[Markers in the evolution and control of HIV infection].
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AIDS Serodiagnosis↗
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Assessing the effects of human mixing patterns on human immunodeficiency virus-1 interhost phylogenetics through social network simulation.
Geneticists seeking to understand HIV-1 evolution among human hosts generally assume that hosts represent a panmictic population. Social science research demonstrates that the network patterns over which HIV-1 spreads are highly nonrandom, but the effect of these patterns on the genetic diversity of HIV-1 and other sexually transmitted pathogens has yet to be thoroughly examined. In addition, interhost phylogenetic models rarely account explicitly for genetic diversity arising from intrahost dynamics. This study outlines a graph-theoretic framework (exponential random graph modeling, ERGM) for the estimation, inference, and simulation of dynamic partnership networks. This approach is used to simulate HIV-1 transmission and evolution under eight mixing patterns resembling those observed in empirical human populations, while simultaneously incorporating intrahost viral diversity. Models of parametric growth fit panmictic populations well, yielding estimates of total viral effective population on the order of the product of infected host size and intrahost effective viral population size. Populations exhibiting patterns of nonrandom mixing differ more widely in estimates of effective population size they yield, however, and reconstructions of population dynamics can exhibit severe errors if panmixis is assumed. I discuss implications for HIV-1 phylogenetics and the potential for ERGM to provide a general framework for addressing these issues.
Evolution, Molecular↗
Mathematical model for the AIDS epidemic's evolution in Romania.
The individuals are distributed in 9 risk groups (adults and children), in which an HIV transmission way is predominant. Taking into account a simplified graph of the HIV infection evolution, kinetic equations for the number of individuals from each risk group--situated in various stages of HIV infection--are written. The approximative solutions of these equations give us: the characteristic exponents of the temporal evolutions of the main and secondary local epidemics; the ratios Ci/Bi and Di/Bi of asymptomatically contaminated and dead (as consequence of AIDS)--versus symptomatically contaminated; the onset of local epidemics in various risk groups; the relative amplitude of the secondary local epidemics versus the main local ones.
Acquired Immunodeficiency Syndrome↗
Mathematical model for the AIDS epidemics evolution in Romania.
The individuals are distributed in 9 risk groups (adults and children), in which an HIV transmission way is predominant. Taking into account a simplified graph of the HIV infection evolution, kinetic equations for the number of individuals from each risk group--situated in various stages of HIV infection--are written. The approximative solutions of these equations give us: the characteristic exponents of the temporal evolutions of the main and secondary local epidemics; the ratios Ci/Bi and Di/Bi of asymptomatically contaminated and dead (as consequence of AIDS) versus symptomatically contaminated; the onset of local epidemics in various risk groups; the relative amplitude of the secondary local epidemics versus the main local ones.
Acquired Immunodeficiency Syndrome↗
Evolutionary dynamics of HIV-1 recombinants: analysis of contemporary and historical viral populations in East Africa.
BACKGROUND: Understanding the genetic evolution of HIV-1 Transmitted/Founder (T/F) virus is crucial for developing effective treatment and prevention strategies due to its rapid mutation and recombination rates. METHODS: This study compared the genetic diversity of 24 contemporary T/F viruses collected between 2016 and 2021 in Uganda and Kenya with 29 historical T/F sequences sampled between 2006 and 2011. RESULTS: Subtype analysis based on near-full-length (NFL) HIV-1 T/F genomes revealed that 57.1% (12/21) of contemporary viruses were recombinants, predominantly involving Subtype A1, D, and increasing Subtype C, with 33.3% (7/21) being A1D recombinants (A1 > D) and 19% (4/21) classified as complex recombinants involving three or more subtypes. Historical viruses showed a similar overall proportion (69%) but were mainly A1D mosaics (D > A1) with recombination confined primarily to the envelope region. In contrast, contemporary viruses shifted towards more complex recombinant patterns affecting additional genomic regions, including pol and accessory genes. Phylogenetic analysis demonstrated that contemporary viruses clustered into distinct, well-supported (98% bootstrap) sub-branches, suggesting divergency attributed to an imbalance in their proportions of subtype A1 and D sequences as well as a different content of A1 and D segments in the A1/D mosaic recombinants. CONCLUSIONS: These findings underscore the dynamic and shifting nature of HIV-1 genetic diversity in East Africa, highlighting the need for continuous molecular surveillance and region-specific treatment guidelines.
