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Epstein-Barr virus has developed multiple strategies to ensure its long-term persistence in the infected B cells of immunocompetent hosts. These include the establishment of cell-phenotype-specific programs of viral gene expression and the transduction of cellular genes that modulate immune responses. Cytotoxic T cells may specifically influence the evolution of this genetically stable virus.
This lecture includes three sections. Firstly, the concepts of genotype, subtype and quasi-specie are described. The appearance of virus is correlated with the evolution of the medical picture, and their resistance to antiviral agents. Secondly, the most modern genetical and molecular biology techniques, including DNA sequencing are studied. Thirdly, some examples of the investigation lines carried out at the Microbiology Department of the Granada Medicine School are explained, especially regarding to papillomavirus, hepatitis C virus, hepatitis G virus, virus associated to transfusions (TTV) and human immunodeficiency. The great transcendence that the genetical variability has to establish pathogeny and therapy control is emphasized.
Cytotoxic T lymphocytes (CTLs) are critical for the control of human immunodeficiency virus, but containment of virus replication can be undermined by mutations in CTL epitopes that lead to virus escape. We analyzed the evolution in vivo of an immunodominant, HLA-A2-restricted CTL epitope and found two principal, diametrically opposed evolutionary pathways that exclusively affect T cell-receptor contact residues. One pathway was characterized by acquisition of CTL escape mutations and the other by selection for wild-type amino acids. The pattern of CTL responses to epitope variants shaped which variant(s) prevailed in the virus population. The pathways notably influenced the amount of plasma virus, as patients with efficient CTL selection had lower plasma viral loads than did patients without efficient selection. Thus, viral escape from CTL responses does not necessarily correlate with disease progression.
Publication in this journal of the abstracts of the Nineteenth Symposium of the International Association for Comparative Research on Leukemia and Related Diseases in Mannheim/Heidelberg led editor and publisher to suggest an article introducing comparative research in leukemia and related diseases. Our survey briefly summarizes the history of this symposium, as it evolved from a meeting on animal leukemia virus into one dealing with viral and genetic aspects of human and animal leukemia and related diseases. The scientific evolution of the Abelson murine leukemia virus with its abl oncogene in the 1970s to what currently appears as the most reliable marker for human chronic myeloid leukemia is merely one example.
For developing efficient vaccines, it is essential to identify which amino acid changes are most important to the survival of the virus. We investigate the amino acid substitution features in the Avian Infectious Bronchitis Virus (AIBV) antigenic domain of a vaccine serotype (DE072) and a virulent viral strain (GA98) to better understand adaptive evolution of AIBV. In addition, the SARS Coronavirus (SARS-CoV) was also analyzed in the same way. It is interesting to find that extreme comparability exists between AIBV and SARS in amino acid substitution pattern. It suggests that amino acid changes that result in overall shift of residue charge and polarity should be paid special attention to during the development of vaccines.
The nonstructural protein (NS1) genes of eight H9N2 subtype influenza virus strains isolated from diseased chickens on different farms during 1996 - 2001 were amplified and sequenced. The nucleotide and deduced amino acid sequences of NS1 genes of these isolates were compared. The results showed that the homologies of nucleotide and amino acid of the isolates were 96.5% - 99.5% and 94.5 - 98.6%, respectively. These indicated that NS1 genes of H9N2 influenza viruses isolated in China were well conserved. Comparison of the amino acid sequences of NS1 genes of these isolates with those of H9N2 viruses isolated in Hong Kong of China, Korea and Pakistan demonstrated that nonstructural (NS1) proteins of the eight strains had a deletion of 13 amino acid residues at the carboxy terminus. Phylogenetic analyses showed NS1 genes of these isolates belonged to the same lineage and derived from an early chicken H9 virus isolated in 1994. The NS1 genes of the eight isolates belong to different sublineages from those of the H9N2 viruses isolated in Hong Kong, Korea and Pakistan, suggesting that the geographical distribution plays a significant role in the evolution of the H9N2 subtype influenza viruses.
The natural function of viruses is to deliver their genetic material to cells. Among the most effective of viruses in doing that is Simian Virus-40 (SV40). The properties that make SV40 a successful virus make it an attractive candidate for use as a gene delivery vehicle: high titer replication, infectivity for almost all nucleated cell types whether the cells are dividing or resting, potential for integration into cellular DNA, a peculiar pathway for entering cells that bypasses the cells' antigen processing apparatus, very high stability, and the apparent ability to activate expression of its own capsid genes in trans. Exploiting these and other characteristics of wild type (wt) SV40, increasing numbers of laboratories are studying recombinant (r) SV40-derived vectors. Among the uses to which these vectors have been applied are: delivering therapy to inhibit HIV, hepatitis C virus (HCV) and other viruses; correction of inherited hepatic and other protein deficiencies; immunizing against lentiviral and other antigens; treatment of inherited and acquired diseases of the central nervous system; protecting the lung and other organs from free radical-induced injury; and many others. The effectiveness of these vectors is a reflection of the adaptive evolution that produced their parent virus, wt SV40. This article explores how and why these vectors work, their strengths and their limitations, and provides a functional model for their exploitation for experimental and clinical applications.
