Katrina A. Lythgoe

Virulence and Pathogenesis of HIV-1 Infection: An Evolutionary Perspective

Background Why some individuals develop AIDS rapidly whereas others remain healthy without treatment for many years remains a central question of HIV research. Of the quantities that predict how quickly an untreated infection progresses, the most widely used is set-point viral load. This measure varies by orders of magnitude between infected individuals and is predictive of infectiousness and time to onset of AIDS. Host factors, predominantly linked to the immune system, are known to influence the set point, but much variation remains unexplained. A transmission chain with heritable virulence. Individuals infected with HIV show differences in clinical progression. Untreated infections are characterized by viral loads (the viral particle density in the blood) that are relatively stable for years, but they can differ by orders of magnitude between individuals. Host factors clearly influence viral load, but viral loads have also recently been found to correlate among individuals in transmission pairs and chains. This indicates a moderate to strong influence of viral genotype on the viral load. Strikingly, this influence persists for years and across transmission events, despite intense within-host viral evolution. A transmission chain with heritable virulence. Individuals infected with HIV show differences in clinical progression. Untreated infections are characterized by viral loads (the viral particle density in the blood) that are relatively stable for years, but they can differ by orders of magnitude between individuals. Host factors clearly influence viral load, but viral loads have also recently been found to correlate among individuals in transmission pairs and chains. This indicates a moderate to strong influence of viral genotype on the viral load. Strikingly, this influence persists for years and across transmission events, despite intense within-host viral evolution. Advances We review recent evidence showing that HIV genotype influences the set-point viral load far more than anticipated. Our summary of published estimates suggests that 33% (95% confidence interval, 20 to 46%) of the variation is attributable to the virus. Because set-point viral load is heritable (partially controlled by virus genotype) and is linked to transmissibility, it is likely to have evolved to maintain transmission fitness and may continue to evolve in response to diverse selection pressures. These findings are unexpected and paradoxical because rapid and error-prone viral replication should favor within-host adaptation and rapidly scramble signals of viral genotype as infection progresses, rather than leaving a lasting footprint that is preserved throughout an infection and from one infection to the next in transmission chains. Outlook We propose that resolving the paradox of heritability of set-point viral load will provide new insights into the mechanisms of HIV pathogenesis. To this end, we provide three parsimonious, testable, and nonexclusive explanatory mechanisms. The first states that HIV evolution in virulence genes is more functionally constrained than previously thought. The second proposes that virulence of HIV is mediated through the virus’s capacity to systemically activate target cells in which it can efficiently replicate. The capacity to activate would not be expected to evolve rapidly because it does not provide a specific selective advantage to virus strains that activate more cells; rather, it is an advantage shared by all viruses. The third mechanism implicates the preferential transmission of viruses that are stored in nonreplicating cells or during early infection, and the disproportionate influence on long-term pathogenesis of these early viruses. In addition to these insights into mechanisms of pathogenesis, we believe that this research highlights a major gap in our knowledge of HIV. The identification of the genetic determinants of HIV virulence, which appear to vary between closely related strains of the virus, should be a major priority. Thus, whole-genome association studies that are focused on the virus genome should be pursued and expanded, as well as more functional and mechanistic studies, which could be guided by hypotheses such as those presented here. HIV Virulence A major focus of research on HIV is on host responses to infection—understandably, because the virus targets the immune system and because of the interest in vaccine development. In reviewing what little research has been done on viral virulence determinants, Fraser et al. (10.1126/science.1243727) present evolutionary explanations for some of the poorly understood phenomena that mark HIV infection, including long-term survivorship, latency, rapid within-host evolution, and inheritability of between-host virulence. Why some individuals develop AIDS rapidly whereas others remain healthy without treatment for many years remains a central question of HIV research. An evolutionary perspective reveals an apparent conflict between two levels of selection on the virus. On the one hand, there is rapid evolution of the virus in the host, and on the other, new observations indicate the existence of virus factors that affect the virulence of infection whose influence persists over years in infected individuals and across transmission events. Here, we review recent evidence that shows that viral genetic factors play a larger role in modulating disease severity than anticipated. We propose conceptual models that reconcile adaptive evolution at both levels of selection. Evolutionary analysis provides new insight into HIV pathogenesis.

