Current Infectious Disease Reports

, Volume 6, Issue 2, pp 151–158 | Cite as

The clinical implications of reduced viral fitness

  • Jason D. Barbour
  • Robert M. Grant


Viral fitness, defined as the extent of viral adaptation to the host environment, arises from tissue tropism, immune system evasion, drug resistance, and viral replication capacity. The fitness of wild-type and drug-resistant HIV-1 varies widely, associating with plasma viremia, CD4+ T-cell count, and clinical progression. HIV-1 fitness may be measured in competitive culture assays, single cycle assays, or single cycle assays based on a subgenomic fragment of HIV-1, which has been standardized as the replication capacity assay (pol RC). During virologic failure of antiretroviral therapy, CD4 T-cell counts remain elevated while pol RC declines and remains durably lower because of drug-selected changes in the gag and pol genes. CD4 T-cell sparing also is observed among patients without evidence of drug resistance who carry a low pol RC virus. Reduced HIV-1 replication capacity and virulence may occur because of drug resistance or viral escape from host immune responses.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Mellors JW, Munoz A, Giorgi JV, et al.: Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997, 126:946–954.PubMedGoogle Scholar
  2. 2.
    Carrington M, O’Brien SJ: The influence of HLA genotype on AIDS. Annu Rev Med 2003, 54:535–551.PubMedCrossRefGoogle Scholar
  3. 3.
    Eron JJ, Benoit SL, Jemsek J, et al.: Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party. N Engl J Med 1995, 333:1662–1669.PubMedCrossRefGoogle Scholar
  4. 4.
    Ledergerber B, Egger M, Opravil M, et al.: Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet 1999, 353:863–868. This was the first report indicating that virologic failure of combination antiretroviral therapy was not associated with increased rates of clinical progression.PubMedCrossRefGoogle Scholar
  5. 5.
    Korber B, Muldoon M, Theiler J, et al.: Timing the ancestor of the HIV-1 pandemic strains. Science 2000, 288:1789–1796.PubMedCrossRefGoogle Scholar
  6. 6.
    Hahn BH, Shaw GM, De Cock KM, Sharp PM: AIDS as a zoonosis: scientific and public health implications. Science 2000, 287:607–614.PubMedCrossRefGoogle Scholar
  7. 7.
    Peeters M, Fransen K, Delaporte E, et al.: Isolation and characterization of a new chimpanzee lentivirus (simian immunodeficiency virus isolate cpz-ant) from a wild-captured chimpanzee. AIDS 1992, 6:447–451.PubMedCrossRefGoogle Scholar
  8. 8.
    Carr J, Ives J, Kelly L, et al.: Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo. Antiviral Res 2002, 54:79–88.PubMedCrossRefGoogle Scholar
  9. 9.
    Shankar N, Baghdayan AS, Gilmore MS: Modulation of virulence within a pathogenicity island in vancomycin-resistant Enterococcus faecalis. Nature 2002, 417:746–750.PubMedCrossRefGoogle Scholar
  10. 10.
    Baba T, Takeuchi F, Kuroda M, et al.: Genome and virulence determinants of high virulence community-acquired MRSA. Lancet 2002, 359:1819–1827.PubMedCrossRefGoogle Scholar
  11. 11.
    Enserink M: Resistant staph finds new niches. Science 2003, 299:1639–1641.PubMedCrossRefGoogle Scholar
  12. 12.
    Erlich KS, Mills J, Chatis P, et al.: Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989, 320:293–296.PubMedCrossRefGoogle Scholar
  13. 13.
    Barnes PF, Cave MD: Molecular epidemiology of tuberculosis. N Engl J Med 2003, 349:1149–1156.PubMedCrossRefGoogle Scholar
  14. 14.
    Bonhoeffer S, Barbour AD, De Boer RJ: Procedures for reliable estimation of viral fitness from time-series data. Proc R Soc Lond B Biol Sci 2002, 269:1887–1893.CrossRefGoogle Scholar
  15. 15.
    Grant RM, Liegler T, Elkin C, et al.: Protease inhibitor resistant HIV-1 has marked decreased fitness in vivo. Paper presented at the 8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, February 4–8, 2001.Google Scholar
  16. 16.
    Namikawa R, Kaneshima H, Lieberman M, et al.: Infection of the SCID-hu mouse by HIV-1. Science 1988, 242:1684–1686.PubMedCrossRefGoogle Scholar
  17. 17.
    Glushakova S, Baibakov B, Zimmerberg J, Margolis LB: Experimental HIV infection of human lymphoid tissue: correlation of CD4+ T cell depletion and virus syncytium-inducing/nonsyncytium-inducing phenotype in histocultures inoculated with laboratory strains and patient isolates of HIV type 1. AIDS Res Hum Retroviruses 1997, 13:461–471.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedGoogle Scholar
