scholarly journals A de novo approach to inferring within-host fitness effects during untreated HIV-1 infection

2019 ◽  
Author(s):  
Christopher J. R. Illingworth ◽  
Jayna Raghwani ◽  
David Serwadda ◽  
Nelson K. Sewankambo ◽  
Merlin L. Robb ◽  
...  
Keyword(s):  
Positive Selection ◽  
Sequence Data ◽  
Viral Population ◽  
Clonal Interference ◽  
Neutralising Antibodies ◽  
Host Diversity ◽  
Fitness Effects ◽  
Ctl Escape ◽  
Hiv 1

AbstractIn the absence of effective antiviral therapy, HIV-1 evolves in response to the within-host environment, of which the immune system is an important aspect. During the earliest stages of infection, this process of evolution is very rapid, driven by a small number of CTL escape mechanisms. As the infection progresses, immune escape variants evolve under reduced magnitudes of selection, while competition between an increasing number of polymorphic alleles (i.e., clonal interference) makes it difficult to quantify the magnitude of selection acting upon specific variant alleles. To tackle this complex problem, we developed a novel multi-locus inference method to evaluate the role of selection during the chronic stage of within-host infection. We applied this method to targeted sequence data from the p24 and gp41 regions of HIV-1 collected from 34 patients with long-term untreated HIV-1 infection. We identify a broad distribution of beneficial fitness effects during infection, with a small number of variants evolving under strong selection and very many variants evolving under weaker selection. The uniquely large number of infections analysed granted a previously unparalleled statistical power to identify loci at which selection could be inferred to act with statistical confidence. Our model makes no prior assumptions about the nature of alleles under selection, such that any synonymous or non-synonymous variant may be inferred to evolve under selection. However, the majority of variants inferred with confidence to be under selection were non-synonymous in nature, and in nearly all cases were associated with either CTL escape in p24 or neutralising antibody escape in gp41. Sites inferred to be under selection in multiple hosts have high within-host and between-host diversity albeit not all sites with high between-host diversity were inferred to be under selection at the within-host level. Our identification of selection at sites associated with resistance to broadly neutralising antibodies (bNAbs) highlights the need to fully understand the role of selection in untreated individuals when designing bNAb based therapies.Author SummaryDuring the within-host evolution of HIV-1, the diversity of the viral population increases, with many beneficial variants competing against each other. This competition, known as clonal interference, makes the identification of variants under positive selection a challenging task. We here apply a novel method for the inference of selection to targeted within-host sequence data describing changes in the p24 and gp41 genes during HIV-1 infection in 34 patients. Our method adopts a parsimonious approach, assigning selection to the smallest number of variants necessary to explain the evolution of the system. The large size of our dataset allows for the confident identification of variants under selection, alleles at certain loci being repeatedly inferred as under selection within multiple individuals. While early CTL escape mutations have been identified to evolve under strong positive selection, we identify a distribution of beneficial fitness effects in which a large number of mutations are under weak selection. Variants that were confidently identified under selection were primarily found to be associated with either CTL escape in p24 or neutralising antibody escape in gp41, including sites associated with escape from broadly neutralising antibodies. We find that the most frequently selected loci have high diversity both within-host and at the between-host level.

scholarly journals Fitness-Balanced Escape Determines Resolution of Dynamic Founder Virus Escape Processes in HIV-1 Infection

2015 ◽  
Vol 89 (20) ◽  
pp. 10303-10318 ◽  
Author(s):  
Justine E. Sunshine ◽  
Brendan B. Larsen ◽  
Brandon Maust ◽  
Ellie Casey ◽  
Wenje Deng ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Evolution ◽  
T Cell Responses ◽  
Fitness Cost ◽  
Viral Population ◽  
Cell Responses ◽  
Founder Virus ◽  
Ctl Escape ◽  
The Impact ◽  
Hiv 1

