Human Immunodeficiency Virus Type 1 env Evolves toward Ancestral States upon Transmission to a New Host

The evolutionary rates of hepatitis B virus (HBV) estimated using contemporary sequences are 10 2 to 10 4 times higher than those derived from archaeological and genetic evidence. This discrepancy makes the origin of HBV and the time scale of its spread, both of which are critical for studying the burden of HBV pathogenicity, largely unresolved. To evaluate whether the dual demands (i.e., adaptation within hosts and colonization between hosts) of the viral life cycle affect this conundrum, the HBV quasispecies dynamics within and among hosts from a family consisting of a grandmother, her 5 children, and her 2 granddaughters, all of whom presumably acquired chronic HBV through mother-to-infant transmission, were examined by PCR cloning and next-generation sequencing methods. We found that the evolutionary rate of HBV between hosts was considerably lower than that within hosts. Moreover, the between-host substitution rates of HBV decreased as transmission numbers between individuals increased. Both observations were due primarily to changes at nonsynonymous rather than synonymous sites. There were significantly more multiple substitutions than expected for random mutation processes, and 97% of substitutions were changed from common to rare amino acid residues in the database. Continual switching between colonization and adaptation resulted in a rapid accumulation of mutations at a limited number of positions, which quickly became saturated, whereas substitutions at the remaining regions occurred at a much lower rate. Our study may help to explain the time-dependent HBV substitution rates reported in the literature and provide new insights into the origin of the virus. IMPORTANCEIt is known that the estimated hepatitis B virus (HBV) substitution rate is time dependent, but the reason behind this observation is still elusive. We hypothesize that owing to the small genome size of HBV, transmission between hosts and adaptation within hosts must exhibit high levels of fitness trade-offs for the virus. By studying the HBV quasispecies dynamics for a chain of sequentially infected transmissions within a family, we found the HBV substitution rate between patients to be negatively correlated with the number of transmissions. Continual switching between hosts resulted in a rapid accumulation of mutations at a limited number of genomic sites, which quickly became saturated in the short term. Nevertheless, substitutions at the remaining regions occurred at a much lower rate. Therefore, the HBV substitution rate decreased as the divergence time increased. H epatitis B virus (HBV) is one of the most common infectious agents in the world. According to the World Health Organization (WHO), more than a third of the world's population (2 billion people) has been infected with HBV, and 240 million people among them are chronic carriers (1). Despite its importance, the evolutionary origins of HBV and the time scale of its spread remain elusive. For example, if the evolutionary history of HBV is calibrated using phylodynamic ph...

Section: Discussionmentioning

confidence: 99%

New Insights into the Evolutionary Rate of Hepatitis B Virus at Different Biological Scales

Lin

Liu

Chien

et al. 2015

“…Functional requirements render the V3 loop very conserved (50) with respect to length and glycosylation, which contrasts with the other variable regions, in which large variations, both indels and changes in glycosylation, seem to be allowed without consequences for viral replication fitness (41). The fact that multiple common reverse mutations relative to the consensus B sequence were observed may be indicative of sequence constraints on at least some regions of Env (23). However, common amino acid changes observed in this study may be related to the fact that we studied only a small group of patients infected with relatively closely related virus strains (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Autologous Neutralizing Humoral Immunity and Evolution of the Viral Envelope in the Course of Subtype B Human Immunodeficiency Virus Type 1 Infection

Bunnik

Pisas

Nuenen

et al. 2008

157

172

Most human immunodeficiency virus type 1 (HIV-1)-infected individuals develop an HIV-specific neutralizing antibody (NAb) response that selects for escape variants of the virus. Here, we studied autologous NAb responses in five typical CCR5-using progressors in relation to viral NAb escape and molecular changes in the viral envelope (Env) in the period from seroconversion until after AIDS diagnosis. In sera from three patients, high-titer neutralizing activity was observed against the earliest autologous virus variants, followed by declining humoral immune responses against subsequent viral escape variants. Autologous neutralizing activity was undetectable in sera from two patients. Patients with high-titer neutralizing activity in serum showed the strongest positive selection pressure on Env early in infection. In the initial phase of infection, gp160 length and the number of potential N-linked glycosylation sites (PNGS) increased in viruses from all patients. Over the course of infection, positive selection pressure declined as the NAb response subsided, coinciding with reversions of changes in gp160 length and the number of PNGS. A number of identical amino acid changes were observed over the course of infection in the viral quasispecies of different patients. Our results indicate that although neutralizing autologous humoral immunity may have a limited effect on the disease course, it is an important selection pressure in virus evolution early in infection, while declining HIV-specific humoral immunity in later stages may coincide with reversion of NAb-driven changes in Env.

“…As noted above, epitopic forms of peptides are composed of high-database-frequency amino acid variants, whereas escape forms are typically found at lower database frequencies. Furthermore, we have shown that phylogenetically ancestral states are composed largely of the most common amino acids at each site within the HIV-1 proteome, due in part to convergent evolution in multiple hosts (12,23). Hence, the resetting of the viral genome we previously observed is hypothesized to be due in part to reversion at amino acid sites to epitopic forms no Our findings also have important implications for HIV-1 vaccine designs that seek to reduce disease progression and transmission rates if the goal of sterilizing immunity cannot be attained (41).…”

Section: Discussionmentioning

confidence: 99%

“…Amino acids associated with high viral replicative fitness are likely to be carried with high frequency in HIV infection. Indeed, infection of a new host results in the reacquisition of mutations that are more ancestral or consensus-like (23). Therefore, viruses with amino acids found at higher frequencies in the Los Alamos National Laboratory (LANL) HIV sequence database (32) might reasonably be hypothesized to be associated with better replicative capacity or to be more stable in the absence of host immune a Amino acid sequences of CD8 ϩ T-cell epitopes identified by IFN-␥ ELISPOT assays are shown, with newly defined epitopes highlighted in bold.…”

Section: Relationship Between Amino Acid Sites Under Positive Selectimentioning

confidence: 99%

Selection on the Human Immunodeficiency Virus Type 1 Proteome following Primary Infection

Liu¹,

McNevin

Cao

et al. 2006

Self Cite

116

191

Typically during human immunodeficiency virus type 1 (HIV-1) infection, a nearly homogeneous viral population first emerges and then diversifies over time due to selective forces that are poorly understood. To identify these forces, we conducted an intensive longitudinal study of viral genetic changes and T-cell immunity in one subject at <17 time points during his first 3 years of infection, and in his infecting partner near the time of transmission. Autologous peptides covering amino acid sites inferred to be under positive selection were powerful for identifying HIV-1-specific cytotoxic-T-lymphocyte (CTL) epitopes. Positive selection and mutations resulting in escape from CTLs occurred across the viral proteome. We detected 25 CTL epitopes, including 14 previously unreported. Seven new epitopes mapped to the viral Env protein, emphasizing Env as a major target of CTLs. One-third of the selected sites were associated with epitopic mutational escapes from CTLs. Most of these resulted from replacement with amino acids found at low database frequency. Another one-third represented acquisition of amino acids found at high database frequency, suggesting potential reversions of CTL epitopic sites recognized by the immune system of the transmitting partner and mutation toward improved viral fitness in the absence of immune targeting within the recipient. A majority of the remaining selected sites occurred in the envelope protein and may have been subjected to humoral immune selection. Hence, a majority of the amino acids undergoing selection in this subject appeared to result from fitness-balanced CTL selection, confirming CTLs as a dominant selective force in HIV-1 infection.