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HIV-1 over time: fitness loss or robustness gain?

In a recent issue of Nature Reviews Microbiology1 Arien and colleagues discussed the possibility that HIV-1 is measurably attenuated over time, based on reduced replication fitness in vitro. Historical isolates out-competed recent isolates in 176 out of 238 comparisons2, although only twice in 4 matched competitions between isolates of subtype B-CCR5. Whether decreased fitness in vitro equates with diminished HIV-1 virulence is debatable, especially without any evidence of reduced disease severity or transmission, as stable3,4,5 or worsening6,7 prognostic markers have been reported over time.

As an alternative to the possible adaptation to the host, we propose that HIV-1 is shifting towards the possession of increasingly robust population characteristics (providing greater resilience against niche perturbations), which sustain survival and proliferation during environmental fluctuations at the expense of replication fitness, so exemplifying the 'survival of the flattest' effect8.

HIV-1 evolution over time may correspond to the relocalization of circulating viruses from regions of high fitness and low mutational support to lower fitness and high mutational support, so reflecting the trade-offs between intra-host replication and inter-host transmission (Fig. 1). Genotypes on high, narrow fitness peaks are hypersensitive to mutations compared with genotypes on flatter, lower peaks, where more mutants can retain near-optimum fitness. High mutational support refers to the greater numbers of offspring surviving a mutation, which offsets the disadvantages of lower fitness. This interpretation stems from the observation that despite similar mean intra-group fitness values between historical and recent isolates, inter-group fitness differences favoured the historical isolates2 (Fig. 1).

Figure 1: Fitness landscapes of historical and recent isolates of HIV-1.

The fitness landscapes shown represent data published by Arien and colleagues1. The height of the peaks corresponds to the mean replication fitness values for inter-group virus competitions, whereas the area under the peaks corresponds to the mean replication fitness values for intra-group competitions. Compared with historical isolates, recent isolates appear to constitute a network of lower fitness, with flatter peaks and fewer amplitude changes between peaks and valleys. 3D plots were obtained using Mathematica 6 (Wolfram Research, Champaign, Illinois, USA).

As HIV-1 encounters fluctuating pressures within and between hosts (for example, different immune pressures or compartments, local extinctions and population outgrowths), genetic robustness (defined as phenotypic constancy despite mutational change9) could arise, as it allows biological systems to maintain their function despite perturbations. In silico studies have demonstrated that organisms on low, flat peaks can displace fast-replicating organisms on higher, narrower peaks — an effect termed 'survival of the flattest'8,9,10,11. This effect can also be viewed as a pressure to occupy highly connected, rather than sparse, areas of a network9. Although phenotypic constancy could appear to be at odds with the ever-increasing HIV-1 diversity, robustness and diversity are not mutually exclusive. Robustness combined with flexibility renders the exploratory behaviour of the virus less uncertain, by buffering it from lethal mutational effects12,13.

Although robust properties and escape mutations accruing in HIV-1 are plausible explanations for its lower fitness as the epidemic proceeds, we stress that diminished fitness does not necessarily imply attenuation. For individuals infected with ever-newer HIV-1 generations, adverse outcomes could be expected. A partially debilitated virus could be better controlled by the host immune response, which would result in reduced or delayed disease progression and potentially attenuation. By contrast, a gain in robustness could ensure more transmissions and thus greater dissemination. Moreover, adaptation to common human leukocyte antigen alleles could gradually result in multi-escape variants, with impaired fitness balanced by a reduced susceptibility to cytotoxic T-lymphocyte recognition. This scenario of increased transmissions fostered by mutational robustness, coupled with less effective immune responses, contrasts starkly with attenuation.


  1. 1

    Arien, K. K., Vanham, G. & Arts, E. J. Is HIV-1 evolving to a less virulent form in humans? Nature Rev. Microbiol. 5, 141–151 (2007).

    CAS  Article  Google Scholar 

  2. 2

    Arien, K. K. et al. Replicative fitness of historical and recent HIV-1 isolates suggests HIV-1 attenuation over time. AIDS 19, 1555–1564 (2005).

    Article  PubMed  Google Scholar 

  3. 3

    Holmberg, S. et al. Recent infection with human immunodeficiency virus and possible rapid loss of CD4 T lymphocytes. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 9, 291–296 (1995).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Galai, N. et al. Temporal trends of initial CD4 cell counts following human immunodeficiency virus seroconversion in Italy, 1985–1992. The human immunodeficiency virus Italian seroconversion study. Am. J. Epidemiol. 143, 278–282 (1996).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Müller, V. et al. Stable virulence levels in the HIV epidemic of Switzerland over two decades. AIDS 20, 889–894 (2006).

    Article  PubMed  Google Scholar 

  6. 6

    Dorrucci, M., Rezza, G., Porter, K. & Phillips, A. Temporal trends in postseroconversion CD4 cell count and HIV load: the concerted action on seroconversion to AIDS and death in Europe collaboration, 1985–2002. J. Infect. Dis. 195, 525–534 (2007).

    Article  PubMed  Google Scholar 

  7. 7

    Dorrucci, M., Phillips, A., Longo, B. & Rezza, G. Changes over time in post-seroconversion CD4 cell counts in the Italian HIV-seroconversion study: 1985–2002. AIDS 19, 331–335 (2005).

    PubMed  Google Scholar 

  8. 8

    Wilke, C. O., Wang, J. L., Ofria, C., Lenski, R. E. & Adami, C. Evolution of digital organisms at high mutation rates leads to survival of the flattest. Nature 412, 331–333 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    van Nimwegen, E., Crutchfield, J. P. & Huynen, M. Neutral evolution of mutational robustness. Proc. Natl Acad. Sci. USA 96, 9716–9720 (1999).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Schuster, P. & Swetina, J. Stationary mutant distributions and evolutionary optimization. Bull. Math. Biol. 50, 635–660 (1988).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    White, J. S. & Adami, C. Bifurcation into functional niches in adaptation. Artif. Life 10, 135–144 (2004).

    Article  PubMed  Google Scholar 

  12. 12

    Bloom, J. D., Labthavikul, S. T., Otey, C. R. & Arnold, F. H. Protein stability promotes evolvability. Proc. Natl Acad. Sci. USA 103, 5869–5874 (2006).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Kirschner, M. & Gerhart, J. Evolvability. Proc. Natl Acad. Sci. USA 95, 8420–8427 (1998).

    CAS  Article  PubMed  Google Scholar 

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This work was supported by grants from the Seattle Primary Infection Program (PO1 57005) and the University of Washington Center for AIDS Research (PO1 AI570005 and 61–480, RO1 AI058894 and AI047734).

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Correspondence to James I. Mullins.

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Rolland, M., Brander, C., Nickle, D. et al. HIV-1 over time: fitness loss or robustness gain?. Nat Rev Microbiol 5, 1–2 (2007).

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