ABSTRACTTo understand the interplay between host cytotoxic T-lymphocyte (CTL) responses and the mechanisms by which HIV-1 evades them, we studied viral evolutionary patterns associated with host CTL responses in six linked transmission pairs. HIV-1 sequences corresponding to full-length p17 and p24gagwere generated by 454 pyrosequencing for all pairs near the time of transmission, and seroconverting partners were followed for a median of 847 days postinfection. T-cell responses were screened by gamma interferon/interleukin-2 (IFN-γ/IL-2) FluoroSpot using autologous peptide sets reflecting any Gag variant present in at least 5% of sequence reads in the individual's viral population. While we found little evidence for the occurrence of CTL reversions, CTL escape processes were found to be highly dynamic, with multiple epitope variants emerging simultaneously. We found a correlation between epitope entropy and the number of epitope variants per response (r= 0.43;P= 0.05). In cases in which multiple escape mutations developed within a targeted epitope, a variant with no fitness cost became fixed in the viral population. When multiple mutations within an epitope achieved fitness-balanced escape, these escape mutants were each maintained in the viral population. Additional mutations found to confer escape but undetected in viral populations incurred high fitness costs, suggesting that functional constraints limit the available sites tolerable to escape mutations. These results further our understanding of the impact of CTL escape and reversion from the founder virus in HIV infection and contribute to the identification of immunogenic Gag regions most vulnerable to a targeted T-cell attack.IMPORTANCERapid diversification of the viral population is a hallmark of HIV-1 infection, and understanding the selective forces driving the emergence of viral variants can provide critical insight into the interplay between host immune responses and viral evolution. We used deep sequencing to comprehensively follow viral evolution over time in six linked HIV transmission pairs. We then mapped T-cell responses to explore if mutations arose due to adaption to the host and found that escape processes were often highly dynamic, with multiple mutations arising within targeted epitopes. When we explored the impact of these mutations on replicative capacity, we found that dynamic escape processes only resolve with the selection of mutations that conferred escape with no fitness cost to the virus. These results provide further understanding of the complicated viral-host interactions that occur during early HIV-1 infection and may help inform the design of future vaccine immunogens.

scholarly journals Characterizing the Diverse Mutational Pathways Associated with R5-Tropic Maraviroc Resistance: HIV-1 That Uses the Drug-Bound CCR5 Coreceptor

2015 ◽  
Vol 89 (22) ◽  
pp. 11457-11472 ◽  
Author(s):  
Xiaowei Jiang ◽  
Felix Feyertag ◽  
Conor J. Meehan ◽  
Grace P. McCormack ◽  
Simon A. Travers ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Treatment Failure ◽  
Positive Selection ◽  
Antiretroviral Drugs ◽  
Viral Population ◽  
Cell Protein ◽  
V3 Loop ◽  
Evolutionary Analysis ◽  
Resistance Pathway ◽  
Hiv 1