HIV-1↗
Human immunodeficiency virus type 1 in faeces and serum: evidence against independently evolving subpopulations.
It is not known whether independent tissue-specific evolution accounts for the differences between human immunodeficiency virus type 1 (HIV-1) subpopulations in intestinal tissue and blood. To study this, sequential serum samples from three persons were analysed for the presence of HIV-1 V3 genotypes which were detected exclusively in faeces at a specific time-point. For two persons the faeces genotype was found in serum samples collected before the time of faeces collection: 7 months for one person and 32 months for the other person. In the third person, serum collected 1 month after faeces collection contained the faeces genotype in abundance. These data indicate that a difference between intestinal tissue and blood HIV-1 subpopulations is not the result of complete compartmentalization and independent HIV-1 evolution in intestinal tissue, but that it reflects an unequal distribution of HIV-1 in different tissues.
Amino Acid Sequence↗
HIV screening for pregnant women in south eastern France: evolution 1992-1994-1996.
OBJECTIVES: To assess the evolution of the HIV screening practices towards pregnant women between 1992 and 1996, in relation with the 1993 French mandatory obligation to offer prenatal HIV testing and recent therapeutic possibilities to reduce HIV vertical transmission. STUDY DESIGN: Three successive surveys (January 1992, May 1994 and May 1996) about HIV screening policies among medical chiefs of all prenatal care and abortion departments of South Eastern France. Sixty-seven of the 74 departments concerned agreed to participate in the three surveys. RESULTS: The proportion of departments practising routine prenatal HIV screening had not increased since 1992 (89%) but systematic women's consent is more often requested (65.5 vs. 38.2%, P < 0.01). In the context of abortion, HIV testing is more often routinely offered (38.1 vs. 16.4%, P < 0.05) but selective screening remains a frequent practice (29.1%). CONCLUSION: Mandatory proposal of HIV testing to women who terminate could improve access to test but is not sufficient to guarantee adequate preventive counselling.
Abortion, Induced↗
Dried blood spots collected on filter paper: an international resource for the diagnosis and genetic characterization of human immunodeficiency virus type-1.
The collection of dried blood spots (DBS) on filter paper provides a powerful approach for the development of large-scale, population-based screening programs. DBS methods are particularly valuable in developing countries and isolated rural regions where resources are limited. Large numbers of field specimens can be economically collected and shipped to centralized reference laboratories for genetic and (or) serological analysis. Alternatively, the dried blood can be stored and used as an archival resource to rapidly establish the frequency and distribution of newly recognized mutations, confirm patient identity or track the origins and emergence of newly identified pathogens. In this report, we describe how PCR-based technologies are beginning to interface with international screening programmes for the diagnosis and genetic characterization of human immunodeficiency virus type 1 (HIV-1). In particular, we review recent progress using DBS specimens to resolve the HIV-1 infection status of neonates, monitor the genetic evolution of HIV-1 during early infancy and establish a sentinel surveillance system for the systematic monitoring of HIV-1 genetic variation in Asia.
AIDS Serodiagnosis↗
Low genetic barrier to large increases in HIV-1 cross-resistance to protease inhibitors during salvage therapy.