What the genome sequence is revealing about trypanosome antigenic variation

African trypanosomes evade humoral immunity through antigenic variation, whereby they switch expression of the gene encoding their VSG (variant surface glycoprotein) coat. Switching proceeds by duplication of silent VSG genes into a transcriptionally active locus. The genome project has revealed that most of the silent archive consists of hundreds of subtelomeric VSG tandem arrays, and that most of these are not functional genes. Precedent suggests that they can contribute combinatorially to the formation of expressed, functional genes through segmental gene conversion. These findings from the genome project have major implications for evolution of the VSG archive and for transmission of the parasite in the field.

Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation

Pathogens often persist during infection because of antigenic variation in which they evade immunity by switching between distinct surface antigen variants. A central question is how ordered appearance of variants, an important determinant of chronicity, is achieved. Theories suggest that it results directly from a complex pattern of transition connectivity between variants or indirectly from effects such as immune cross-reactivity or differential variant growth rates. Using a mathematical model based only on known infection variables, we show that order in trypanosome infections can be explained more parsimoniously by a simpler combination of two key parasite-intrinsic factors: differential activation rates of parasite variant surface glycoprotein (VSG) genes and density-dependent parasite differentiation. The model outcomes concur with empirical evidence that several variants are expressed simultaneously and that parasitaemia peaks correlate with VSG genes within distinct activation probability groups. Our findings provide a possible explanation for the enormity of the recently sequenced VSG silent archive and have important implications for field transmission.

New insights into the evolutionary rate of HIV-1 at the within-host and epidemiological levels

Over calendar time, HIV-1 evolves considerably faster within individuals than it does at the epidemic level. This is a surprising observation since, from basic population genetic theory, we would expect the genetic substitution rate to be similar across different levels of biological organization. Three different mechanisms could potentially cause the observed mismatch in phylogenetic rates of divergence: temporal changes in selection pressure during the course of infection; frequent reversion of adaptive mutations after transmission; and the storage of the virus in the body followed by the preferential transmission of stored ancestral virus. We evaluate each of these mechanisms to determine whether they are likely to make a major contribution to the mismatch in phylogenetic rates. We conclude that the cycling of the virus through very long-lived memory CD4+ T cells, a process that we call ‘store and retrieve’, is probably the major contributing factor to the rate mismatch. The preferential transmission of ancestral virus needs to be integrated into evolutionary models if we are to accurately predict the evolution of immune escape, drug resistance and virulence in HIV-1 at the population level. Moreover, early infection viruses should be the major target for vaccine design, because these are the viral strains primarily involved in transmission.

Preexposure prophylaxis will have a limited impact on HIV-1 drug resistance in sub-Saharan Africa: a comparison of mathematical models.

Background:Preexposure prophylaxis (PrEP) with tenofovir and emtricitabine can prevent new HIV-1 infections, but there is a concern that use of PrEP could increase HIV drug resistance resulting in loss of treatment options. We compared standardized outcomes from three independent mathematical models simulating the impact of PrEP on HIV transmission and drug resistance in sub-Saharan African countries. Methods:All models assume that people using PrEP receive an HIV test every 3–6 months. The models vary in structure and parameter choices for PrEP coverage, effectiveness of PrEP (at different adherence levels) and the rate with which HIV drug resistance emerges and is transmitted. Results:The models predict that the use of PrEP in conjunction with antiretroviral therapy will result in a lower prevalence of HIV than when only antiretroviral therapy is used. With or without PrEP, all models suggest that HIV drug resistance will increase over the next 20 years due to antiretroviral therapy. PrEP will increase the absolute prevalence of drug resistance in the total population by less than 0.5% and amongst infected individuals by at most 7%. Twenty years after the introduction of PrEP, the majority of drug-resistant infections is due to antiretroviral therapy (50–63% across models), whereas 40–50% will be due to transmission of drug resistance, and less than 4% to the use of PrEP. Conclusion:HIV drug resistance resulting from antiretroviral therapy is predicted to far exceed that resulting from PrEP. Concern over drug resistance should not be a reason to limit the use of PrEP.

