Dataset Information

Low frequency of CXCR4-using viruses in patients at the time of primary non-subtype-B HIV-1 infection.

ABSTRACT: We used genotypic and phenotypic assays to estimate the frequency of X4/DM viruses in 131 patients infected with non-subtype-B viruses at the time of primary HIV-1 infection (PHI). All patients were enrolled in the French PRIMO Cohort from 1996 to 2007. Most strains belonged to CRF02_AG (51.1%) and subtype A (14.5%). Sixteen viruses (12.2%) were classified as CXCR4 tropic ("X4 strains") by the combined criteria of amino acids 11 and 25 of the V3 loop (11/25) and net charge rules and/or the SVMgeno2pheno(10%) algorithm: 6 strains by the combined genotypic rule, 7 by the SVMgeno2pheno(10%) algorithm, and 3, clustering in subtype D, by both algorithms. However, only one strain (0.8%), belonging to subtype A, was defined as a dual-tropic (DM) virus by the phenotypic assay. The 67 CRF02_AG strains included 2 classified as X4 strains by the combined genotypic rule (3%) and 2 others classified as X4 strains by SVMgeno2pheno(10%) (3%), but none of these 4 strains was an X4 or DM strain according to the phenotypic assay. These results suggest that the cellular virus reservoir was established with X4 strains in very few non-subtype-B-infected patients at the time of PHI. Genotypic predictions can overestimate the proportion of non-subtype-B X4 viruses at PHI.

SUBMITTER: Frange P

PROVIDER: S-EPMC2953081 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Low frequency of CXCR4-using viruses in patients at the time of primary non-subtype-B HIV-1 infection.

Frange Pierre P Chaix Marie-Laure ML Raymond Stéphanie S Galimand Julie J Deveau Christiane C Meyer Laurence L Goujard Cécile C Rouzioux Christine C Izopet Jacques J

Journal of clinical microbiology 20100804 10

We used genotypic and phenotypic assays to estimate the frequency of X4/DM viruses in 131 patients infected with non-subtype-B viruses at the time of primary HIV-1 infection (PHI). All patients were enrolled in the French PRIMO Cohort from 1996 to 2007. Most strains belonged to CRF02_AG (51.1%) and subtype A (14.5%). Sixteen viruses (12.2%) were classified as CXCR4 tropic ("X4 strains") by the combined criteria of amino acids 11 and 25 of the V3 loop (11/25) and net charge rules and/or the SVMge ...[more]

PMID: 20686090

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Project description:BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is spreading rapidly and is now responsible for >50% of HIV-1 infections worldwide, and >95% of infections in southern Africa and central Asia. These regions are burdened with the overwhelming majority of HIV-1 infections, yet we know very little about the pathogenesis of C-HIV. In addition to CCR5 and CXCR4, the HIV-1 envelope glycoproteins (Env) may engage a variety of alternative coreceptors for entry into transfected cells. Whilst alternative coreceptors do not appear to have a broad role in mediating the entry of HIV-1 into primary cells, characterizing patterns of alternative coreceptor usage in vitro can provide valuable insights into mechanisms of Env-coreceptor engagement that may be important for HIV-1 pathogenesis. RESULTS: Here, we characterized the ability of luciferase reporter viruses pseudotyped with HIV-1 Envs (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naïve subjects experiencing progression from chronic to advanced C-HIV infection over an approximately 3-year period, who either exclusively maintained CCR5-using (R5) variants (n = 20 subjects) or who experienced a coreceptor switch to CXCR4-using (X4) variants (n = 1 subject), to utilize alternative coreceptors for entry. At a population level, CCR5 usage by R5 C-HIV Envs was strongly linked to usage of FPRL1, CCR3 and CCR8 as alternative coreceptors, with the linkages to FPRL1 and CCR3 usage becoming statistically more robust as infection progressed from chronic to advanced stages of disease. In contrast, acquisition of an X4 Env phenotype at advanced infection was accompanied by a dramatic loss of FPRL1 usage. Env mutagenesis studies confirmed a direct link between CCR5 and FPRL1 usage, and showed that the V3 loop crown, but not other V3 determinants of CCR5-specificity, was the principal Env determinant governing the ability of R5 C-HIV Envs from one particular subject to engage FPRL1. CONCLUSIONS: Our results suggest that, in the absence of coreceptor switching, the ability of R5 C-HIV viruses to engage certain alternative coreceptors in vitro, in particular FPRL1, may reflect an altered use of CCR5 that is selected for during progressive C-HIV infection, and which may contribute to C-HIV pathogenicity.