  20. 20.
    Yeni PG, Hammer SM, Carpenter CC, et al.: Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA 2002, 288:222–235.PubMedCrossRefGoogle Scholar
  21. 21.
    Hammer SM, Squires KE, Hughes MD, et al.: A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997, 337:725–733.PubMedCrossRefGoogle Scholar
  22. 22.
    Back NK, Nijhuis M, Keulen W, et al.: Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. Embo J 1996, 15:4040–4049.PubMedGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    Marschner IC, Collier AC, Coombs RW, et al.: Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis 1998, 177:40–47.PubMedCrossRefGoogle Scholar
  25. 25.
    Goudsmit J, de Ronde A, de Rooij E, de Boer R: Broad spectrum of in vivo fitness of human immunodeficiency virus type 1 subpopulations differing at reverse transcriptase codons 41 and 215. J Virol 1997, 71:4479–4484.PubMedGoogle Scholar
  26. 26.
    Riva C, Violin M, Cozzi-Lepri A, et al.: Transmitted virus with substitutions at position 215 and risk of virological failure in antiretroviral-naive patients starting highly active antiretroviral therapy. Paper presented at the XI International HIV Drug Resistance Workshop. Sevilla, Spain, July 2–5, 2002.Google Scholar
  27. 27.
    Hirsch M, Steigbigel R, Staszewski S, et al.: A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy. J Infect Dis 1999, 180:659–665.PubMedCrossRefGoogle Scholar
  28. 28.
    Andre P, Groettrup M, Klenerman P, et al.: An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses. Proc Natl Acad Sci USA 1998, 95:13120–13124.PubMedCrossRefGoogle Scholar
  29. 29.
    Martinez-Picado J, Morales-Lopetegi K, Wrin T, et al.: Selection of drug-resistant HIV-1 mutants in response to repeated structured treatment interruptions. AIDS 2002, 16:895–899.PubMedCrossRefGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    Zennou V, Mammano F, Paulous S, et al.: Loss of viral fitness associated with multiple Gag and Gag-Pol processing defects in human immunodeficiency virus type 1 variants selected for resistance to protease inhibitors in vivo. J Virol 1998, 72:3300–3306.PubMedGoogle Scholar
  32. 32.
    Croteau G, Doyon L, Thibeault D, et al.: Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors. J Virol 1997, 71:1089–1096.PubMedGoogle Scholar
  33. 33.
    Dauber DS, Ziermann R, Parkin N, et al.: Altered substrate specificity of drug-resistant human immunodeficiency virus type 1 protease. J Virol 2002, 76:1359–1368.PubMedGoogle Scholar
  34. 34.
    Deeks SG, Barbour JD, Martin JN, et al.: Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis 2000, 181:946–953.PubMedCrossRefGoogle Scholar
  35. 35.
    Winkelstein W Jr, Samuel M, Padian NS, Wiley JA: Selected sexual practices of San Francisco heterosexual men and risk of infection by the human immunodeficiency virus. JAMA 1987, 257:1470–1471.PubMedCrossRefGoogle Scholar
  36. 36.
    Nijhuis M, Schuurman R, de Jong 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.PubMedCrossRefGoogle Scholar
  37. 37.
    Deeks SG, Hoh R, Grant RM, et al.: CD4+ T cell kinetics and activation in human immunodeficiency virus-infected patients who remain viremic despite long-term treatment with protease inhibitor-based therapy. J Infect Dis 2002, 185:315–323.PubMedCrossRefGoogle Scholar
  38. 38.
    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. This paper demonstrated that continued viral evolution toward high phenotypic resistance to PI and NRTI components of antiretroviral therapy did not lead to recovery of replication capacity. Secondary resistance mutations, which were observed in most patients, did not “compensate” and restore pol RC, thereby allowing CD4 counts to remain elevated for the duration of observation.PubMedCrossRefGoogle Scholar
  39. 39.
    Gatanaga H, Suzuki Y, Tsang H, et al.: Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors. J Biol Chem 2002, 277:5952–5961.PubMedCrossRefGoogle Scholar
  40. 40.