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To characterize the genetic properties of currently circulating strains of wild-type measles viruses, we constructed and sequenced cDNA clones of the nucleoprotein (N) and matrix (M) genes of wild-type strains isolated between 1958 and 1989. The N and M genes of wild-type isolates from the prevaccine era (before 1964) were highly related to each other and to the N and M genes of a currently used measles vaccine strain, Moraten. The N and M genes of these viruses differed by no more than 0.5% at the nucleotide level. In contrast, the N and M genes of wild-type viruses isolated between 1977 and 1989 showed genetic drift, with the greatest amount of drift occurring in the viruses isolated from recent cases in the United States. Overall, the M genes were slightly more conserved at the nucleotide level (2.6% nucleotide, 3.3% amino acid) than the N genes (4.8% nucleotide, 3.4% amino acid). Alignment of the predicted protein sequences of the N genes revealed two regions of amino acid heterogeneity. The evolutionary patterns for the N and M genes suggested that the wild-type viruses isolated in the United States in 1989 were more related to wild-type viruses isolated in the United Kingdom between 1983 and 1988 than to viruses isolated in the United States in 1983.
To better define the clinical and biological evolution of infants after vertical human immunodeficiency virus type 1 infection, we analyzed 94 consecutive infected patients followed up after their first clinical symptoms. The expression of clinical symptoms and biological abnormalities followed a bimodal distribution, some patients having an early and severe disease and the others having a slowly progressive one. One third of our patients suffered from early onset of opportunistic infection (OI). These patients had a significantly higher incidence of severe encephalopathy compared with patients without OI. The rate of survival at 3 years was 48% +/- 24%. In contrast, the patients without early OI or severe encephalopathy had a probability of survival at 3 years of 97% +/- 3%. This probability was not modified by the occurrence of bacterial infection or lymphoid interstitial pneumonitis. Lymphoid interstitial pneumonitis occurred at a mean age of 29 months, significantly later than OI or severe encephalopathy. Laboratory results at initial examination were correlated with clinical symptoms. Thus, when the number of CD4 lymphocytes was less than 500/mm3, children suffered more frequently from life-threatening symptoms (OI and severe encephalopathy): 15 of 22 vs 14 of 69. The same was true when the lymphocytes did not proliferate after antigenic stimulation, when anti-p18 and/or anti-p25 antibodies were absent in the serum, and when p24 antigen was detected in serum. Finally, severe encephalopathy was associated with low anti-human immunodeficiency virus cerebrospinal fluid antibody titer, whereas 88% of patients with moderate or no encephalopathy had signs of intrathecal anti-human immunodeficiency virus antibody synthesis. In conclusion, a subgroup of patients expressed very early signs of severe immunodeficiency and encephalopathy, whereas the majority of patients had a longer survival and less severe clinical symptoms during their first years of life than previously thought.
Influenza A viruses of the H3 subtype caused the 1968 Hong Kong pandemic, the hemagglutinin (HA) gene being introduced into humans following a reassortment event with an avian virus. Receptor specificity and serum inhibitor sensitivity of the HA of influenza A viruses are linked to the host species. Human H3 viruses preferentially recognize N-acetyl sialic acid linked to galactose by alpha2,6 linkages (Neu5Acalpha2,6Gal) and are sensitive to serum inhibitors, whereas avian and equine viruses preferentially recognize Neu5Acalpha2,3Gal linkages and are resistant to serum inhibitors. We have examined the receptor specificity and serum inhibitor sensitivity of H3 human influenza A viruses from the time they were introduced into the human population to gain insight into the mechanism of viral molecular evolution and host tropism. All of the viruses were sensitive to neutralization and hemagglutination inhibition by horse serum. Early H3 viruses were resistant to pig and rabbit serum inhibitors. Viruses isolated after 1977 were uniformly sensitive to inhibition by pig and rabbit sera. The recognition of Neu5Acalpha2,3Gal or Neu5Acalpha2,6Gal linkages was not correlated with the serum sensitivity. These data showed that the receptor specificity of HA, measured as inhibitor sensitivity, has changed during replication in humans since its introduction from an avian virus.