HIV-1 resistance to protease inhibitors (PIs) is characterized by extensive cross-resistance within this drug class. Some PIs, however, appear less affected by cross-resistance and are often prescribed in salvage therapy regimens for patients who have failed previous PI treatment. To examine the capacity of HIV-1 to adapt to these treatment changes, we have followed the evolution of HIV-1 protease genotypes and phenotypes in 21 protease-inhibitor-experienced patients in whom 26 weeks of an aggressive salvage regimen associating lopinavir, amprenavir and ritonavir failed to suppress viral replication. Baseline genotypes exhibited a median of seven resistance mutations in the protease. After 26 weeks of treatment, changes in protease genotypes were seen in 13/21 patients. The evolution of these protease genotypes was rapid, with more than one-third of the changes occurring during the first 6 weeks. Although the mean number of additional mutations was small (2.15 new mutations at week 26) these mutations were sufficient to promote remarkable changes in resistance phenotype. In several patients, some of the new mutations were found to exist before salvage treatment as part of minority quasi-species. Thus, in the face of the strong pharmacological pressure exerted by combinations of PIs to which it has never been exposed, and in spite of limited cross-resistance to these drugs before salvage therapy, HIV-1 can rapidly adapt its resistance genotype and phenotype at a minimal evolutionary cost.
Drug Administration Schedule↗
Markov modelling of immunological and virological states in HIV-1 infected patients.
The purpose of this study was to evaluate the evolution of HIV infected patients and to bring out some significant factors associated with this pathology. The main criteria revealing the State of illness is viral load measurement (VL). However the CD4 lymphocytes also represent an important marker as these reflect the State of the immune reservoir. Many studies have been carried out in this field and different models have been proposed with a view to a better understanding of this disease. Multi State Markov models defined in terms of CD4 counts, or in terms of viral load, have proved to be very useful tools for modelling HIV disease progression. The model we have developed in this study is based on both the CD4 lymphocytes counts and VL. Markov models are characterized by transition intensities. In this paper we explored several structures in succession. First, we used a homogeneous continuous time Markov process with four states defined by crossed values of CD4 and VL in a given patient at a given time. Then, the effect of certain covariates on the infection process was introduced into the model via the transition intensity functions, as with a Cox regression model. Since the hypothesis of homogeneity may be unrealistic in certain cases, we also considered piecewise homogeneous Markov models. Finally, the effects of covariates and time were combined in a piecewise homogeneous model with a covariate. We applied these methods to data from 1313 HIV-infected patients included in the NADIS cohort.
Age Factors↗
Patterns of changes in human immunodeficiency virus type 1 V3 sequence populations late in infection.
We have used a V3-specific heteroduplex tracking assay (V3-HTA) with probes from two different human immunodeficiency virus type 1 (HIV-1) subtypes to examine the extent and pace of HIV-1 evolution late in infection. Twenty-four subjects with advanced HIV-1 infection (CD4(+) T-cell count, <100/microl) and stable viral loads were studied using blood plasma samples collected over a study period of approximately 9 months, during which time most of the subjects were treated with reverse transcriptase inhibitors. The V3-HTA patterns from the first and last time points were evaluated initially to determine the amounts of change in V3 sequence populations, which were primarily changes in abundance in preexisting sequence populations. Three of the 24 subjects had major changes (greater than 50% total change in the relative abundance of the sequence populations), 11 subjects had intermediate changes (10 to 50% total change), and 10 subjects had minimal changes (less than 10% total change). The average total amount of change was between two- and threefold greater in subjects with X4-like variants, although there was no correlation between average viral load and the presence of X4-like variants. V3-HTA patterns in monthly samples from 11 of the subjects were also compared. In two subjects, the amount of change exceeded 40% in a 1-month period. Overall, the pace of change in V3 populations varied between subjects and was not constant within a subject over time. Sequence analysis of the V3 variants showed that R5-like variants (not containing any X4-associated substitutions) continued to be maintained in three subjects in the presence of X4-like variants, indicating that X4 variants do not always outgrow R5 variants. The coreceptor usage of the V3 sequences from two subjects was determined using a cell fusion assay. One subject had an X4 variant that was maintained at a low level for at least 9 months, during which time the predominant variants were R5X4 (dualtropic), while in the second subject the reverse situation was observed. One of the dualtropic variants had a novel sequence motif in V3, suggesting another evolutionary pathway to altered tropism. These studies begin to probe the complexities and pace of V3 evolution in vivo, revealing dynamic patterns of change among multiple V3 sequence variants in a subset of subjects.
