scholarly journals An application of population genetic theory to synonymous gene sequence evolution in the human immunodeficiency virus (HIV)

1994 ◽  
Vol 64 (1) ◽  
pp. 1-9 ◽  
Author(s):  
John K. Kelly
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mutation Rate ◽  
Population Genetic ◽  
Gene Sequence ◽  
High Rate ◽  
Viral Population ◽  
Recent Common Ancestor ◽  
Synonymous Mutations ◽  
Immunodeficiency Virus ◽  
Hiv 1

SummaryA population genetic model is developed and then applied to the synonymous gene sequence variation observed in samples of the Human Immunodeficiency Virus Type 1 (HIV-1). The samples, which were taken from several previous studies, contain sequences of the envelope glycoprotein gene (gp 120) of HIV-1. This analysis suggests that the viral population within an infected patient at any specific time is likely to be composed of close relatives. The viruses in a sample are likely to share a recent common ancestor probably due to consistent positive selection for non-synonymous mutations coupled with low recombination in this region of the genome. There is no substantial difference in synonymous evolutionary rate between samples of sequences obtained from Peripheral Blood Mononucleate Cells (PBMCs) and samples taken from blood plasma. This is likely to be due to the high rate of migration between these 2 HIV sub-populations. The mutation rate for the genetic region examined is estimated at 9·20 × 10−4per site per month. Under the assumptions of the estimation procedure, this estimate can be bounded between 8·50 and 9·91 × 10−4with 95% confidence. When coupled with direct estimates of mutation rate, the rate of synonymous evolution suggests that the mean number of generations per month for HIV-1in vivois between 1 and 4.

scholarly journals The Interaction of Vpr with Uracil DNA Glycosylase Modulates the Human Immunodeficiency Virus Type 1 In Vivo Mutation Rate

2000 ◽  
Vol 74 (15) ◽  
pp. 7039-7047 ◽  
Author(s):  
Louis M. Mansky ◽  
Sandra Preveral ◽  
Luc Selig ◽  
Richard Benarous ◽  
Serge Benichou
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mutation Rate ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Dna Glycosylase ◽  
Uracil Dna Glycosylase ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The Vpr protein of human immunodeficiency virus type 1 (HIV-1) influences the in vivo mutation rate of the virus. Since Vpr interacts with a cellular protein implicated in the DNA repair process, uracil DNA glycosylase (UNG), we have explored the contribution of this interaction to the mutation rate of HIV-1. Single-amino-acid variants of Vpr were characterized for their differential UNG-binding properties and used to trans complement vpr null mutant HIV-1. A striking correlation was established between the abilities of Vpr to interact with UNG and to influence the HIV-1 mutation rate. We demonstrate that Vpr incorporation into virus particles is required to influence the in vivo mutation rate and to mediate virion packaging of the nuclear form of UNG. The recruitment of UNG into virions indicates a mechanism for how Vpr can influence reverse transcription accuracy. Our data suggest that distinct mechanisms evolved in primate and nonprimate lentiviruses to reconcile uracil misincorporation into lentiviral DNA.

scholarly journals Comparisons of Human Immunodeficiency Virus Type 1 Envelope Variants in Blood and Genital Fluids near the Time of Male-to-Female Transmission

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Corey A. Williams-Wietzikoski ◽  
Mary S. Campbell ◽  
Rachel Payant ◽  
Airin Lam ◽  
Hong Zhao ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Genital Tract ◽  
Recent Common Ancestor ◽  
Female Partners ◽  
Immunodeficiency Virus ◽  
Male To Female ◽  
Hiv 1

