scholarly journals New insights into the evolutionary rate of HIV-1 at the within-host and epidemiological levels

2012 ◽  
Vol 279 (1741) ◽  
pp. 3367-3375 ◽  
Author(s):  
Katrina A. Lythgoe ◽  
Christophe Fraser
Keyword(s):  
Immune Escape ◽  
Population Level ◽  
The Body ◽  
Biological Organization ◽  
Calendar Time ◽  
Adaptive Mutations ◽  
Preferential Transmission ◽  
Ancestral Virus ◽  
Hiv 1 ◽  
Major Target

Over calendar time, HIV-1 evolves considerably faster within individuals than it does at the epidemic level. This is a surprising observation since, from basic population genetic theory, we would expect the genetic substitution rate to be similar across different levels of biological organization. Three different mechanisms could potentially cause the observed mismatch in phylogenetic rates of divergence: temporal changes in selection pressure during the course of infection; frequent reversion of adaptive mutations after transmission; and the storage of the virus in the body followed by the preferential transmission of stored ancestral virus. We evaluate each of these mechanisms to determine whether they are likely to make a major contribution to the mismatch in phylogenetic rates. We conclude that the cycling of the virus through very long-lived memory CD4 + T cells, a process that we call ‘store and retrieve’, is probably the major contributing factor to the rate mismatch. The preferential transmission of ancestral virus needs to be integrated into evolutionary models if we are to accurately predict the evolution of immune escape, drug resistance and virulence in HIV-1 at the population level. Moreover, early infection viruses should be the major target for vaccine design, because these are the viral strains primarily involved in transmission.

scholarly journals Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

2012 ◽  
Vol 86 (24) ◽  
pp. 13202-13216 ◽  
Author(s):  
J. M. Carlson ◽  
C. J. Brumme ◽  
E. Martin ◽  
J. Listgarten ◽  
M. A. Brockman ◽  
...  
Keyword(s):  
Cellular Immunity ◽  
Immune Escape ◽  
Population Level ◽  
Hiv 1

scholarly journals Modeling the immunological pre-adaptation of HIV-1

2020 ◽  
Author(s):  
Christiaan H. van Dorp ◽  
Michiel van Boven ◽  
Rob J. de Boer
Keyword(s):  
Disease Progression ◽  
Immune Escape ◽  
Human Leukocyte ◽  
Population Level ◽  
Dependent Manner ◽  
Hla Alleles ◽  
Leukocyte Antigen ◽  
Slow Progression ◽  
High Heritability ◽  
Hiv 1

AbstractIt is becoming increasingly evident that the evolution of HIV-1 is to a large extent determined by the immunological background of the host. On the population-level this results in associations between specific human leukocyte antigen (HLA) alleles and polymorphic loci of the virus. Furthermore, some HLA alleles that were previously associated with slow progression to AIDS have been shown to lose their protective effect, because HLA-specific immunological escape variants have spread through the population. This phenomenon is known as immunological pre-adaptation. Apart from adapting to human immune responses, the set-point virus load (SPVL) of HIV-1 is thought to have evolved to values that optimize the population-level fitness of the virus. This suggestion is supported by considerable heritability of the SPVL. Previous modeling studies show that whether or not SPVL optimization is expected to occur depends sensitively on the underlying assumptions with respect to the extent of within-versus between-host selection. Here we use a detailed and semi-realistic multi-level HIV-1 model in which immunological pre-adaptation and SPVL evolution can emerge from the underlying interactions of the virus with the immune system of the host. This enables us to study the effect of immunological escape on disease progression, and how disease progression may be molded by SPVL evolution. We find that the time to AIDS could decrease significantly (0.5-1.0 years) in a HLA-dependent manner by immunological pre-adaptation over the long-term course of the epidemic (> 100 years). We find that SPVL is not expected to evolve to optimize the population-level fitness of HIV-1, even though high heritability of the SPVL emerges from continual selection of immune-escape mutations.

scholarly journals The Role of the BCL-2 Family of Proteins in HIV-1 Pathogenesis and Persistence

