Fraser C, Hollingsworth TD, Chapman R, de Wolf F, Hanage WP. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis

Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(44):17441-6. DOI: 10.1073/pnas.0708559104
Source: PubMed


The natural course of HIV-1 infection is characterized by a high degree of heterogeneity in viral load, not just within patients over time, but also between patients, especially during the asymptomatic stage of infection. Asymptomatic, or set-point, viral load has been shown to correlate with both decreased time to AIDS and increased infectiousness. The aim of this study is to characterize the epidemiological impact of heterogeneity in set-point viral load. By analyzing two cohorts of untreated patients, we quantify the relationships between both viral load and infectiousness and the duration of the asymptomatic infectious period. We find that, because both the duration of infection and infectiousness determine the opportunities for the virus to be transmitted, this suggests a trade-off between these contributions to the overall transmission potential. Some public health implications of variation in set-point viral load are discussed. We observe that set-point viral loads are clustered around those that maximize the transmission potential, and this leads us to hypothesize that HIV-1 could have evolved to optimize its transmissibility, a form of adaptation to the human host population. We discuss how this evolutionary hypothesis can be tested, review the evidence available to date, and highlight directions for future research.

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Available from: T. Deirdre Hollingsworth
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    • "Life history theory suggests that negative genetic correlations (trade-offs) between different components of the parasite life cycle can influence the evolution of the optimal parasite phenotype (Stearns, 1992). Previous work has shown trade-offs among a variety of parasite life history traits including within-and among-host transmission, ability to avoid clearance by the host immune system, and parasite life expectancy (de Roode et al., 2008; Ebert, 1998; Fraser et al., 2007; Mackinnon et al., 2008; Mackinnon and Read, 1999). These trade-offs are of considerable interest because they drive the evolution of virulence, which is the level of parasite-induced harm to the host (Ebert and Bull, 2003). "
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    ABSTRACT: The vector-to-host and host-to-vector transmission steps are the two critical events that define the life cycle of any vector-borne pathogen. We expect negative genetic correlations between these two transmission phenotypes, if parasite genotypes specialized at invading the vector are less effective at infecting the vertebrate host and vice versa. We used the tick-borne bacterium Borrelia afzelii, a causative agent of Lyme borreliosis in Europe, to test whether genetic trade-offs exist between tick-to-host, systemic (host-to-tick), and a third mode of co-feeding (tick-to-tick) transmission. We worked with six strains of B. afzelii that were differentiated according to their ospC gene. We compared the three components of transmission among the B. afzelii strains using laboratory rodents as the vertebrate host and a laboratory colony of Ixodes ricinus as the tick vector. We used next generation matrix models to combine these transmission components into a single estimate of the reproductive number (R0) for each B. afzelii strain. We also tested whether these strain-specific estimates of R0 were correlated with the strain-specific frequencies in the field. We found significant genetic variation in the three transmission components among the B. afzelii strains. This is the first study to document genetic variation in co-feeding transmission for any tick-borne pathogen. We found no evidence of trade-offs as the three pairwise correlations of the transmission rates were all positive. The R0 values from our laboratory study explained 45% of the variation in the frequencies of the B. afzelii ospC strains in the field. Our study suggests that laboratory estimates of pathogen fitness can predict the distribution of pathogen strains in nature.
    Full-text · Article · Mar 2015 · Ticks and Tick-borne Diseases
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    • "The relative contribution of the asymptomatic stage to the total transmission during HIV-1 infection was shown to be 71% in a serial monogamy scenario and 42% in a random mixing scenario, while the primary infection accounts for 9% and 31% respectively of the transmission in the two scenarios, and the latestage infection for 20% and 27% respectively (Hollingsworth et al., 2008). The overall transmission potential across all stages is a function of SPVL (Fraser et al., 2007). "
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    ABSTRACT: The asymptomatic phase of HIV-1 infections is characterised by a stable set-point viral load (SPVL) within patients. The SPVL is a strong predictor of disease progression and shows considerable variation of multiple orders of magnitude between patients. Recent studies have found that the SPVL in donor and recipient pairs is strongly correlated indicating that the virus genotype strongly influences viral load. Viral genetic factors that increase both viral load and the replicative capacity of the virus would result in rapid within-host evolution to higher viral loads. Reconciling a stable SPVL over time with high SPVL heritability requires viral genetic factors that strongly influence SPVL but only weakly influence the competitive ability of the virus within hosts. We propose a virus trait that affects the activation of target cells, and therefore viral load, but does not confer a competitive advantage to the virus. We incorporate this virus-induced target cell activation into within- and between-host models and determine its effect on the competitive ability of virus strains and on the variation in SPVL in the host population. On the within-host level, our results show that higher rates of virus-induced target cell activation increase the SPVL and confer no selective advantage to the virus. This leads to a build up of diversity in target cell activation rates in the virus population during within-host evolution. On the between-host level, higher rates of target cell activation and therefore higher SPVL affect the transmission potential of the virus. Random selection of a new founder strain from the diverse virus population within a donor results in a standing variation in SPVL in the host population. Therefore, virus-induced target cell activation can explain the heritability of SPVL, the absence of evolution to higher viral loads during infection and a large standing variation in SPVL between hosts.
    Full-text · Article · Dec 2013
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    • "According to a recent meta-analysis, HIV virulence has increased over the past two decades, but the upward trend has plateaued off in the last few years (Herbeck et al. 2011). Because current levels of HIV virulence maximize the transmission potential of the virus (Fraser et al. 2007; Shirreff et al. 2011), we predict that HIV is unlikely to get much more virulent, if at all, in years to come. "
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    ABSTRACT: An important component of pathogen evolution at the population level is evolution within hosts. Unless evolution within hosts is very slow compared to the duration of infection, the composition of pathogen genotypes within a host is likely to change during the course of an infection, thus altering the composition of genotypes available for transmission as infection progresses. We develop a nested modeling approach that allows us to follow the evolution of pathogens at the epidemiological level by explicitly considering within-host evolutionary dynamics of multiple competing strains and the timing of transmission. We use the framework to investigate the impact of short-sighted within-host evolution on the evolution of virulence of human immunodeficiency virus (HIV), and find that the topology of the within-host adaptive landscape determines how virulence evolves at the epidemiological level. If viral reproduction rates increase significantly during the course of infection, the viral population will evolve a high level of virulence even though this will reduce the transmission potential of the virus. However, if reproduction rates increase more modestly, as data suggest, our model predicts that HIV virulence will be only marginally higher than the level that maximizes the transmission potential of the virus.
    Full-text · Article · Oct 2013 · Evolution
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