Project description:Aiming to answer the broad question "When does mutation occur?" this study examined the time of appearance, dominance, and completeness of in vivo Gag mutations in primary HIV-1 subtype C infection.A primary HIV-1C infection cohort comprised of 8 acutely and 34 recently infected subjects were followed frequently up to 500 days post-seroconversion (p/s). Gag mutations were analyzed by employing single-genome amplification and direct sequencing. Gag mutations were determined in relation to the estimated time of seroconversion. Time of appearance, dominance, and completeness was compared for different types of in vivo Gag mutations.Reverse mutations to the wild type appeared at a median (IQR) of 62 (44;139) days p/s, while escape mutations from the wild type appeared at 234 (169;326) days p/s (p<0.001). Within the subset of mutations that became dominant, reverse and escape mutations appeared at 54 (30;78) days p/s and 104 (47;198) days p/s, respectively (p<0.001). Among the mutations that reached completeness, reverse and escape mutations appeared at 54 (30;78) days p/s and 90 (44;196) days p/s, respectively (p=0.006). Time of dominance for reverse mutations to and escape mutations from the wild type was 58 (44;105) days p/s and 219 (90;326) days p/s, respectively (p<0.001). Time of completeness for reverse and escape mutations was 152 (100;176) days p/s and 243 (101;370) days p/s, respectively (p=0.001). Fitting a Cox proportional hazards model with frailties confirmed a significantly earlier time of appearance (hazard ratio (HR): 2.6; 95% CI: 2.3-3.0), dominance (4.8 (3.4-6.8)), and completeness (3.6 (2.3-5.5)) of reverse mutations to the wild type Gag than escape mutations from the wild type. Some complex mutational pathways in Gag included sequential series of reversions and escapes.The study identified the timing of different types of in vivo Gag mutations in primary HIV-1 subtype C infection in relation to the estimated time of seroconversion. Overall, the in vivo reverse mutations to the wild type occurred significantly earlier than escape mutations from the wild type. This shorter time to incidence of reverse mutations remained in the subsets of in vivo Gag mutations that reached dominance or completeness.

Project description:BACKGROUND:Entry inhibitors, such as Maraviroc, bind to CCR5 inhibiting entry of CCR5 utilizing viruses (R5 viruses). In the course of HIV infection, CXCR4 utilizing viruses (X4 viruses) may emerge and outgrow R5 viruses, and potentially limit the effectiveness of Maraviroc. The use of Maraviroc is reserved for salvage therapy in South Africa. OBJECTIVE:In this study, we examined the frequency of R5 and X4 viruses, using next generation sequencing, in patients under treatment to draw inferences on the utility of Maraviroc in a South African population. STUDY DESIGN:Proviral DNA was isolated from peripheral blood mononuclear cells (PBMC) of 72 chronically HIV infected patients on antiretroviral treatment. HIV V3 loop gene was amplified and sequenced on an Illumina MiniSeq platform. Viral subtypes were determined by the jumping profile Hidden Markov Model (jpHMM) and REGA genotyping tools. De Novo consensus sequences were derived for the majority and minority populations for each patient using Geneious® software version 8.1.5. HIV-1 tropism was inferred using PSSMsinsi, Geno2pheno and Phenoseq-C web-based tools. RESULTS:Quality V3 loop sequences were obtained from 72 patients, with 5 years (range: 0-16) median duration on treatment. Subtypes A1, B and C viruses were identified at frequencies of 4% (3/72), 4% (3/72) and 92% (66/72) respectively. Fifty four percent (39/72) of patients exclusively harboured R5 viral quasispecies; and 21% (15/72) exclusively harbored X4 viral quasispecies. Twenty five percent of patients (18/72) harbored dual/mixture of R5X4 quasispecies. Of these 18 patients, about 28% (5/18) harbored the R5+X4, a mixture with a majority R5 and minority X4 viruses, while about 72% (13/18) harbored the R5X4+ mixture with a majority X4 and minority R5 viruses. The proportion of all patients who harbored X4 viruses either exclusively or dual/mixture was 46% (33/72). Thirty-five percent (23/66) of the patients who were of HIV-1 subtype C harboured X4 viruses (χ2 = 3.58; p = .058), and 57% of these (13/23) harbored X4 viruses exclusively. CD4+ cell count less than 350 cell/μl was associated with the presence of X4 viruses (χ2 = 4.99; p = .008). CONCLUSION:The effectiveness of Maraviroc as a component in salvage therapy may be compromised for a significant number of chronically infected patients harboring CXCR4 utilizing viruses.

Dataset Information

Low frequency of CXCR4-using viruses in patients at the time of primary non-subtype-B HIV-1 infection.

Publications

Low frequency of CXCR4-using viruses in patients at the time of primary non-subtype-B HIV-1 infection.

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