1.3 Impact of Viral Sequence Evolution on Immune Control of HIV-1

Gene overprinting occurs when point mutations within a genomic region with an existing coding sequence create a new one in another reading frame. This process is quite frequent in viral genomes either to maximize the amount of information that they encode or in response to strong selective pressure. The most frequent scenario involves two different reading frames in the same DNA strand (sense overlap). Much less frequent are cases of overlapping genes that are encoded on opposite DNA strands (antisense overlap). One such example is the antisense ORF, asp in the minus strand of the HIV-1 genome overlapping the env gene. The asp gene is highly conserved in pandemic HIV-1 strains of group M, and it is absent in non-pandemic HIV-1 groups, HIV-2, and lentiviruses infecting non-human primates, suggesting that the ~190-amino acid protein that is expressed from this gene (ASP) may play a role in virus spread. While the function of ASP in the virus life cycle remains to be elucidated, mounting evidence from several research groups indicates that ASP is expressed in vivo. There are two alternative hypotheses that could be envisioned to explain the origin of the asp ORF. On one hand, asp may have originally been present in the ancestor of contemporary lentiviruses, and subsequently lost in all descendants except for most HIV-1 strains of group M due to selective advantage. Alternatively, the asp ORF may have originated very recently with the emergence of group M HIV-1 strains from SIVcpz. Here, we used a combination of computational and statistical approaches to study the genomic region of env in primate lentiviruses to shed light on the origin, structure, and sequence evolution of the asp ORF. The results emerging from our studies support the hypothesis of a recent de novo addition of the antisense ORF to the HIV-1 genome through a process that entailed progressive removal of existing internal stop codons from SIV strains to HIV-1 strains of group M, and fine tuning of the codon sequence in env that reduced the chances of new stop codons occurring in asp. Altogether, the study supports the notion that the HIV-1 asp gene encodes an accessory protein, providing a selective advantage to the virus.

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SANTA-SIM: simulating viral sequence evolution dynamics under selection and recombination

Virus Evolution ◽

10.1093/ve/vez003 ◽

2019 ◽

Vol 5 (1) ◽

Cited By ~ 5

Author(s):

Abbas Jariani ◽

Christopher Warth ◽

Koen Deforche ◽

Pieter Libin ◽

Alexei J Drummond ◽

...

Keyword(s):

Software Package ◽

Point Mutations ◽

Sequence Evolution ◽

Biological Processes ◽

Viral Sequence ◽

Recombination Point ◽

Wide Range ◽

Cross Platform ◽

Evolution Dynamics ◽

Inference Methods

Abstract Simulations are widely used to provide expectations and predictive distributions under known conditions against which to compare empirical data. Such simulations are also invaluable for testing and comparing the behaviour and power of inference methods. We describe SANTA-SIM, a software package to simulate the evolution of a population of gene sequences forwards through time. It models the underlying biological processes as discrete components: replication, recombination, point mutations, insertion–deletions, and selection under various fitness models and population size dynamics. The software is designed to be intuitive to work with for a wide range of users and executable in a cross-platform manner.

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Nef genotype influences immune control in individuals living with HIV-1 who carrying protective alleles

Journal of Virus Eradication ◽

10.1016/s2055-6640(20)31027-x ◽

2019 ◽

Vol 5 ◽

pp. 5

Author(s):

F. Method Mwimanzi ◽

I. Ngare ◽

M. Mori ◽

J. Mann ◽

P. Goulder ◽

...

Keyword(s):

Immune Control ◽

Living With Hiv ◽

Hiv 1

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HIV-1 Epitope Variability Is Associated with T Cell Receptor Repertoire Instability and Breadth

Journal of Virology ◽

10.1128/jvi.00771-17 ◽

2017 ◽

Vol 91 (16) ◽

Cited By ~ 4

Author(s):

Arumugam Balamurugan ◽

Deon Claiborne ◽

Hwee L. Ng ◽

Otto O. Yang

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Viral Evolution ◽

Inverse Correlation ◽

Cell Receptor ◽

Immune Control ◽

Major Barrier ◽

Receptor Repertoire ◽

Hiv 1

ABSTRACT Mutational escape of HIV-1 from HIV-1-specific CD8+ T lymphocytes (CTLs) is a major barrier for effective immune control. Each epitope typically is targeted by multiple clones with distinct T cell receptors (TCRs). While the clonal repertoire may be important for containing epitope variation, determinants of its composition are poorly understood. We investigate the clonal repertoire of 29 CTL responses against 23 HIV-1 epitopes longitudinally in nine chronically infected untreated subjects with plasma viremia of <3,000 RNA copies/ml over 17 to 179 weeks. The composition of TCRs targeting each epitope varied considerably in stability over time, although clonal stability (Sorensen index) was not significantly time dependent within this interval. However, TCR stability inversely correlated with epitope variability in the Los Alamos HIV-1 Sequence Database, consistent with TCR evolution being driven by epitope variation. Finally, a robust inverse correlation of TCR breadth against each epitope versus epitope variability further suggested that this variability drives TCR repertoire diversification. In the context of studies demonstrating rapidly shifting HIV-1 sequences in vivo, our findings support a variably dynamic process of shifting CTL clonality lagging in tandem with viral evolution and suggest that preventing escape of HIV-1 may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways. IMPORTANCE Mutational escape of HIV-1 from HIV-1-specific CD8+ T lymphocytes (CTLs) is a major barrier to effective immune control. The number of distinct CTL clones targeting each epitope is proposed to be an important factor, but the determinants are poorly understood. Here, we demonstrate that the clonal stability and number of clones for the CTL response against an epitope are inversely associated with the general variability of the epitope. These results show that CTLs constantly lag epitope mutation, suggesting that preventing HIV-1 escape may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways.