Base Sequence↗
Evolutionary dynamics of human retroviruses investigated through full-genome scanning.
To test hypotheses on the differences in retroviral genetic diversity, we compared the evolutionary dynamics of the human immunodeficiency virus type 1 (HIV-1) group M and the primate T-cell lymphotropic virus (PTLV) using a full-genome analysis. Evolutionary rates and nonsynonymous/synonymous substitution rate ratios were estimated across the genome using a maximum likelihood sliding window approach, and molecular clock properties were investigated. We confirm a remarkable difference in genetic stability and selective pressure at the interhost level. While there is evidence for adaptive evolution in HIV-1, the evolution of PTLV is almost exclusively characterized by negative selection or nearly neutral processes. For both retroviruses, evolutionary rate estimates across the genome reflect the differential selective constraints. However, based on the relationship between evolutionary rate and selective pressure and based on the comparison of synonymous substitution rates, the differences in rate between HIV-1 and PTLV cannot be explained by selective forces only. Several evolutionary and statistical assumptions, examined using a Bayesian coalescent method, were shown to have little influence on our inference.
Bayes Theorem↗
Initiation of therapy during primary HIV type 1 infection results in a continuous decay of proviral DNA and a highly restricted viral evolution.
A latent pool of HIV-1 is established early in memory CD4+ T lymphocytes and persists during antiretroviral therapy. Also, viral replication may continue in subjects despite undetectable viremia. However, it remains unclear whether this residual replication results in any significant sequence evolution. We were therefore interested in studying the viral evolution and HIV-1 DNA dynamics in subjects with primary infection receiving or not receiving early potent antiretroviral therapy. In 16 subjects, HIV-1 DNA load was monitored from 1 to 23 days, up to 1253 days, after onset of symptoms. Extensive sequential cloning and sequence analysis of the V3 region was performed in four subjects. In the treated subjects a continuous decline in the proviral load was found, corresponding to a half-life of about 6 months. As expected in newly infected individuals the founder virus populations showed high intrasubject sequence similarity. Also, a limited increase in the viral divergence was detected during the first 6 months in three treated subjects. Thereafter, no significant sequence changes were found despite analysis of a large number of clones. Our data thus suggest that early and successful therapy in compliant subjects with primary HIV-1 infection results in a highly restricted viral evolution and a decline in the proviral load close to the decay rate of human memory T lymphocytes.
DNA, Viral↗
Diversification and specialization of HIV protease function during in vitro evolution.
Our goal is to understand how enzymes adapt to utilize novel substrates. We and others have shown that directed evolution tends to generate enzyme variants with broadened substrate specificity. Broad-specificity enzymes are generally deleterious to living cells, so this observed trend might be an artifact of the most commonly employed high throughput screens. Here, we demonstrate a more natural and effective screening strategy for directed evolution. The gene encoding model enzyme HIV protease was randomly mutated, and the resulting library was expressed in Escherichia coli cells to eliminate cytotoxic broad-specificity variants. The surviving variants were screened for clones with activity against a reporter enzyme. The wild-type human immunodeficiency virus type I protease (HIV PR) is cytotoxic and exhibits no detectable activity in reactions with beta-galactosidase (BGAL). In contrast, the selected variants were nontoxic and exhibited greater activity and specificity against BGAL than did the wild-type HIV PR in reactions with any substrate. A single round of whole gene random mutagenesis and conventional high-throughput screening does not usually effect complete inversions of substrate specificity. This suggests that a combination of positive and purifying selection engenders more rapid adaptation than positive selection alone.
Adaptation, Biological↗
HIV diversity, molecular epidemiology, and the role of recombination.