2019 ◽  
Vol 33 (1) ◽  
Author(s):  
Aswath P. Chandrasekar ◽  
Nathan W. Cummins ◽  
Andrew D. Badley
Keyword(s):  
Antiretroviral Therapy ◽  
Therapeutic Target ◽  
Chronic Condition ◽  
Immune Escape ◽  
Latent Reservoir ◽  
Fatal Infection ◽  
Promising Therapeutic Target ◽  
Hiv 1 ◽  
Major Target

SUMMARY Advances in HIV-1 therapy have transformed the once fatal infection into a manageable, chronic condition, yet the search for a widely applicable approach to cure remains elusive. The ineffectiveness of antiretroviral therapy (ART) in reducing the size of the HIV-1 latent reservoir has prompted investigation into the mechanisms of HIV-1 latency and immune escape. One of the major regulators of apoptosis, the BCL-2 protein, alongside its homologous family members, is a major target of HIV-1-induced change. Recent studies have now demonstrated the association of this protein with cells that support proviral forms in the setting of latency and have helped identify BCL-2 as a novel and promising therapeutic target for HIV-1 therapy directed at possible cure. This review aims to systematically review the interactions of HIV-1 with BCL-2 and its homologs and to examine the possibility of using BCL-2 inhibitors in the study and elimination of the latent reservoir.

scholarly journals Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor

2008 ◽  
Vol 14 (12) ◽  
pp. 1390-1395 ◽  
Author(s):  
Angel Varela-Rohena ◽  
Peter E Molloy ◽  
Steven M Dunn ◽  
Yi Li ◽  
Megan M Suhoski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Hiv 1

scholarly journals Variants of Human Immunodeficiency Virus Type 1 That Efficiently Use CCR5 Lacking the Tyrosine-Sulfated Amino Terminus Have Adaptive Mutations in gp120, Including Loss of a Functional N-Glycan

2005 ◽  
Vol 79 (7) ◽  
pp. 4357-4368 ◽  
Author(s):  
Emily J. Platt ◽  
Danielle M. Shea ◽  
Patrick P. Rose ◽  
David Kabat
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Strong Interactions ◽  
Amino Terminus ◽  
Adaptive Mutations ◽  
Amino Terminal ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT By selecting the R5 human immunodeficiency virus type 1 (HIV-1) strain JR-CSF for efficient use of a CCR5 coreceptor with a badly damaged amino terminus [i.e., CCR5(Y14N)], we previously isolated variants that weakly utilize CCR5(Δ18), a low-affinity mutant lacking the normal tyrosine sulfate-containing amino-terminal region of the coreceptor. These previously isolated HIV-1JR-CSF variants contained adaptive mutations situated exclusively in the V3 loop of their gp120 envelope glycoproteins. We now have weaned the virus from all dependency on the CCR5 amino terminus by performing additional selections with HeLa-CD4 cells that express only a low concentration of CCR5(Δ18). The adapted variants had additional mutations in their V3 loops, as well as one in the V2 stem (S193N) and four alternative mutations in the V4 loop that eliminated the same N-linked oligosaccharide from position N403. Assays using pseudotyped viruses suggested that these new gp120 mutations all made strong contributions to use of CCR5(Δ18) by accelerating a rate-limiting CCR5-dependent conformational change in gp41 rather than by increasing viral affinity for this damaged coreceptor. Consistent with this interpretation, loss of the V4 N-glycan at position N403 also enhanced HIV-1 use of a different low-affinity CCR5 coreceptor with a mutation in extracellular loop 2 (ECL2) [i.e., CCR5(G163R)], whereas the double mutant CCR5(Δ18,G163R) was inactive. We conclude that loss of the N-glycan at position N403 helps to convert the HIV-1 envelope into a hair-trigger form that no longer requires strong interactions with both the CCR5 amino terminus and ECL2 but efficiently uses either site alone. These results demonstrate a novel functional role for a gp120 N-linked oligosaccharide and a high degree of adaptability in coreceptor usage by HIV-1.

