Faster HIV-1 Disease Progression among Brazilian Individuals Recently Infected with CXCR4-Utilizing Strains

Astakhova

BioMed Research International

et al. 2016

Introduction. Specific molecular epidemic features of HIV infection in Tyumen Oblast (TO), Russia, were studied. Methods. The genome sequences encoding HIV-1 protease-reverse transcriptase, integrase, and major envelope protein were examined for 72 HIV-1 specimens isolated from the TO resident infected in 2000–2015. Results. The recorded prevalence of HIV-1 subtype A (A1) is 93.1%; HIV-1 subtype B continues to circulate in MSM risk group (1.4%). Solitary instances of HIV-1 recombinant forms, CRF63_02A1 (1.4%) and CRF03_AB (1.4%), were detected as well as two cases of HIV-1 URF63_A1 (2.8%). Phylogenetic analysis showed no HIV-1 clustering according to the duration of infection and risk groups but revealed different epidemic networks confirming that HIV infection spread within local epidemic foci. A high incidence of CXCR4-tropic HIV-1 variants and a higher rate of secondary mutations influencing the virus fitness (K20R, L10V, and I) are observed among the virus specimens isolated from newly infected individuals. Conclusions. The current HIV-1 epidemic in TO develops within the local epidemic networks. Similar to the previous period, HIV-1 subtype A is predominant in TO with sporadic cases of importation of HIV-1 recombinant forms circulating in adjacent areas.

Section: Discussionmentioning

confidence: 99%

HIV-1 Epidemiology, Genetic Diversity, and Primary Drug Resistance in the Tyumen Oblast, Russia

Astakhova

BioMed Research International

et al. 2016

“…Extensive efforts over the past decades have explored mechanisms associated with early AIDS progression (29 ), but the etiology underlying such rapid progression remains poorly understood. Early emergence of CXCR4-utilizing HIV strains was found to accelerate disease progression (5 ). We have isolated primary HIV from CD4 ϩ T cells of 15 EHI patients enrolled in this study (13 RPs,2 CPs).…”

Section: Discussionmentioning

confidence: 99%

“…The unique pathogenic development of HIV-infected patients with rapid progression, representing 10%-15% of the HIVpositive population (2 ), remains less understood than those with chronic progression or elite controllers. Limited studies previously carried out with this patient population have identified several viral, genetic, and immunologic factors that are associated with rapid disease progression, such as the early emergence of CXCR4-utilizing HIV strains, risk single-nucleotide polymorphisms (SNPs) 3 within interleukin-7R␣ or Toll-like receptor loci, and high concentrations of IP-10 (interferon ␥ induced protein) in the plasma (3)(4)(5)(6)(7). Several months after HIV seroconversion, plasma viremia reaches a steady state or viral set point, which is an important determinant of the rate of HIV disease progression (8 ).…”

mentioning

confidence: 99%

Transcriptomic Analysis of Peripheral Blood Mononuclear Cells in Rapid Progressors in Early HIV Infection Identifies a Signature Closely Correlated with Disease Progression

Zhang

et al. 2013

Clinical Chemistry

BACKGROUND:A substantial percentage (10%-15%) of HIV-infected individuals experience a sharp decline in CD4 ϩ T-cell counts and progress to AIDS quickly after primary infection. Identification of biomarkers distinguishing rapid progressors (RPs) vs chronic progressors (CPs) is critical for early clinical intervention and could provide novel strategies to facilitate vaccine design and immune therapy.

“…Although this number can vary for the different virus subtypes, the percentage of CXCR4-tropic HIV isolates is generally low and tends to rise with disease progression (3)(4)(5)(6). Nevertheless, the fraction of CCR5-tropic viruses in clinical specimens continues to stay at Ͼ50% throughout the course of infection (7,8).…”

mentioning

confidence: 99%

A Diagnostic HIV-1 Tropism System Based on Sequence Relatedness

et al. 2015

dKey clinical studies for HIV coreceptor antagonists have used the phenotyping-based Trofile test. Meanwhile various simplerto-do genotypic tests have become available that are compatible with standard laboratory equipment and Web-based interpretation tools. However, these systems typically analyze only the most prominent virus sequence in a specimen. We present a new diagnostic HIV tropism test not needing DNA sequencing. The system, XTrack, uses physical properties of DNA duplexes after hybridization of single-stranded HIV-1 env V3 loop probes to the clinical specimen. Resulting "heteroduplexes" possess unique properties driven by sequence relatedness to the reference and resulting in a discrete electrophoretic mobility. A detailed optimization process identified diagnostic probe candidates relating best to a large number of HIV-1 sequences with known tropism. From over 500 V3 sequences representing all main HIV-1 subtypes (Los Alamos database), we obtained a small set of probes to determine the tropism in clinical samples. We found a high concordance with the commercial TrofileES test (84.9%) and the Web-based tool Geno2Pheno (83.0%). Moreover, the new system reveals mixed virus populations, and it was successful on specimens with low virus loads or on provirus from leukocytes. A replicative phenotyping system was used for validation. Our data show that the XTrack test is favorably suitable for routine diagnostics. It detects and dissects mixed virus populations and viral minorities; samples with viral loads (VL) of <200 copies/ml are successfully analyzed. We further expect that the principles of the platform can be adapted also to other sequence-divergent pathogens, such as hepatitis B and C viruses. The predominant virus variant in early stages of the clinical manifestation of disease, CCR5-tropic HIV, is found in approximately 80% of treatment-naive patients (1, 2). Although this number can vary for the different virus subtypes, the percentage of CXCR4-tropic HIV isolates is generally low and tends to rise with disease progression (3-6). Nevertheless, the fraction of CCR5-tropic viruses in clinical specimens continues to stay at Ͼ50% throughout the course of infection (7,8). As such, the molecular interactions between the viral envelope and the cellular chemokine receptor CCR5 were recognized as potentially attractive targets for drug development and have yielded compounds and drugs able to specifically block CCR5-tropic HIV (9-11). It is this selectivity of the inhibition of one (CCR5) and not the other (CXCR4) viral coreceptor that necessitates tropism testing prior to prescribing drugs of this particular class. Although the chemokine receptor binding site in the HIV envelope is constituted mainly by the V3 loop, the V1/V2 regions, and the C4 conserved region in the HIV protein gp120, coreceptor tropism is dictated predominantly by amino acid sequences of the V3 region (12, 13). But also sequences of other variable env regions can contribute as secondary sites to the viral tropism (14-17).Initially, all...