ABSTRACTTo better understand the transmission of human immunodeficiency virus type 1 (HIV-1), the genetic characteristics of blood and genital viruses from males were compared to those of the imputed founding virus population in their female partners. Initially serodiscordant heterosexual African couples with sequence-confirmed male-to-female HIV-1 transmission and blood and genital specimens collected near the time of transmission were studied. Single viral templates from blood plasma and genital tract RNA and DNA were sequenced across HIV-1envgp160. Eight of 29 couples examined yielded viral sequences from both tissues. Analysis of these couples’ sequences demonstrated, with one exception, that the women’s founding viral populations arose from a single viral variant and were CCR5 tropic, even though CXCR4 variants were detected within four males. The median genetic distance of the imputed most recent common ancestor of the women’s founder viruses showed that they were closer to the semen viruses than to the blood viruses of their transmitting male partner, but this finding was biased by detection of a greater number of viral clades in the blood. Using multiple assays, the blood and genital viruses were consistently found to be compartmentalized in only two of eight men. No distinct amino acid signatures in the men’s viruses were found to link to the women’s founders, nor did the women’senvsequences have shorter variable loops or fewer N-linked glycosylation sites. The lack of selective factors, except for coreceptor tropism, is consistent with others’ findings in male-to-female and high-risk transmissions. The infrequent compartmentalization between the transmitters’ blood and semen viruses suggests that cell-free blood virus likely includes HIV-1 sequences representative of those of viruses in semen.IMPORTANCEMucosal transmissions account for the majority of HIV-1 infections. Identification of the viral characteristics associated with transmission would facilitate vaccine design. This study of HIV strains from transmitting males and their seroconverting female partners found that the males’ genital tract viruses were rarely distinct from the blood variants. The imputed founder viruses in women were genetically similar to both the blood and genital tract variants of their male partners, indicating a lack of evidence for genital tract-specific lineages. These findings suggest that targeting vaccine responses to variants found in blood are likely to also protect from genital tract variants.

scholarly journals Fitness Landscape of Human Immunodeficiency Virus Type 1 Protease Quasispecies

2007 ◽  
Vol 81 (5) ◽  
pp. 2485-2496 ◽  
Author(s):  
Guerau Fernàndez ◽  
Bonaventura Clotet ◽  
Miguel Angel Martínez
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Fitness Landscape ◽  
Catalytic Efficiency ◽  
Viral Population ◽  
Protease Gene ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Here we show, at a high resolution (1%), the human immunodeficiency virus type 1 (HIV-1) protease gene quasispecies landscape from three infected naïve individuals. A huge range of genetic configurations was found (67%, 71%, and 80% of the nucleotide clones from the three individuals, respectively, were different), and these configurations created a dense net that linked different parts of the viral population. Similarly, a vast diversity of different protease activities was also found. Importantly, 65% of the analyzed enzymes had detectable protease activity, and 11% of the minority individual variants showed similar or better fitness than the master (most abundant) enzyme, suggesting that the viral complexity in this genomic region does not exclusively depend on the enzyme's catalytic efficiency. Several high-fitness minority variants had only one substitution compared to the master sequence, supporting the possibility that the rugged HIV-1 protease quasispecies fitness landscape may be formed by a continuous network that can be traversed by single mutational steps without passing through defective or less-adapted proteins.

scholarly journals Timing and Reconstruction of the Most Recent Common Ancestor of the Subtype C Clade of Human Immunodeficiency Virus Type 1

2004 ◽  
Vol 78 (19) ◽  
pp. 10501-10506 ◽  
Author(s):  
Simon A. A. Travers ◽  
Jonathan P. Clewley ◽  
Judith R. Glynn ◽  
Paul E. M. Fine ◽  
Amelia C. Crampin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Common Ancestor ◽  
Recent Common Ancestor ◽  
Subtype C ◽  
Most Recent Common Ancestor ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) subtype C is responsible for more than 55% of HIV-1 infections worldwide. When this subtype first emerged is unknown. We have analyzed all available gag (p17 and p24) and env (C2-V3) subtype C sequences with known sampling dates, which ranged from 1983 to 2000. The majority of these sequences come from the Karonga District in Malawi and include some of the earliest known subtype C sequences. Linear regression analyses of sequence divergence estimates (with four different approaches) were plotted against sample year to estimate the year in which there was zero divergence from the reconstructed ancestral sequence. Here we suggest that the most recent common ancestor of subtype C appeared in the mid- to late 1960s. Sensitivity analyses, by which possible biases due to oversampling from one district were explored, gave very similar estimates.

scholarly journals Stochastic Interplay between Mutation and Recombination during the Acquisition of Drug Resistance Mutations in Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 79 (21) ◽  
pp. 13572-13578 ◽  
Author(s):  
Christian L. Althaus ◽  
Sebastian Bonhoeffer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Population Size ◽  
Mutation Rate ◽  
Population Genetic ◽  
Resistance Mutations ◽  
Effective Population ◽  
Drug Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Population Sizes