THE COEVOLUTION OF PARASITES WITH HOST‐ACQUIRED IMMUNITY AND THE EVOLUTION OF SEX

Abstract. Here I present a deterministic model of the coevolution of parasites with the acquired immunity of their hosts, a system in which coevolutionary oscillations can be maintained. These dynamics can confer an advantage to sexual reproduction within the parasite population, but the effect is not strong enough to outweigh the twofold cost of sex. The advantage arises primarily because sexual reproduction impedes the response to fluctuating epistasis and not because it facilitates the response to directional selection—in fact, sexual reproduction often slows the response to directional selection. Where the cost of sexual reproduction is small, a polymorphism can be maintained between the sexuals and the asexuals. A polymorphism is maintained in which the advantage gained due to recombination is balanced by the cost of sex. At much higher costs of sex, a polymorphism between the asexual and sexual populations can still be maintained if the asexuals do not have a full complement of genotypes available to them, because the asexuals only outcompete those sexuals with which they share the same selected alleles. However, over time we might expect the asexuals to amass the full array of genotypes, thus permanently eliminating sexuals from the population. The sexuals may avoid this fate if the parasite population is finite. Although the model presented here describes the coevolution of parasites with the acquired immune responses of their hosts, it can be compared with other host‐parasite models that have more traditionally been used to investigate Red Queen theories of the evolution of sex.

IS HIV SHORT‐SIGHTED? INSIGHTS FROM A MULTISTRAIN NESTED MODEL

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.

A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda

Evolutionary theory hypothesizes that intermediate virulence maximizes pathogen fitness as a result of a trade-off between virulence and transmission, but empirical evidence remains scarce. We bridge this gap using data from a large and long-standing HIV-1 prospective cohort, in Uganda. We use an epidemiological-evolutionary model parameterised with this data to derive evolutionary predictions based on analysis and detailed individual-based simulations. We robustly predict stabilising selection towards a low level of virulence, and rapid attenuation of the virus. Accordingly, set-point viral load, the most common measure of virulence, has declined in the last 20 years. Our model also predicts that subtype A is slowly outcompeting subtype D, with both subtypes becoming less virulent, as observed in the data. Reduction of set-point viral loads should have resulted in a 20% reduction in incidence, and a three years extension of untreated asymptomatic infection, increasing opportunities for timely treatment of infected individuals. DOI: http://dx.doi.org/10.7554/eLife.20492.001

Effects of Acquired Immunity and Mating Strategy on the Genetic Structure of Parasite Populations

Although it may have profound effects on how researchers seek to tackle many infectious diseases, little is known of the genetic structure of many pathogen populations. Previous models have suggested that if levels of cross‐protection are high, parasite populations may be structured into discrete strains with nonoverlapping antigenic repertoires, even among populations that reproduce sexually. Here, I consider a discrete model of the coevolution of parasites with host‐acquired immunity. In this model, if the effective recombination rate is low, strain structure can be maintained for very high levels of cross‐protection. However, if the effective recombination rate is higher, this strain structure can no longer be maintained. The effective recombination rate is affected by the actual recombination rate between immunologically selected loci, the proportion of individuals that reproduce sexually, whether recombination occurs inside or outside of the host or vector, and the level of cross‐protection. The model predicts that for Plasmodium falciparum, where reproduction occurs inside of a vector, we expect to see strain structure in areas of low transmission but not in areas of high transmission. Strain structure is unlikely to be seen in parasites that reproduce outside of a host or vector, such as Strongyloides ratti.

Short-Sighted Virus Evolution and a Germline Hypothesis for Chronic Viral Infections

With extremely short generation times and high mutability, many viruses can rapidly evolve and adapt to changing environments. This ability is generally beneficial to viruses as it allows them to evade host immune responses, evolve new behaviours, and exploit ecological niches. However, natural selection typically generates adaptation in response to the immediate selection pressures that a virus experiences in its current host. Consequently, we argue that some viruses, particularly those characterised by long durations of infection and ongoing replication, may be susceptible to short-sighted evolution, whereby a virus’ adaptation to its current host will be detrimental to its onward transmission within the host population. Here we outline the concept of short-sighted viral evolution and provide examples of how it may negatively impact viral transmission among hosts. We also propose that viruses that are vulnerable to short-sighted evolution may exhibit strategies that minimise its effects. We speculate on the various mechanisms by which this may be achieved, including viral life history strategies that result in low rates of within-host evolution, or the establishment of a ‘germline’ lineage of viruses that avoids short-sighted evolution. These concepts provide a new perspective on the way in which some viruses have been able to establish and maintain global pandemics.