Fitness Costs and Diversity of the Cytotoxic T Lymphocyte (CTL) Response Determine the Rate of CTL Escape during Acute and Chronic Phases of HIV Infection

Ganusov, Vitaly V.; Goonetilleke, Nilukshi Preethika; Liu, Michael K. P.; Ferrari, Guido; Shaw, George M.; McMichael, Andrew J.; Borrow, Persephone; Korber, Bette T.; Perelson, Alan S.

doi:10.1128/jvi.00655-11

Cited by 150 publications

(290 citation statements)

References 102 publications

(148 reference statements)

Supporting

Mentioning

269

Contrasting

Order By: Relevance

“…Molecular cloning of HIV-1 genomes is labor intensive and thus limits the number of IMCs that can reasonably be characterized. Moreover, predicting which viral genomes are functional in chronically infected individuals is challenging, because immune escape mutations frequently incur fitness costs (38)(39)(40)(41)(42)(43)(44)(45). Virus isolation represents an alternative to cloning, but bulk cultures cannot account for the biological variation of individual quasispecies members.…”

Section: Generation Of Limiting Dilution Hiv-1 Isolates From Sexual Tmentioning

confidence: 99%

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Iyer

Bibollet-Ruche

Sherrill-Mix

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

132

180

View full text Add to dashboard Cite

Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC 50 ) than did donor isolates, and their odds of replicating in CD4 + T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4 + T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response.

show abstract

Section: Generation Of Limiting Dilution Hiv-1 Isolates From Sexual Tmentioning

confidence: 99%

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Iyer

Bibollet-Ruche

Sherrill-Mix

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

132

180

View full text Add to dashboard Cite

show abstract

“…If we restricted our attention only to ENV EL9, meaning that M1 and M12 variants would be indistinguishable, the dark curves are the profiles we would see. In this situation, using existing methods (Asquith et al 2006), we find an escape rate of 0.08 (similar to the value found in Ganusov et al 2011 andGoonetilleke et al 2009), which is significantly less than the first M1 escape rate and the M12 escape rate assumed in the case of null hypotheses A and B.The dynamics of Figure 10 show that between day 9 and 45 post-infection, ENV EL9 escape is driven by ENV 830 selection. Indeed, under both hypothesis, M1 variants eventually drop in frequency while M12 variants escape at a rate of 0.24, suggesting strong selection for ENV 830 mutations and weak or negative selection for ENV EL9 mutations.…”

mentioning

confidence: 61%

Computational Inference Methods for Selective Sweeps Arising in Acute HIV Infection

Leviyang

2013

Genetics

View full text Add to dashboard Cite

During the first weeks of human immunodeficiency virus-1 (HIV-1) infection, cytotoxic T-lymphocytes (CTLs) select for multiple escape mutations in the infecting HIV population. In recent years, methods that use escape mutation data to estimate rates of HIV escape have been developed, thereby providing a quantitative framework for exploring HIV escape from CTL response. Current methods for escape-rate inference focus on a specific HIV mutant selected by a single CTL response. However, recent studies have shown that during the first weeks of infection, CTL responses occur at one to three epitopes and HIV escape occurs through complex mutation pathways. Consequently, HIV escape from CTL response forms a complex, selective sweep that is difficult to analyze. In this work, we develop a model of initial infection, based on the well-known standard model, that allows for a description of multi-epitope response and the complex mutation pathways of HIV escape. Under this model, we develop Bayesian and hypothesis-test inference methods that allow us to analyze and estimate HIV escape rates. The methods are applied to two HIV patient data sets, concretely demonstrating the utility of our approach.A CUTE HIV-1 infection is marked by an initial period of 2-4 weeks in which the viral population expands from one to five infected cells to 10 9 infected cells. Following this expansion period, in the subsequent 1-2 months, the viral load drops and reaches a setpoint (Fiebig et al. 2003;Mehandru et al. 2004Mehandru et al. , 2007Keele et al. 2008). Cytotoxic T lymphocytes (CTLs) are thought to play an important role in shaping acute infection (Goulder and Watkins 2004;Cohen et al. 2011). The onset of CTL response is temporally correlated with the end of the expansion period, suggesting a role for CTLs in controlling viral load. Numerous studies have shown that during acute infection, specific HIV mutations on CTL targeted epitopes sweep to fixation, providing more direct evidence that CTL response shapes the infecting HIV population; see Goulder and Watkins (2004) for a review.In recent years, full-genome sequencing studies have provided an increasingly detailed description of CTL response during acute infection, e.g., Fernandez et al. Recent deep-sequencing data sets have provided a picture of HIV escape at the CTL targeted epitopes, e.g., Fisher et al. (2010), Henn et al. (2012), Bimber et al. (2009). HIV escape mutations at the first CTL targeted epitope rise to significant proportions 1-3 weeks after peak viral load. Escape mutations at the next series of epitopes targeted rise to significant proportion within roughly 4-6 weeks of peak viral load. Importantly, deep-sequencing studies have shown that HIV escape at a targeted epitope often occurs along multiple mutation pathways. The different mutation pathways are simply different nucleotide substitutions in the targeted epitope. During an HIV escape, these different mutations sweep to significant frequencies simultaneously, thereby replacing an HIV population typically ...

show abstract

“…Because there is generally a broad cellular immune response against HIV, CTL-mediated killing through different clones could potentially account for a substantial amount of the infected cell death, especially if killing happens during the intracellular eclipse phase [44]. For broad immune responses, the escape rates from individual CTL clones will be even slower if the killing rate of individual target cells saturates for high densities of CTLs specific for the various epitopes expressed by that target, or if the total CTL density is determined by competition [6]. In such a scenario, the total killing rate will hardly decrease if the virus escapes from only one of the several responses.…”

Section: Discussionmentioning

confidence: 99%

“…Owing to the high mutation rate of HIV, the virus can acquire immune escape mutations and frequently evades recognition from CTLs during the first months of the infection [4][5][6]. Analysing longitudinal data on the evolution of immune escape variants can give insights into the selective pressure that is induced by the CTLs.…”

Section: Introductionmentioning

confidence: 99%

Impaired immune evasion in HIV through intracellular delays and multiple infection of cells

Althaus

Boer

2012

Proc. R. Soc. B.

View full text Add to dashboard Cite

With its high mutation rate, HIV is capable of escape from recognition, suppression and/or killing by CD8 + cytotoxic T lymphocytes (CTLs). The rate at which escape variants replace each other can give insights into the selective pressure imposed by single CTL clones. We investigate the effects of specific characteristics of the HIV life cycle on the dynamics of immune escape. First, it has been found that cells in HIV-infected patients can carry multiple copies of proviruses. To investigate how this process affects the emergence of immune escape, we develop a mathematical model of HIV dynamics with multiple infections of cells. Increasing the frequency of multiple-infected cells delays the appearance of immune escape variants, slows down the rate at which they replace the wild-type variant and can even prevent escape variants from taking over the quasi-species. Second, we study the effect of the intracellular eclipse phase on the rate of escape and show that escape rates are expected to be slower than previously anticipated. In summary, slow escape rates do not necessarily imply inefficient CTL-mediated killing of HIV-infected cells, but are at least partly a result of the specific characteristics of the viral life cycle.

show abstract

Fitness Costs and Diversity of the Cytotoxic T Lymphocyte (CTL) Response Determine the Rate of CTL Escape during Acute and Chronic Phases of HIV Infection

Cited by 150 publications

References 102 publications

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Computational Inference Methods for Selective Sweeps Arising in Acute HIV Infection

Impaired immune evasion in HIV through intracellular delays and multiple infection of cells

Contact Info

Product

Resources

About