    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. This paper demonstrated that cessation of therapy among patients in long-term virologic failure of a PI-based regimen was associated with return of a drug-sensitive, highly virulent form of HIV-1 with restored replication capacity. The study demonstrated that there is a residual antiviral effect of the failing regimen against the resistant viruses, indicating that drug resistance is usually partial. Partial viral load responses were correlated with changes in replication capacity.PubMedCrossRefGoogle Scholar
  41. 41.
    Liegler TJ, Hayden MS, Lee KH, et al.: Protease inhibitor-resistant HIV-1 from patients with preserved CD4 cell counts is cytopathic in activated CD4 T lymphocytes. AIDS 2001, 15:179–184.PubMedCrossRefGoogle Scholar
  42. 42.
    Penn ML, Myers M, Eckstein DA, et al.: Primary and recombinant HIV type 1 strains resistant to protease inhibitors are pathogenic in mature human lymphoid tissues. AIDS Res Hum Retroviruses 2001, 17:517–523.PubMedCrossRefGoogle Scholar
  43. 43.
    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.PubMedCrossRefGoogle Scholar
  44. 44.
    Hazenberg MD, Otto SA, van Benthem BH, et al.: Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS 2003, 17:1881–1888.PubMedCrossRefGoogle Scholar
  45. 45.
    Quinones-Mateu ME, Ball SC, Marozsan AJ, et al.: A dual infection/ competition assay shows a correlation between ex vivo human immunodeficiency virus type 1 fitness and disease progression. J Virol 2000, 74:9222–9233.PubMedCrossRefGoogle Scholar
  46. 46.
    Grant RM, Barbour JD, Wrin T, et al.: Transmission of drug resistant HIV-1 exhibiting lower replication capacity is associated with higher CD4 cell counts. Paper presented at the XI International HIV Drug Resistance Workshop. Sevilla, Spain, July 2–5, 2002.Google Scholar
  47. 47.
    Barbour JD, Hecht FM, Wrin T, et al.: Higher CD4+ T cell counts associated with low viral pro/pol replication capacity among treatment-naïve adults in early HIV-1 infection. J Infect Dis 2004, In press.Google Scholar
  48. 48.
    Daar ES, Kesle K, Lail A, et al.: HIV co-receptor tropism and replication capacity predict HIV progression [abstract H-1722c]. Paper presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, September 14–17, 2003.Google Scholar
  49. 49.
    Barbour JD, Wrin T, Deeks SG, et al.: Examination of wide variation in replication capacity of wild-type HIV-1: analysis of genotype-phenotype association via tree-structured methods. Paper presented at the XII International HIV Drug Resistance Workshop. Los Cabos, Mexico, June 10–14, 2003.Google Scholar
  50. 50.
    Moore CB, John M, James IR, et al.: Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 2002, 296:1439–1443.PubMedCrossRefGoogle Scholar
  51. 51.
    Little SJ, Holte S, Routy JP, et al.: Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med 2002, 347:385–394.PubMedCrossRefGoogle Scholar
  52. 52.
    Huang W, Gamarnik A, Limoli K, et al.: Amino acid substitutions at position 190 of human immunodeficiency virus type 1 reverse transcriptase increase susceptibility to delavirdine and impair virus replication. J Virol 2003, 77:1512–1523.PubMedCrossRefGoogle Scholar
  53. 53.
    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.PubMedCrossRefGoogle Scholar
  54. 54.
    Gerondelis P, Archer RH, Palaniappan C, et al.: The P236L delavirdine-resistant human immunodeficiency virus type 1 mutant is replication defective and demonstrates alterations in both RNA 5′-end- and DNA 3′-end-directed RNase H activities. J Virol 1999, 73:5803–5813.PubMedGoogle Scholar
  55. 55.
    Hazuda DJ, Felock P, Witmer M, et al.: Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000, 287:646–650.PubMedCrossRefGoogle Scholar
  56. 56.
    Leigh Brown AJ, Frost SD, Mathews WC, et al.: Transmission fitness of drug-resistant human immunodeficiency virus and the prevalence of resistance in the antiretroviral-treated population. J Infect Dis 2003, 187:683–686.CrossRefGoogle Scholar
  57. 57.
    Grant RM, Hecht FM, Warmerdam M, et al.: Time trends in primary HIV-1 drug resistance among recently infected persons. JAMA 2002, 288:181–188.PubMedCrossRefGoogle Scholar
  58. 58.
    Gray RH, Wawer MJ, Brookmeyer R, et al.: Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001, 357:1149–1153.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • Jason D. Barbour
  • Robert M. Grant
    • 1
  1. 1.Gladstone Institute of Virology and ImmunologySan FranciscoUSA

Personalised recommendations