Epidemiological processes leave a fingerprint in the pattern of genetic structure of virus populations. Here, we provide a new method to infer epidemiological parameters directly from viral sequence data. The method is based on phylogenetic analysis using a birth-death model (BDM) rather than the commonly used coalescent as the model for the epidemiological transmission of the pathogen. Using the BDM has the advantage that transmission and death rates are estimated independently and therefore enables for the first time the estimation of the basic reproductive number of the pathogen using only sequence data, without further assumptions like the average duration of infection. We apply the method to genetic data of the HIV-1 epidemic in Switzerland.

Abstract1 2 6 0 VOLUME 22 | NUMBER 11 | NOVEMBER 2016 nature medicine a r t i c l e s bnAbs have become blueprints for vaccine design owing to their unequalled activity against divergent HIV-1 strains and proven potency in preventing and suppressing HIV-1 infection after in vivo administration [1][2][3][4][5][6][7][8] . Elicitation of potent bnAb activity is relatively rare in natural HIV-1 infection: only 10-25% of infected individuals develop breadth, and an estimated 1% generate highly potent bnAb, or 'elite neutralization' , activity 9,10 . Although much is known about the functional properties of bnAbs, the parameters that govern their evolution in natural infection remain unknown, which is a critical limitation for vaccine development. To date, no vaccine approach has induced bnAb responses that match those elicited in natural infection 1,11 . Defining what restricts and promotes bnAb evolution in certain individuals will be crucial for devising successful vaccine regimens, as the same restrictions are likely to be encountered during immunization.Observations that bnAb activity arises predominantly in viremic individuals after several years of infection and is linked to lower CD4 + cell counts (referred to here as CD4 levels) 4,12-14 strongly suggest that prolonged exposure to viral antigen is needed for induction of bnAbs.Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 × 10 −5 ). Thus, key host, disease and viral determinants, including subtypespecific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.This may be necessary in part to allow the extensive antibody-affinity maturation that is characteristic of many HIV-1-specific bnAbs 15,16 . Similarly, antigen levels may be relevant, as bnAbs have been found to evolve less frequently in individuals with lower viral loads 1,4,13,17 . Individual case studies delineating pathways of bnAb maturation have highlighted the tight interplay between virus escape and antibody adaptation that precedes the development of a broad neutralization response [18][19][20][21][22][23] . In line with this, the viral envelop...

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Our analysis suggests (1) the absence of a self-sustaining epidemic of HIV-1 subtype B in HETs in Switzerland and (2) a temporally decreasing clustering of HIV infections in HETs and IDUs.

HIV virulence, i.e. the time of progression to AIDS, varies greatly among patients. As for other rapidly evolving pathogens of humans, it is difficult to know if this variance is controlled by the genotype of the host or that of the virus because the transmission chain is usually unknown. We apply the phylogenetic comparative approach (PCA) to estimate the heritability of a trait from one infection to the next, which indicates the control of the virus genotype over this trait. The idea is to use viral RNA sequences obtained from patients infected by HIV-1 subtype B to build a phylogeny, which approximately reflects the transmission chain. Heritability is measured statistically as the propensity for patients close in the phylogeny to exhibit similar infection trait values. The approach reveals that up to half of the variance in set-point viral load, a trait associated with virulence, can be heritable. Our estimate is significant and robust to noise in the phylogeny. We also check for the consistency of our approach by showing that a trait related to drug resistance is almost entirely heritable. Finally, we show the importance of taking into account the transmission chain when estimating correlations between infection traits. The fact that HIV virulence is, at least partially, heritable from one infection to the next has clinical and epidemiological implications. The difference between earlier studies and ours comes from the quality of our dataset and from the power of the PCA, which can be applied to large datasets and accounts for within-host evolution. The PCA opens new perspectives for approaches linking clinical data and evolutionary biology because it can be extended to study other traits or other infectious diseases.

The fraction of ambiguous nucleotide calls in bulk sequencing of human immunodeficiency virus type 1 (HIV-1) carries important information on viral diversity and the age of infection. In particular, a fraction of ambiguous nucleotides of >.5% provides evidence against a recent infection event <1 year ago.

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The HIV-1 reservoir is the major hurdle to a cure. We here evaluate viral and host characteristics associated with reservoir size and long-term dynamics in 1,057 individuals on suppressive antiretroviral therapy for a median of 5.4 years. At the population level, the reservoir decreases with diminishing differences over time, but increases in 26.6% of individuals. Viral blips and low-level viremia are significantly associated with slower reservoir decay. Initiation of ART within the first year of infection, pretreatment viral load, and ethnicity affect reservoir size, but less so long-term dynamics. Viral blips and low-level viremia are thus relevant for reservoir and cure studies.