ABSTRACT The emergence of drug resistance mutations in human immunodeficiency virus (HIV) has been a major setback in the treatment of infected patients. Besides the high mutation rate, recombination has been conjectured to have an important impact on the emergence of drug resistance. Population genetic theory suggests that in populations limited in size recombination may facilitate the acquisition of beneficial mutations. The viral population in an infected patient may indeed represent such a population limited in size, since current estimates of the effective population size range from 500 to 105. To address the effects of limited population size, we therefore expand a previously described deterministic population genetic model of HIV replication by incorporating the stochastic processes that occur in finite populations of infected cells. Using parameter estimates from the literature, we simulate the evolution of drug-resistant viral strains. The simulations show that recombination has only a minor effect on the rate of acquisition of drug resistance mutations in populations with effective population sizes as small as 1,000, since in these populations, viral strains typically fix beneficial mutations sequentially. However, for intermediate effective population sizes (104 to 105), recombination can accelerate the evolution of drug resistance by up to 25%. Furthermore, a reduction in population size caused by drug therapy can be overcome by a higher viral mutation rate, leading to a faster evolution of drug resistance.

scholarly journals Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

2002 ◽  
Vol 76 (14) ◽  
pp. 7000-7009 ◽  
Author(s):  
Gustavo H. Kijak ◽  
Viviana Simon ◽  
Peter Balfe ◽  
Jeroen Vanderhoeven ◽  
Sandra E. Pampuro ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Treatment Failure ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Treatment Interruption ◽  
Viral Population ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.

scholarly journals High Rates of Human Immunodeficiency Virus Type 1 Recombination: Near-Random Segregation of Markers One Kilobase Apart in One Round of Viral Replication

2003 ◽  
Vol 77 (20) ◽  
pp. 11193-11200 ◽  
Author(s):  
Terence Rhodes ◽  
Heather Wargo ◽  
Wei-Shau Hu
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Leukemia Virus ◽  
Viral Population ◽  
Recombination Rates ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT One of the genetic consequences of packaging two copies of full-length viral RNA into a single retroviral virion is frequent recombination during reverse transcription. Many of the currently circulating strains of human immunodeficiency virus type 1 (HIV-1) are recombinants. Recombination can also accelerate the generation of multidrug-resistant HIV-1 and therefore presents challenges to effective antiviral therapy. In this study, we determined that HIV-1 recombination rates with markers 1.0, 1.3, and 1.9 kb apart were 42.4, 50.4, and 47.4% in one round of viral replication. Because the predicted recombination rate of two unlinked markers is 50%, we conclude that markers 1 kb apart segregated in a manner similar to that for two unlinked markers in one round of retroviral replication. These recombination rates are exceedingly high even among retroviruses. Recombination rates of markers separated by 1 kb are 4 and 4.7% in one round of spleen necrosis virus and murine leukemia virus replication, respectively. Therefore, HIV-1 recombination can be 10-fold higher than that of other retroviruses. Recombination can be observed only in the proviruses derived from heterozygous virions that contain two genotypically different RNAs. The high rates of HIV-1 recombination observed in our studies also indicate that heterozygous virions are formed efficiently during HIV-1 replication and most HIV-1 virions are capable of undergoing recombination. Our results demonstrate that recombination is an effective mechanism to break the genetic linkage between neighboring sequences, thereby reassorting the HIV-1 genome and increasing the diversity in the viral population.

scholarly journals Comparative Selection of the K65R and M184V/I Mutations in Human Immunodeficiency Virus Type 1-Infected Patients Enrolled in a Trial of First-Line Triple-Nucleoside Analog Therapy (Tonus IMEA 021)

2005 ◽  
Vol 79 (15) ◽  
pp. 9572-9578 ◽  
Author(s):  
Christophe Delaunay ◽  
Françoise Brun-Vézinet ◽  
Roland Landman ◽  
Gilles Collin ◽  
Gilles Peytavin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleoside Analogs ◽  
Clonal Analysis ◽  
High Rate ◽  
K65r Mutation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Tonus was a pilot study in which previously untreated human immunodeficiency virus type 1 (HIV-1)-infected patients received the combination of abacavir, lamivudine, and tenofovir once a day. There was a high rate of early virological failure, and the M184V and K65R mutations were frequently detected at week 12 (W12). The objective of this study was to examine the selection dynamics of the K65R and M184V/I mutations. Bulk sequencing of the reverse transcriptase (RT) gene was performed on plasma HIV-1 RNA at baseline, W4, and W12 for 21 patients with detectable viral loads. The RT genes from baseline, W4, and W12 plasma samples from five patients who developed both M184V and K65R but with different mutational patterns were also cloned and screened for the K65R mutation by selective real-time PCR. At baseline, bulk sequencing and clonal analysis showed only wild-type RT sequences. At W4, M184V/I was detected in 12/19 patients and K65K/R in 2 patients by bulk sequencing. At W12, M184V/I was found in 18/20 patient, together with the K65R in 13 patients. At W4, clonal analysis revealed the K65R mutation in 0.6 to 48% of clones in the five patients studied. At W12, the K65R mutation was found in 30 to 100% of clones. K65R and M184V/I seemed to arise in separate clones, followed by an enrichment of viruses containing both mutations. The clinical relevance of this independent evolution is unclear. M184V/I was selected more frequently than K65R at W4. However, K65R was also detected early using a clone-sensitive genotyping method. All three nucleoside analogs are known to select the K65R and/or M184V/I mutation. This convergent genetic pathway to resistance, associated with lower antiretroviral potency, may explain the high selection rate of these mutations in this trial.

