BA: Retroviral recombination can lead to linkage of reverse transcriptase mutations that confer increased zidovudine resistance. J Virol 1995, 69:669–674.
Lu J, Kuritzkes DR: A novel recombinant marker virus assay for comparing the relative fitness of hiv-1 reverse transcriptase variants. J Acquir Immune Defic Syndr 2001, 27:7–13.
Martinez-Picado J, Savara AV, Sutton L, D’Aquila RT: Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1. J Virol 1999, 7:3744–3752.
Martinez-Picado J, Savara AV, Shi L, et al.: Fitness of human immunodeficiency virus type 1 protease inhibitor-selected single mutants. Virology 2000, 275:318–322.
Harrigan PR, Bloor S, Larder BA: Relative replicative fitness of zidovudine-resistant human immunodeficiency virus type 1 isolates in vitro. J Virol 1998, 72:3773–3778.
Frost SD, Nijhuis M, Schuurman R, et al.: Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection. J Virol 2000, 74:6262–6268.
Quinones-Mateu ME, Tadele M, Parera M, et al.: Insertions in the reverse transcriptase increase both drug resistance and viral fitness in a human immunodeficiency virus type 1 isolate harboring the multi-nucleoside reverse transcriptase inhibitor resistance 69 insertion complex mutation. J Virol 2002, 76:10546–10552.
Archer RH, Dykes C, Gerondelis P, et al.: Mutants of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase resistant to nonnucleoside reverse transcriptase inhibitors demonstrate altered rates of RNase H cleavage that correlate with HIV-1 replication fitness in cell culture. J Virol 2000, 74:8390–8401.
Dykes C, Fox K, Lloyd A, et al.: Impact of clinical reverse transcriptase sequences on the replication capacity of HIV-1 drug-resistant mutants. Virology 2001, 285:193–203.
Seman AL, Pewen WF, Fresh LF, et al.: The replicative capacity of rhesus macaque peripheral blood mononuclear cells for simian immunodeficiency virus in vitro is predictive of the rate of progression to AIDS in vivo. J Gen Virol 2000, 81(Pt 10):2441–2449.
Newstein MC, Desrosiers RC: Effects of reverse-transcriptase mutations M184V and E89G on simian immunodeficiency virus in Rhesus monkeys. J Infect Dis 2001, 184:1262–1267.
Van Rompay KK, Matthews TB, Higgins J, et al.: Virulence and reduced fitness of simian immunodeficiency virus with the M184V mutation in reverse transcriptase. J Virol 2002, 76:6083–6092.
Shibata R, Igarashi T, Haigwood N, et al.: Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys. Nat Med 1999, 5:204–210.
Soderberg K, Denekamp L, Nikiforow S, et al.: A nucleotide substitution in the tRNA(Lys) primer binding site dramatically increases replication of recombinant simian immunodeficiency virus containing a human immunodeficiency virus type 1 reverse transcriptase. J Virol 2002, 76:5803–5806.
Ambrose Z, Hughes SH, Kewal-Ramani VN: A new reverse transcriptase-SHIV-1to study HIV-1 non-nucleoside reverse transcriptase inihibitor-resistance in pigtailed macaques. Antiviral Ther 2002, 7:S44.
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.
Stoddart CA, Liegler TJ, Mammano F, et al.: Impaired replication of protease inhibitor-resistant HIV-1 in human thymus. Nat Med 2001, 7:712–718. Detailed study of infections of thymus explants or SCID/hu thy/liv with HIV-1-containing protease mutations.
Penn ML, Myers M, Eckstein DA, et al.: Primary and recombinant HIV-1 type 1 strains resistant to protease inhibitors are pathogenic in mature human lymphoid tissues. AIDS Res Hum Retroviruses 2001, 17:517–523.
Picchio GR, Valdez H, Sabbe R, et al.: Altered viral fitness of HIV-1 following failure of protease inhibitor-based therapy. J Acquir Immune Defic Syndr 2000, 25:289–295.
Petropoulos CJ, Parkin NT, Limoli KL, et al.: A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 2000, 44:920–928. Description of phenosense assay used as basis for commercial replication capacity assay.
Lennerstrand J, Hertogs K, Stammers DK, Larder BA: Correlation between viral resistance to zidovudine and resistance at the reverse transcriptase level for a panel of human immunodeficiency virus type 1 mutants. J Virol 2001, 75:7202–7205.
Gao HQ, Boyer PL, Sarafianos SG, et al.: The role of steric hindrance in 3TC resistance of human immunodeficiency virus type-1 reverse transcriptase. J Mol Biol 2000, 300:403–418.
Iga M, Matsuda Z, Okayama A, et al.: Rapid phenotypic assay for human immunodeficiency virus type 1 protease using in vitro translation. J Virol Method 2002, 106:25–37.
Deeks SG, Wrin T, Liegler T, et al.: Virologic and immunologic consequences of discontinuing combination antiretroviraldrug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001, 344:472–480. Initial study of changes in replication capacity after discontinuing antiretroviral therapy.
Nijhuis M, Schuurman R, deJong D, et al.: Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. AIDS 1999, 13:2349–2359. Study of replication capacity upon initiation of a new PI regimen.
Mammano F, Petit C, Clavel F: Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients. J Virol 1998, 72:7632–7637. Another study of replication capacity upon initiation of a new PI regimen.
Barbour JD, Wrin T, Grant RM, et al.: Evolution of phenotypic drug susceptibility and viral replication capacity during longterm virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults. J Virol 2002, 76:11104–11112. A third study of replication capacity upon initiation of a new PI regimen, and observations of the changes in replication capacity detected during suboptimal therapy.
Grant RM, Barbour JD, Wrin T, et al.: Transmission of Drug Resistant HIV-1 exhibiting lower replication capacity is associated with higher CD4 counts. Antiviral Ther 2002, 7:S41.
Brenner BG, Routy JP, Petrella M, et al.: Persistence and fitness of multidrug-resistant human immunodeficiency virus type 1 acquired in primary infection. J Virol 2002, 76:1753–1761.
Lecossier D, Bouchonnet F, Schneider P, et al.: Discordant increases in CD4+ T cells in human immunodeficiency virusinfected patients experiencing virologic treatment failure: role of changes in thymic output and T cell death. J Infect Dis 2001, 183:1009–1016.
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Maldarelli, F. HIV-1 fitness and replication capacity: What are they and can they help in patient management?. Curr Infect Dis Rep 5, 77–84 (2003). https://doi.org/10.1007/s11908-003-0068-9
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DOI: https://doi.org/10.1007/s11908-003-0068-9