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Sequence evolution and escape from specific immune pressure of an HIV-1 Rev epitope with extensive sequence similarity to human nucleolar protein 6

Tissue Antigens ◽

10.1111/j.1399-0039.2012.01837.x ◽

2012 ◽

Vol 79 (3) ◽

pp. 174-185 ◽

Cited By ~ 3

Author(s):

S. D. Allard ◽

A. L. de Goede ◽

B. De Keersmaecker ◽

C. Heirman ◽

P. Lacor ◽

...

Keyword(s):

Sequence Similarity ◽

Nucleolar Protein ◽

Sequence Evolution ◽

Extensive Sequence ◽

Immune Pressure ◽

Hiv 1

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Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1–Specific CD8+ T Cells

PLoS Medicine ◽

10.1371/journal.pmed.0050100 ◽

2008 ◽

Vol 5 (5) ◽

pp. e100 ◽

Cited By ~ 163

Author(s):

Hendrik Streeck ◽

Zabrina L Brumme ◽

Michael Anastario ◽

Kristin W Cohen ◽

Jonathan S Jolin ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Viral Sequence ◽

Functional Profile ◽

Hiv 1

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Detection of viral sequence fragments of HIV-1 subfamilies yet unknown

BMC Bioinformatics ◽

10.1186/1471-2105-12-93 ◽

2011 ◽

Vol 12 (1) ◽

pp. 93 ◽

Cited By ~ 17

Author(s):

Thomas Unterthiner ◽

Anne-Kathrin Schultz ◽

Jan Bulla ◽

Burkhard Morgenstern ◽

Mario Stanke ◽

...

Keyword(s):

Viral Sequence ◽

Hiv 1

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The Prevalence of HIV-1 DNA in AIDS-Related Lymphoma throughout the Epidemic in the US

Blood ◽

10.1182/blood.v118.21.5205.5205 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5205-5205

Author(s):

Leanne C Huysentruyt ◽

Lawrence D Kaplan ◽

Michael S. McGrath

Keyword(s):

Highly Active Antiretroviral Therapy ◽

Conflicts Of Interest ◽

Kaposi Sarcoma ◽

Sequence Evolution ◽

Genomic Amplification ◽

Hiv Dna ◽

Non Hodgkin Lymphoma ◽

Highly Active ◽

Reported Data ◽

Hiv 1

Abstract Abstract 5205 Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) are the two most common AIDS-defining cancers and significantly contribute to HIV-related deaths. While highly active antiretroviral therapy (HAART) has produce a sharp decline in the incidence of KS and AIDS-related NHL (ARL), HIV-infected patients are still at a high risk for developing these malignancies. Recent studies evaluating HIV-1 DNA in 91 AIDS-related KS cases demonstrated a significant decrease in the prevalence of HIV-1 DNA positive KS cases post-HAART (after 1996; 16.7%) as compared to pre-HAART (before 1996; 45%) corresponding to the decrease in incidence of this cancer since the introduction of HAART. Additionally HIV was more prevalent in sites of visceral KS (51.9%) as compared to skin KS (30.7%). We have recently evaluated the HIV sequence evolution in the context of metastatic ARL and identified lymphoma-specific HIV compartmentalized within tumor sites that was genetically distinct from HIV in non-tumor sites suggesting a specific form of HIV arises within individuals who develop ARL. The goal of this research was to determine the prevalence and quantity of HIV DNA in 119 ARL biopsies representing the entire span of the HIV epidemic (1982–2005). Whole genomic amplification was performed on DNA extracted from three 10um paraffin embedded tissue sections and the presence of HIV-1 DNA was determined by quantitative amplification of the HIV gag gene. Of the 119 cases, 45% contained detectable levels of HIV DNA. The HIV antigen was predominantly localized to macrophages. A subset of the ARL cases in this study contained approximately 1 HIV copy per cell which is extremely high considering previously reported data describing HIV-infected lymph nodes contained approximately 1 HIV copy per 1000 cells. Similar to what was observed for KS, the prevalence of HIV-positive ARLs has decreased in the post-HAART era (39%) when compared to pre-HAART (54%). While the prevalence of HIV-1 DNA positive ARLs declined in the post-HAART era, it was not to the same extent as what was observed for KS. Thus, our data is consistent with a decrease in the incidence of both tumor types in the post-HAART era. The higher prevalence of HIV-1 DNA in visceral sites of KS and lymphoma specific-HIV sequences in sites of metastatic lymphoma suggests that HIV, especially HIV infected macrophages, may play a role in the pathogenesis of KS and ARL disease progression. Disclosures: No relevant conflicts of interest to declare.

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