In order to investigate the existing notion that the human immunodeficiency virus type 1 (HIV-1) infection in Puerto Rico (PR) was imported from the continental United States of America (USA) we sequenced and analyzed 900 bases of the HIV-1 pol sequence from individuals in PR for comparison with pol sequences from the USA mainland. The sequences were derived by direct sequencing of reverse transcription-polymerase chain reaction products generated from plasma virus. The products were sequenced in both directions and the complementary strands were compared prior to analysis. These processed sequences and GenBank sequences from the continental USA were subjected to phylogenetic analyses. The PR and USA sequences did not form independent clusters, indicating a shared HIV-1 infection. This may be due to the continuous human traffic or, less likely, may indicate a similar evolution of a common source virus. Analysis of drug resistance mutations, fairly similar in frequency in the PR and USA sequences analyzed here, supports human traffic as a rationale for the common infection. This work indicates that an efficacious vaccine developed for use in the USA mainland will also be effective in prevention in PR and perhaps the other countries of the Caribbean region.
APOBEC3G (A3G) is an antiretroviral host factor that functions by deaminating dC to dU in retroviral cDNA. HIV-1 Vif protein counteracts A3G via a ubiquitin-proteasome pathway. In the case of a simple retrovirus such as the murine leukemia virus (MLV), it remains unclear why it can replicate in cells expressing APOBEC3 (A3) even though it doesn't possess any accessory proteins such as Vif. In this study, we demonstrate that MLV escapes from murine A3 (mA3) via two distinct novel mechanisms. First, viral RNA (vRNA) blocks the binding of mA3 to Gag, resulting in the exclusion of mA3 from MLV virions. Second, viral protease (vPR) cleaves mA3 after maturation of virions. Here, we suggest that each virus has its own strategy to escape from A3 proteins and that these mechanisms might be used by other viruses that do not possess Vif-like protein. On the other hand, mice possess another form of mA3, delta exon5, that escapes from the cleavage by vPR to show more antiviral activity than the wild type mA3. This also suggests that battles between host intrinsic immunity and viruses have led to the evolution of proteins on both sides.
This paper summarizes the current knowledge on the human immunodeficiency virus (HIV) and related retroviruses, describing basic characteristics of this new group of viruses such as morphologic and genetic structure, biological and cultural properties, virus growth characteristics, genetic variability and virus replication. The discovery of new human and simian retroviruses has prompted the World Health Organization (WHO) to convene a group of experts to establish criteria for their characterization. This will allow rapid identification of new variants that may arise and allow public health measures to be implemented accordingly. Different approaches are made to nomenclature in view of the evolution of knowledge about these viruses, and a system of nomenclature has been proposed by the WHO working group. This system, inspired by the one developed for the influenza viruses, is practical and descriptive, providing information on the origins of the organism and its type.
The rapid evolution of drug resistance remains a major obstacle for HIV therapy. The capacity of the virus for recombination is widely believed to facilitate the evolution of drug resistance. Here, we challenge this intuitive view. We develop a population genetic model of HIV replication that incorporates the processes of mutation, cellular superinfection, and recombination. We show that cellular superinfection increases the abundance of low fitness viruses at the expense of the fittest strains due to the mixing of viral proteins during virion assembly. Moreover, we argue that whether recombination facilitates the evolution of drug resistance depends critically on how resistance mutations interact to determine viral fitness. Contrary to the commonly held belief, we find that, under the most plausible biological assumptions, recombination is expected to slow down the rate of evolution of multi-drug-resistant virus during therapy.
Static latency is the hallmark of all herpes viruses. The varicella zoster virus, for instance, causes varicella (chickenpox), and after a latent phase of between 5 and 40 years, it can give rise to herpes zoster (shingles). This latency and the subsequent reactivation has intrigued and puzzled virologists. Although several factors have been suggested, it is unknown what triggers reactivation. However, latency can be explained with a simple evolutionary model. Here, we demonstrate that a simple, yet efficient, bet-hedging strategy might have evolved in a number of viruses, especially those belonging to the herpes virus family and most importantly in varicella zoster virus. We show that the evolution of latency can be explained by the population dynamics of infectious diseases in fluctuating host populations.
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Secondary effector T-cell populations generated by cross-priming with heterologous influenza A viruses operate only in H-2K or H-2D compatible situations, when assayed on SV40-transformed target cells infected with a range of influenza A viruses. The H2-Kb allele is associated with a total failure in the generation of influenza-immune cytotoxic T cells, though this is not seen for the primary response to vaccinia virus. In both influenza and vaccinia development of effector T cells operating at H-2Db is greatly depressed in B10.A(2R) (kkkddb) and B10.A(4R) (kkbbbb), but not in B10 (bbbbbb), mice. However, there is no defect in viral antigen expression at either H-2Kk or H-2Db in B10.A(2R) target cells. This apparently reflects some inadequacy in the stimulator environment, as (A/J X B6) F1 T cells can be induced to respond at H-2Db when exposed to vaccinia virus in an irradiated B6 but not in a B10.A(4R) recipient. The present report, together with the accompanying paper by Zinkernagel and colleagues, records the first rigorous demonstration of both a nonresponder situation and a probable Ir-gene effect for conventional infectious viruses. Possible implications for the evolution of H-2 polymorphism and mechanisms of Ir gene function are discussed.