scholarly journals Population-level rhythms in human skin with implications for circadian medicine

2018 ◽  
Vol 115 (48) ◽  
pp. 12313-12318 ◽  
Author(s):  
Gang Wu ◽  
Marc D. Ruben ◽  
Robert E. Schmidt ◽  
Lauren J. Francey ◽  
David F. Smith ◽  
...  
Keyword(s):  
Human Subjects ◽  
Population Level ◽  
The Body ◽  
Human Epidermis ◽  
Single Sample ◽  
Circadian Phase ◽  
Potential Source ◽  
Pairwise Correlations ◽  
Important Barrier

Skin is the largest organ in the body and serves important barrier, regulatory, and sensory functions. The epidermal layer shows rhythmic physiological responses to daily environmental variation (e.g., DNA repair). We investigated the role of the circadian clock in the transcriptional regulation of epidermis using a hybrid experimental design, in which a limited set of human subjects (n = 20) were sampled throughout the 24-h cycle and a larger population (n = 219) were sampled once. We found a robust circadian oscillator in human epidermis at the population level using pairwise correlations of clock and clock-associated genes in 298 epidermis samples. We then used CYCLOPS to reconstruct the temporal order of all samples, and identified hundreds of rhythmically expressed genes at the population level in human epidermis. We compared these results with published time-series skin data from mice and found a strong concordance in circadian phase across species for both transcripts and pathways. Furthermore, like blood, epidermis is readily accessible and a potential source of biomarkers. Using ZeitZeiger, we identified a biomarker set for human epidermis that is capable of reporting circadian phase to within 3 hours from a single sample. In summary, we show rhythms in human epidermis that persist at the population scale and describe a path to develop robust single-sample circadian biomarkers.

scholarly journals Defining HIV-1 Envelope N-Glycan Microdomains through Site-Specific Heterogeneity Profiles

2018 ◽  
Vol 93 (1) ◽  
Author(s):  
Audra A. Hargett ◽  
Qing Wei ◽  
Barbora Knoppova ◽  
Stacy Hall ◽  
Zhi-Qiang Huang ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Immune Escape ◽  
High Resolution Mass Spectrometry ◽  
National Laboratory ◽  
Site Specific ◽  
Los Alamos National Laboratory ◽  
Glycosylation Sites ◽  
Env Protein ◽  
Hiv 1

ABSTRACT The HIV-1 envelope (Env) glycans shield the surface of Env from the immune system and form integral interactions important for a functional Env. To understand how individual N-glycosylation sites (NGS) coordinate to form a dynamic shield and evade the immune system through mutations, we tracked 20 NGS in Env from HIV-transmitted/founder (T/F) and immune escape variants and their mutants involving the N262 glycan. NGS were profiled in a site-specific manner using a high-resolution mass spectrometry (MS)-based workflow. Using this site-specific quantitative heterogeneity profiling, we empirically characterized the interdependent NGS of a microdomain in the high-mannose patch (HMP). The changes (shifts) in NGS heterogeneity between the T/F and immune escape variants defined a range of NGS that we further probed for exclusive combinations of sequons in the HMP microdomain using the Los Alamos National Laboratory HIV sequence database. The resultant sequon combinations, including the highly conserved NGS N262, N448, and N301, created an immune escape map of the conserved and variable sequons in the HMP microdomain. This report provides details on how some clustered NGS form microdomains that can be identified and tracked across Env variants. These microdomains have a limited number of N-glycan-sequon combinations that may allow the anticipation of immune escape variants. IMPORTANCE The Env protein of HIV is highly glycosylated, and the sites of glycosylation can change as the virus mutates during immune evasion. Due to these changes, the glycan location and heterogeneity of surrounding N-glycosylation sites can be altered, resulting in exposure of different glycan or proteoglycan surfaces while still producing a viable HIV variant. These changes present a need for vaccine developers to identify Env variants with epitopes most likely to induce durable protective responses. Here we describe a means of anticipating HIV-1 immune evasion by dividing Env into N-glycan microdomains that have a limited number of N-glycan sequon combinations.

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