Current HIV/AIDS Reports

, Volume 2, Issue 1, pp 29–34 | Cite as

The role of viral fitness in HIV pathogenesis

  • Jason D. Barbour
  • Robert M. Grant

Abstract

The development of clinical symptoms, and clinical progression among persons infected with HIV-1 is the manifestation of the effects of the pathogenic viral life cycle of HIV-1. Individual variants of HIV-1 vary widely in features that determine viral fitness and virulence. HIV-1 exploits host antiviral responses, the APOBEC3G cytidine deaminase, and the low-fidelity HIV-1 reverse transcriptase, to ensure new variants with novel phenotypic features are continually present for expansion in response to changing conditions in the host, such as immune responses, or antiretroviral therapy. This highlevel variance has led to a wide range in observed fitness and virulence, across strains of HIV-1. The HIV-1 pol replication capacity assay (pol RC) measures features of viral fitness, associates with elevated CD4+ T-cell counts, yet is not strongly associated with HIV-1 RNA levels. The biological basis for elevated CD4+ T-cell counts among those carrying a virus of low pol RC may be because of lowered virus infectivity, or restricted tissue replication.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Yu Q, Konig R, Pillai S, et al.: Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome. Nat Struct Mol Biol 2004, 11:435–442.CrossRefPubMedGoogle Scholar
  2. 2.
    Preston BD, Poiesz BJ, Loeb LA: Fidelity of HIV-1 reverse transcriptase. Science 1988, 242:1168–1171.CrossRefPubMedGoogle Scholar
  3. 3.
    Mansky LM, Temin HM: Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 1995, 69:5087–5094.PubMedGoogle Scholar
  4. 4.
    Shriner D, Rodrigo AG, Nickle DC, Mullins JI: Pervasive genomic recombination of HIV-1 in vivo. Genetics 2004, 167:1573–1583.CrossRefPubMedGoogle Scholar
  5. 5.
    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
  6. 6.
    Grant RM, Liegler T, Elkin C: 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
  7. 7.
    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.CrossRefPubMedGoogle Scholar
  8. 8.
    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.CrossRefPubMedGoogle Scholar
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 11.
    Nijhuis M, van Maarseveen NM, Schipper P, et al.: Novel HIVdrug resistance mechanism leading to protease inhibitor (PI) resistance in response to a high genetic barrier PI in vitro. Antiviral Therapy 2004, 9:42.Google Scholar
  12. 12.
    Myint L, Matsuda M, Matsuda Z, et al.: Gag noncleavage site mutations contribute to full recovery of viral fitness in protease inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004, 48:444–452.CrossRefPubMedGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    Barbour JD, Wrin T, Grant RM, et al.: Evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults. J Virol 2002, 76:11104–11112. This report demonstrated that viral/pol RC did not recover despite continuing viral evolution under anti-retroviral drug pressure. This suggested that the clinical phenotype of elevated CD4+ counts among patients failing a protease inhibitor-based regimen was durable.CrossRefPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    Deeks SG, Martin, JN, Hoh R, et al.: Continued reverse transcriptase inhibitor therapy is sufficient to maintain short-term partial suppression of multidrug resistant viremia. Paper presented at the 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 10–14, 2003.Google Scholar
  17. 17.
    Barbour JD, Hecht FM, Wrin T, et al.: Higher CD4+ T-cell counts associated with low-viral pol replication capacity among treatment-naive adults in early HIV-1 infection. J Infect Dis 2004, 190:251–256.CrossRefPubMedGoogle Scholar
  18. 18.
    Barbour JD, Hecht FM, Wrin T, et al.: Persistence of primarydrug resistance mmong recently HIV-1 infected adults AIDS. 2004, 1683–1689.Google Scholar
  19. 19.
    Daar ES, Kesle K, Lail A, et al.: HIV coreceptor tropism and replication capacity predict HIV progression. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy [abstract]. Chicago, IL; September 14–17, 2003.Google Scholar
  20. 20.
    Kaur A, Grant RM, Means RE, et al.: Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus macaques. J Virol 1998, 72:9597–9611. This report demonstrates that a primate lentivirus, SIV, may replicate well in two different primate species, yet only be virulent in one, the rhesus macaque. This result emphasizes the concept that fitness and virulence are distinct features of a virus lifecycle, dependent upon the host environment.PubMedGoogle Scholar
  21. 21.
    Liegler TJ, Hayden MS, Lee KH, et al.: Protease inhibitorresistant HIV-1 from patients with preserved CD4 cell counts is cytopathic in activated CD4 T lymphocytes. Aids 2001, 15:179–184.CrossRefPubMedGoogle Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    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. Stoddart et al. demonstrated that protease inhibitor resistance diminished the ability of HIV-1 to replicate in human thymic tissue, and did not deplete the thymic explant of CD4+ and CD8+ thymotcytes. This result suggested that tissue-specific blocks to replication -dependent on the viral strain -may allow tissues such as the thymus to generate or expand lymphocyte populations, repopulating the periphery CD4+ T-cell population.CrossRefPubMedGoogle Scholar
  24. 24.
    Barbour J, Sinclair ES, Wrin T, et al.: CD8+ T-cell activation levels may be predicted by pol replication capacity of drug resistant and wild-type HIV1. Antiviral Therapy 2004, 9:74.Google Scholar
  25. 25.
    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
  26. 26.
    Namikawa R, Kaneshima H, Lieberman M, et al.: Infection of the SCID-hu mouse by HIV-1. Science 1988, 242:1684–1686.CrossRefPubMedGoogle Scholar
  27. 27.
    Glushakova S, Baibakov B, Zimmerberg J, Margolis LB: Experimental HIV infection of human lymphoid tissue: correlation of CD4+ T cell-depletion and virus syncytiuminducing/ nonsyncytium-inducing phenotype in histocultures inoculated with laboratory strains and patient isolates of HIV type 1. AIDS Res Hum Retro 1997, 13:461–471.CrossRefGoogle Scholar
  28. 28.
    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

Copyright information

© Current Science Inc 2005

Authors and Affiliations

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

Personalised recommendations