ABSTRACTEntry inhibitors represent a potent class of antiretroviral drugs that target a host cell protein, CCR5, an HIV-1 entry coreceptor, and not viral protein. Lack of sensitivity can occur due to preexisting virus that uses the CXCR4 coreceptor, while true resistance occurs through viral adaptation to use a drug-bound CCR5 coreceptor. To understand this R5 resistance pathway, we analyzed >500 envelope protein sequences and phenotypes from viruses of 20 patients from the clinical trials MOTIVATE 1 and 2, in which treatment-experienced patients received maraviroc plus optimized background therapy. The resistant viral population was phylogenetically distinct and associated with a genetic bottleneck in each patient, consistent withde novoemergence of resistance. Recombination analysis showed that the C2-V3-C3 region tends to genotypically correspond to the recombinant's phenotype, indicating its primary importance in conferring resistance. Between patients, there was a notable lack of commonality in the specific sites conferring resistance, confirming the unusual nature of R5-tropic resistance. We used coevolutionary and positive-selection analyses to characterize the genotypic determinants of resistance and found that (i) there are complicated covariation networks, indicating frequent coevolutionary/compensatory changes in the context of protein structure; (ii) covarying sites under positive selection are enriched in resistant viruses; (iii) CD4 binding sites form part of a unique covariation network independent of the V3 loop; and (iv) the covariation network formed between the V3 loop and other regions of gp120 and gp41 intersects sites involved in glycosylation and protein secretion. These results demonstrate that while envelope sequence mutations are the key to conferring maraviroc resistance, the specific changes involved are context dependent and thus inherently unpredictable.IMPORTANCEThe entry inhibitor drug maraviroc makes the cell coreceptor CCR5 unavailable for use by HIV-1 and is now used in combination antiretroviral therapy. Treatment failure with drug-resistant virus is particularly interesting because it tends to be rare, with lack of sensitivity usually associated with the presence of CXCR4-using virus (CXCR4 is the main alternative coreceptor HIV-1 uses, in addition to CD4). We analyzed envelope sequences from HIV-1, obtained from 20 patients who enrolled in maraviroc clinical trials and experienced treatment failure, without detection of CXCR4-using virus. Evolutionary analysis was employed to identify molecular changes that confer maraviroc resistance. We found that in these individuals, resistant viruses form a distinct population that evolved once and was successful as a result of drug pressure. Further evolutionary analysis placed the complex network of interdependent mutational changes into functional groups that help explain the impediments to the emergence of maraviroc-associated R5 drug resistance.

The role of broad HIV-1 neutralising antibodies and vaccine protection from heterologous HIV-1 infection in chimpanzees

1997 ◽  
Vol 56 ◽  
pp. 292 ◽  
Author(s):  
Willy Bogers ◽  
Wim Koornstra ◽  
Åsa Bjömdal ◽  
Peter ten Haaft ◽  
Simon Beddows ◽  
...  
Keyword(s):  
Neutralising Antibodies ◽  
Vaccine Protection ◽  
Hiv 1

scholarly journals Resolving genetic linkage reveals patterns of selection in HIV-1 evolution

2019 ◽  
Author(s):  
Muhammad S. Sohail ◽  
Raymond H. Y. Louie ◽  
Matthew R. McKay ◽  
John P. Barton
Keyword(s):  
Neutralizing Antibodies ◽  
Genetic Linkage ◽  
Time Series Data ◽  
Quantitative Description ◽  
Viral Population ◽  
Series Data ◽  
Weak Selection ◽  
Clonal Interference ◽  
Selection For ◽  
Hiv 1

Identifying the genetic drivers of adaptation is a necessary step in understanding the dynamics of rapidly evolving pathogens and cancer. However, signals of selection are obscured by the complex, stochastic nature of evolution. Pervasive effects of genetic linkage, including genetic hitchhiking and clonal interference between beneficial mutants, challenge our ability to distinguish the selective effect of individual mutations. Here we describe a method to infer selection from genetic time series data that systematically resolves the confounding effects of genetic linkage. We applied our method to investigate patterns of selection in intrahost human immunodeficiency virus (HIV)-1 evolution, including a case in an individual who develops broadly neutralizing antibodies (bnAbs). Most variants that arise are observed to have negligible effects on inferred selection at other sites, but a small minority of highly influential variants have strong and far-reaching effects. In particular, we found that accounting for linkage is crucial for estimating selection due to clonal interference between escape mutants and other variants that sweep rapidly through the population. We observed only modest selection for antibody escape, in contrast with strong selection for escape from CD8+ T cell responses. Weak selection for escape from antibody responses may facilitate bnAb development by diversifying the viral population. Our results provide a quantitative description of the evolution of HIV-1 in response to host immunity, including selection on the viral population that accompanies bnAb development. More broadly, our analysis argues for the importance of resolving linkage effects in studies of natural selection.

scholarly journals The early spread and epidemic ignition of HIV-1 in human populations

