Impact of HIV-1 viral subtype on disease progression and response to antiretroviral therapy

<p>Abstract</p> <p>Background</p> <p>Our intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non-B HIV-1 subtypes (A, C, D and the circulating recombinant form, CRF02-AG) in an ethnically diverse population of HIV-1-infected patients in south London.</p> <p>Methods</p> <p>A random sample of 861 HIV-1-infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in-house enzyme-linked immunoassay and <it>env </it>sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi-level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression.</p> <p>Results</p> <p>Complete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02-AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02-AG. However, a statistically significant four-fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01)</p> <p>Conclusions</p> <p>This is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D.</p

THE INFLUENCE OF HIV-1 SUBTYPES C, CRF31_BC AND B ON DISEASE PROGRESSION AND INITIAL VIROLOGIC RESPONSE TO HAART IN A SOUTHERN BRAZILIAN COHORT

Background: Although most HIV-1 infections in Brazil are due to subtype B, Southern Brazil has a high prevalence of subtype C and recombinant forms, such as CRF31_BC. This study assessed the impact of viral diversity on clinical progression in a cohort of newly diagnosed HIV-positive patients. Methods: From July/2004 to December/2005, 135 HIV-infected patients were recruited. The partial pol region was subtyped by phylogeny. A generalized estimating equation (GEE) model was used to examine the relationship between viral subtype, CD4+ T cell count and viral load levels before antiretroviral therapy. Hazard ratio (Cox regression) was used to evaluate factors associated with viral suppression (viral load < 50 copies/mL at six months). Results: Main HIV-1 subtypes included B (29.4%), C (28.2%), and CRF31_BC (23.5%). Subtypes B and C showed a similar trend in CD4+ T cell decline. Comparison of non-B (C and CRF31_BC) and B subtypes revealed no significant difference in the proportion of patients with viral suppression at six months (week 24). Higher CD4+ T cell count and lower viral load were independently associated with viral suppression. Conclusion: No significant differences were found between subtypes; however, lower viral load and higher CD4+ T cell count before therapy were associated with better response

Evolutionary Modeling of Rate Shifts Reveals Specificity Determinants in HIV-1 Subtypes

A hallmark of the human immunodeficiency virus 1 (HIV-1) is its rapid rate of evolution within and among its various subtypes. Two complementary hypotheses are suggested to explain the sequence variability among HIV-1 subtypes. The first suggests that the functional constraints at each site remain the same across all subtypes, and the differences among subtypes are a direct reflection of random substitutions, which have occurred during the time elapsed since their divergence. The alternative hypothesis suggests that the functional constraints themselves have evolved, and thus sequence differences among subtypes in some sites reflect shifts in function. To determine the contribution of each of these two alternatives to HIV-1 subtype evolution, we have developed a novel Bayesian method for testing and detecting site-specific rate shifts. The RAte Shift EstimatoR (RASER) method determines whether or not site-specific functional shifts characterize the evolution of a protein and, if so, points to the specific sites and lineages in which these shifts have most likely occurred. Applying RASER to a dataset composed of large samples of HIV-1 sequences from different group M subtypes, we reveal rampant evolutionary shifts throughout the HIV-1 proteome. Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification. We report further evidence for the emergence of a new sub-subtype, characterized by abundant rate-shifting sites. When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance. Finally, we discuss mechanisms of covariation of rate-shifting sites

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe

[Role of N-linked glycans in the functions of hepatitis C virus envelope glycoproteins].

International audienceHepatitis C virus (HCV) is an enveloped virus and encodes two envelope glycoproteins, E1 and E2. E1 and E2 are transmembrane type I proteins with a N-terminal ectodomain and C-terminal anchor. During their synthesis, E1 and E2 ectodomains are targeted in the endoplasmic reticulum lumen where they are modified by N-linked glycosylation. After their synthesis, E1 and E2 assemble as a non-covalent heterodimer. The N-linked glycosylation is based on the recognition of specific asparagine residue in the context of the consensus sequence Asn-X-Ser/Thr. E1 contains potentially 4 or 5 N-linked glycosylation sites and E2 up to 11. Recent data indicated that some glycans of glycoproteins E1 and E2 play a major role in protein folding and heterodimer formation. Some N-linked glycans of E2 were involved in interactions with CD81, a putative cellular receptor for HCV. It appeared that N-linked glycans of E1 and E2 played an important role of in the viral entry

[Emergent viruses: SARS-associate coronavirus and H5N1 influenza virus].

International audienceTwo viral agents with RNA genome are responsible for emerging illnesses: influenza virus A/H5N1 and Severe Acute Respiratory Syndrome virus (SARS). For the diagnosis of SARS virus infection, an epidemiological investigation is necessary to know whether the patient has been exposed to a risk in a country where the SARS virus is circulating or whether the patient had worked in a laboratory handling SARS virus. The detection of SARS virus is possible in various clinical samples (including urine) by viral culture or RT-PCR. The handling of those samples and RNA extraction must be performed in a BSL3 laboratory. The SARS virus RT-PCR is poorly sensitive, therefore the test should be performed on samples collected consecutively for several days. In front of a suspicion of A/H5N1, similar procedures are recommended. An epidemiologic investigation is necessary to specify whether the patient stayed in a country where A/H5N1 virus was circulating. Clinical samples needed for a specific diagnosis are: nasopharyngeal, throat-swab or fecal samples, cerebrospinal fluid and blood. The presence of A/H5N1 virus is confirmed by viral isolation or RNA detection by RT-PCR. RNA extraction must be performed in a BSL3 laboratory. For diagnosis of A/H5N1 virus infection, RT-PCR test amplifies specifically a fragment of H5 gene (Hemagglutinin). In french laboratories of medical virology, procedures are ready to diagnose the first case of A/H5N1 virus infection and cases of reemerging SARS virus infection

Effect of resistance-associated substitutions on retreatment of direct acting antiviral-exposed patients in the real-world setting (ANRS CO22 HEPATHER)

International audienceRe-treatment of patients with decompensated chronic hepatitis C virus cirrhosis using 24 weeks of sofosbuvir and NS5A inhibitor, with or without ribavirin after failing a 12 week cours