Assessing Predicted HIV-1 Replicative Capacity in a Clinical Setting

Kouyos, Roger D.; Wyl, Viktor von; Hinkley, Trevor; Petropoulos, Christos J.; Haddad, Mojgan; Whitcomb, Jeannette M.; Böni, Jürg; Yerly, Sabine; Cellerai, Cristina; Klimkait, Thomas; Günthard, Huldrych F.; Bonhoeffer, Sebastian

doi:10.1371/journal.ppat.1002321

Cited by 39 publications

(64 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CTL escape mutations may be reverted if the virus harbouring a costly CTL-escape mutation is transmitted to an individual where the mutation does not help evade the new host’s immune system (Carlson et al, 2014; Zanini et al, 2015). Mutations that increase the replicative capacity of the virus in all hosts may also evolve (Kouyos et al, 2011). It is also a possibility that slightly deleterious or beneficial mutations get fixed by genetic drift.…”

Section: Resultsmentioning

confidence: 99%

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

Blanquart

Grabowski

Herbeck

et al. 2016

eLife

View full text Add to dashboard Cite

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

show abstract

Section: Resultsmentioning

confidence: 99%

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

Blanquart

Grabowski

Herbeck

et al. 2016

eLife

View full text Add to dashboard Cite

show abstract

“…2,8 It has been shown that the virulence and the replicative capacity of the virus are highly correlated. 9 Therefore, viral set point during the asymptomatic stage of the disease has been used as a proxy for virulence of the HIV virus. 10 An individual with a high (low) viral load is most probably infected with a strain of HIV-1 that has a high (low) replicative capacity.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of HIV-1 RNA on CD4 Trajectories and Disease Progression Among Antiretroviral-Naive HIV-Infected Adults in Botswana: A Joint Modeling Analysis

Farahani

Novitsky

Wang

et al. 2016

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

Although HIV-1 RNA levels are measured at the time of initial diagnosis, the results are not used for the clinical follow-up of the patients. This study evaluates the prognostic value of the baseline HIV-1 RNA levels (above or below 10,000 copies/ml) on rate of disease progression, among antiretroviral therapy (ART)-naive patients in Botswana. A prospective cohort of 436 HIV-infected ART-naive adults with baseline CD4 > 400 cells/mm 3 were followed quarterly for 5 years in an urban clinic in Botswana. Baseline HIV-1 RNA levels and longitudinal CD4+ T-cell count data were analyzed, using mixed-effects regression jointly modeled with the times to a composite endpoint defined by AIDS-defining clinical conditions or death. During 1,547 person-years (PYs) follow-up time, 106 individuals became eligible for ART initiation (incidence rate: 0.07 PYs) and 6 participants died of AIDS-related illness. There were 203 (47%) individuals with baseline HIV-1 RNA <10,000 copies/ml and 233 (53%) individuals with baseline RNA >10,000 copies/ml. The slope of the predicted CD4 trajectory for individuals with baseline HIV-1 RNA >10,000 copies/ml is 30% steeper than that for those with baseline RNA <10,000. The hazard of reaching the composite endpoint for the individuals with baseline HIV-1 RNA >10,000 copies/ml was 2.3 (95% confidence interval: 1.5-3.0) times higher than that for those with baseline HIV-1 RNA <10,000 copies/ml. CD4 decline in individuals with HIV-1 RNA >10,000 copies/ml is much faster than that in those with RNA <10,000. The elevated HIV-1 RNA can be used as a marker to identify individuals at risk of faster disease progression.

show abstract

“…Small virus-derived peptides called epitopes are presented on the surface of infected cells by the human leukocyte antigen (HLA) class 1 molecules, which then allows CTLs to recognize and kill these cells. Throughout the course of chronic infection, which may last from a few years to a decade, viral diversity and fitness gradually increase [17,72,73]. Antigenic diversity also increases, as HIV continuously generates escape mutations in CTL epitopes, preventing them from being presented or recognized [63,72,[74][75][76].…”

Section: Hiv Pathogenesis Involves Immune-directed Evolutionmentioning

confidence: 99%

Evolutionary dynamics of HIV at multiple spatial and temporal scales

2012

View full text Add to dashboard Cite

Infectious diseases remain a formidable challenge to human health, and understanding pathogen evolution is crucial to designing effective therapeutics and control strategies. Here, we review important evolutionary aspects of HIV infection, highlighting the concept of selection at multiple spatial and temporal scales. At the smallest scale, a single cell may be infected by multiple virions competing for intracellular resources. Recombination and phenotypic mixing introduce novel evolutionary dynamics. As the virus spreads between cells in an infected individual, it continually evolves to circumvent the immune system. We discuss evolutionary mechanisms of HIV pathogenesis and progression to AIDS. Viral spread throughout the human population can lead to changes in virulence and the transmission of immune-evading variation. HIV emerged as a human pathogen due to selection occurring between different species, adapting from related viruses of primates. HIV also evolves resistance to antiretroviral drugs within a single infected host, and we explore the possibility for the spread of these strains between hosts, leading to a drug-resistant epidemic. We investigate the role of latency, drug-protected compartments, and direct cell-to-cell transmission on viral evolution. The introduction of an HIV vaccine may select for viral variants that escape vaccine control, both within an individual and throughout the population. Due to the strong selective pressure exerted by HIV-induced morbidity and mortality in many parts of the world, the human population itself may be co-evolving in response to the HIV pandemic. Throughout the paper, we focus on trade-offs between costs and benefits that constrain viral evolution and accentuate how selection pressures differ at different levels of selection.

show abstract

Assessing Predicted HIV-1 Replicative Capacity in a Clinical Setting

Cited by 39 publications

References 19 publications

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

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

Prognostic Value of HIV-1 RNA on CD4 Trajectories and Disease Progression Among Antiretroviral-Naive HIV-Infected Adults in Botswana: A Joint Modeling Analysis

Evolutionary dynamics of HIV at multiple spatial and temporal scales

Contact Info

Product

Resources

About