Abstract
Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral population within the donor at the time of transmission is also important. To support this argument, we developed a probabilistic model describing HIV-1 transmission in an untreated population, and parameterised the model using both within-host next generation sequencing data and population-level epidemiological data on heterosexual transmission. The most basic HIV-1 transmission models cannot explain simultaneously the low probability of transmission and the non-negligible proportion of infections founded by multiple variants. In our model, transmission can only occur when environmental conditions are appropriate (e.g. abrasions are present in the genital tract of the potential recipient), allowing these observations to be reconciled. As well as reproducing features of transmission in real populations, our model demonstrates that, contrary to expectation, there is not a simple link between the number of viral variants and the number of viral particles founding each new infection. These quantities depend on the timing of transmission, and infections can be founded with small numbers of variants yet large numbers of particles. Including selection, or a bias towards early transmission (e.g. due to treatment), acts to enhance this conclusion. In addition, we find that infections initiated by multiple variants are most likely to have derived from donors with intermediate set-point viral loads, and not from individuals with high set-point viral loads as might be expected. We therefore emphasise the importance of considering viral diversity in donors, and the timings of transmissions, when trying to discern the complex factors governing single or multiple variant transmission.
Highlights
Characterising the strong bottleneck that occurs during HIV-1 transmission, and understanding the role of selection in determining which viral variants are transmitted, are important for HIV-1 prevention strategies (Joseph et al 2015)
It has been observed that infections founded by multiple variants tend to have higher set-point viral loads (SPVLs) than those founded by single variants, with the suggestion that multi-variant transmission might be a trait associated with recipient individuals (Janes et al 2015)
We account for the observations that HIV-1 is only transmitted rarely (Boily et al 2009), but when transmission does occur, multiple viral variants found the new infection reasonably often (Keele et al 2008; Abrahams et al 2009; Bar et al 2010)
Summary
Characterising the strong bottleneck that occurs during HIV-1 transmission, and understanding the role of selection in determining which viral variants are transmitted, are important for HIV-1 prevention strategies (Joseph et al 2015). It is well established that most infections are founded by one or few distinct viral variants (Gottlieb et al 2008; Keele et al 2008; Abrahams et al 2009; Bar et al 2010; Herbeck et al 2011; Rolland et al 2011; Tully et al 2016), with each of these variants referred to as a transmitted/founder (T/F) virus. One T/F virus might naıvely be assumed to mean one T/F viral particle. It is currently unknown whether each T/F virus results from the successful transmission of a single viral particle, or multiple viral particles of the same variant, and as a corollary, how the number of viral particles founding an infection relates to the number of T/F variants. It has been observed that infections founded by multiple variants tend to have higher set-point viral loads (SPVLs) than those founded by single variants, with the suggestion that multi-variant transmission might be a trait associated with recipient individuals (Janes et al 2015)
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