Science ◽  
2014 ◽  
Vol 346 (6205) ◽  
pp. 56-61 ◽  
Author(s):  
Nuno R. Faria ◽  
Andrew Rambaut ◽  
Marc A. Suchard ◽  
Guy Baele ◽  
Trevor Bedford ◽  
...  
Keyword(s):  
Democratic Republic ◽  
Democratic Republic Of Congo ◽  
Sequence Data ◽  
Central Africa ◽  
Human Populations ◽  
Social Changes ◽  
Transport Networks ◽  
Regional Population ◽  
Hiv 1

Thirty years after the discovery of HIV-1, the early transmission, dissemination, and establishment of the virus in human populations remain unclear. Using statistical approaches applied to HIV-1 sequence data from central Africa, we show that from the 1920s Kinshasa (in what is now the Democratic Republic of Congo) was the focus of early transmission and the source of pre-1960 pandemic viruses elsewhere. Location and dating estimates were validated using the earliest HIV-1 archival sample, also from Kinshasa. The epidemic histories of HIV-1 group M and nonpandemic group O were similar until ~1960, after which group M underwent an epidemiological transition and outpaced regional population growth. Our results reconstruct the early dynamics of HIV-1 and emphasize the role of social changes and transport networks in the establishment of this virus in human populations.

scholarly journals Pathogenesis of HIV infection

2013 ◽  
Vol 5 (1S) ◽  
pp. 6 ◽  
Author(s):  
Hassan M. Naif
Keyword(s):  
Disease Progression ◽  
Genetic Factors ◽  
Viral Population ◽  
Hiv Pathogenesis ◽  
The Past ◽  
Risk Of Disease ◽  
Host Genetic ◽  
Hiv 1 ◽  
Made In

Over the past three decades of intense research on the contribution of viral and host factors determining the variability in HIV-1 infection outcome, HIV pathogenesis is still a fascinating topic that requires further study. An understanding of the exact mechanism of how these factors influencing HIV pathogenesis is critical to the development of effective strate- gies to prevent infection. Significant progress has been made in identifying the role of CCR5 (R5) and CXCR4 (X4) HIV strains in disease progression, particularly with the persistence of R5 HIV-1 strains at the AIDS stage. This indicates that R5 strains are as fit as X4 in causing CD4+ T cell depletion and in contribution to disease outcome, and so questions the prerequisite of the shift from R5 to X4 for disease progression. In contrast, the ability of certain HIV strains to readily use CXCR4 for infection or entry into macrophages, as the case with viruses are homozygous for tropism by CCR5delta32. This raises another major paradox in HIV pathogenesis about the source of X4 variants and how do they emerge from a relatively homogeneous R5 viral population after transmission. The interactions between viral phenotypes, tropism and co-receptor usage and how they influence HIV pathogenesis are the main themes addressed in this review. A better understanding of the viral and host genetic factors involved in the fitness of X4 and R5 strains of HIV-1 may facilitate development of specific inhibitors against these viral populations to at least reduce the risk of disease progression.

Role of Cations in the Interaction of Pradimicins with HIV-1 Envelope gp120

2013 ◽  
Vol 13 (16) ◽  
pp. 1907-1915 ◽  
Author(s):  
Bart Hoorelbeke ◽  
Youngju Kim ◽  
Toshikazu Oki ◽  
Yasuhiro Igarashi ◽  
Jan Balzarini
Keyword(s):  
Hiv 1 ◽  
Envelope Gp120

The Changes of Positive Selection Within env Gene of HIV-1 B’, CRF07_BC and CRF08_BC from China Over Time

2017 ◽  
Vol 15 (1) ◽  
pp. 31-37 ◽  
Author(s):  
Tingting Li ◽  
Binlian Sun ◽  
Yanyan Jiang ◽  
Haiyan Zeng ◽  
Yanpeng Li ◽  
...  
Keyword(s):  
Positive Selection ◽  
Hiv 1 ◽  
Over Time
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