scholarly journals Human Immunodeficiency Virus Type 1 Recombination: Rate, Fidelity, and Putative Hot Spots

2002 ◽  
Vol 76 (22) ◽  
pp. 11273-11282 ◽  
Author(s):  
Jianling Zhuang ◽  
Amanda E. Jetzt ◽  
Guoli Sun ◽  
Hong Yu ◽  
George Klarmann ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dna Sequencing ◽  
Human Immunodeficiency Virus Type ◽  
Hot Spots ◽  
Hot Spot ◽  
High Rate ◽  
Vector System ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Previously, we reported that human immunodeficiency virus type 1 (HIV-1) recombines approximately two to three times per genome per replication cycle, an extremely high rate of recombination given the relatively small genome size of HIV-1. However, a recombination hot spot involving sequence of nonretroviral origin was identified in the vector system utilized, raising the possibility that this hot spot skewed the rate of recombination, and the rate of recombination observed was an overestimation. To address this issue, an HIV-1-derived vector system was used to examine the rate of recombination between autologous HIV-1 sequences after restricting replication to a single cycle in the absence of this hot spot. Viral DNA and RNA were analyzed by a combination of the heteroduplex tracking assay, restriction enzyme analysis, DNA sequencing, and reverse transcription-PCR. The results indicate that HIV-1 undergoes recombination at a minimum rate of 2.8 crossovers per genome per cycle. Again, this is a very high rate given the small size of the HIV-1 genome. The results also suggested that there might be local hot spots of recombination at different locations throughout the genome since 13 of the 33 strand transfers identified by DNA sequencing shared the same site of recombination with one or two other clones. Furthermore, identification of crossover segments also allowed examination of mutations at the point of recombination, since it has been predicted from some studies of cell-free systems that mutations may occur with a frequency of 30 to 50% at crossover junctions. However, DNA sequence analysis of crossover junctions indicated that homologous recombination during viral replication was not particularly mutagenic, indicating that there are other factors or conditions not yet reproduced in cell-free systems which contribute to fidelity during retroviral recombination.

scholarly journals 3′-Azido-3′-Deoxythymidine (AZT) and AZT-Resistant Reverse Transcriptase Can Increase the In Vivo Mutation Rate of Human Immunodeficiency Virus Type 1

2000 ◽  
Vol 74 (20) ◽  
pp. 9532-9539 ◽  
Author(s):  
Louis M. Mansky ◽  
Lisa C. Bernard
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Mutation Rate ◽  
Human Immunodeficiency Virus Type ◽  
Antiretroviral Drugs ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT How antiretroviral drug resistance influences human immunodeficiency virus type 1 (HIV-1) evolution is not clear. This study tested the hypothesis that antiretroviral drugs such as 3′-azido-3′-deoxythymidine (AZT) can influence the in vivo mutation rate of HIV-1. It was observed that AZT can increase the rate of HIV-1 mutation by a factor of 7 in a single round of replication. In addition, (−)2′,3′-dideoxy-3′-thiacytidine (3TC) was also found to increase the mutation rate of HIV-1 by a factor of 3. It was also found that HIV-1 drug-resistant reverse transcriptase (RT) variants can influence the in vivo mutation rate. Replication of HIV-1 with AZT-resistant RTs increased the mutation rate by as much as a factor of 3, while replication of HIV-1 with a 3TC-resistant RT (M184V) had no significant effect on the mutation rate. It was observed that only high-level, AZT-resistant RT variants could influence the in vivo mutation rate (i.e., M41L/T215Y and M41L/D67N/K70R/T215Y). In total, these observations indicate that both antiretroviral drugs and drug resistance mutations can influence the in vivo mutation rate of HIV-1.

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