The magnitude of the HIV pandemic and its extensive genetic variation may earn it a unique place among infectious agents. A high mutation rate and a rampant recombination are driving HIV's evolution. Nine subtypes and a variety of recombinant forms of HIV now exist. The source of recombinant forms is the multiple infection of target cells, which becomes highly significant when individuals become infected with two or more divergent strains. In the current paper, we re-examine the role of dual infection and recombination in the generation of HIV-1 diversity, both in individuals and on a global scale. The current molecular epidemiology of HIV-1 is reviewed, emphasizing the latest reports from regional epidemics.
Journal Article↗
Determination of human immunodeficiency virus type 1 subtypes by a rapid method useful for the routine diagnostic laboratory.
The existence of human immunodeficiency virus type 1 (HIV-1) subtypes has many important implications for the global evolution of HIV and for the evaluation of pathogenicity, transmissibility, and candidate HIV vaccines. The aim of this study was to establish a rapid method for determination of HIV-1 subtypes useful for a routine diagnostic laboratory and to investigate the distribution of HIV-1 subtypes in Austrian patients. Samples were tested by a subtyping method based on a 1.3-kb sequence of the polymerase gene generated by a commercially available drug resistance assay. The generated sequence was subtyped by means of an HIV sequence database. Results of 74 routine samples revealed subtype B (71.6%) as the predominant subtype, followed by subtype A (13.5%) and subtype C (6.8%). Subtypes E, F, G, and AE (CM240) were also detected. This subtyping method was found to be very easy to handle, rapid, and inexpensive and has proved suitable for high-throughput routine diagnostic laboratories. The specific polymerase gene sequence, however, must be existent.
Child↗
Independent HIV replication in paired CSF and blood viral isolates during antiretroviral therapy.
BACKGROUND: The goal of highly active antiretroviral therapy in HIV-infected patients is to reduce plasma viral load (VL) below quantifiable levels. Mutations associated with drug resistance within the HIV-1 genome can limit therapeutic success. Low VL implicates a low risk of emergence of resistant mutants. Whether there is divergent development of HIV strains in different biologic compartments is not understood. METHODS: The authors studied VL and the occurrence of mutations conferring resistance in viral genomes isolated from blood and CSF samples of 23 HIV-infected patients. They determined sequences of HIV-1 RNA by reverse transcriptase PCR amplification and direct sequencing. They measured resistance to antiretroviral drugs genotypically by detection of drug-related point mutations and VL by a branched-DNA assay. RESULTS: Amplification of HIV was successful even in patients with plasma or CSF VL below detection limit. VL was considerably lower in CSF as compared with blood (p < 0.0001). There was no correlation between CSF and plasma VL. The mutational pattern in viral copies derived from blood and CSF was not identical. Ten (9%) of the total number of 118 mutations associated with drug resistance occurred in blood isolates only; 14 (11%) were detected exclusively in CSF strains. CONCLUSION: There is evidence for viral replication at HIV RNA levels less than 50/mL. The results suggest divergent evolution of HIV-1 in different biologic compartments. The presence of resistant mutants in the CSF may escape regular diagnostic in blood. Therapeutic success may fail after adapting therapy to genotypic resistance patterns detected in one compartment only.
Adult↗
HIV-1 genotypes in peripheral blood monocytes.
CD4+ T cells and tissue macrophages are well defined as the major targets for human immunodeficiency virus type 1 (HIV-1) infection and replication, and their infection accounts for many aspects of HIV-1 pathogenesis in vivo. HIV-1 genotype and phenotype in monocytes and their potential roles in pathogenicity in vivo remain unknown. Herein is an overview of our initial work on HIV-1 genotype in purified CD14+ monocytes isolated longitudinally during the course of infection starting from the time of infection. Our data provide evidence for HIV-1 evolution in monocytes and their role as a reservoir of HIV-1 in vivo. A better understanding of HIV-1 in monocytes may greatly help the development of new therapeutic strategies for HIV-1 infection.
Amino Acid Sequence↗