The degree of HIV-1 amino acid variability is strictly related to different disease progression rates

The aim of this study is to evaluate the amino acid variability of HIV-1 Gp41, C2–V3, and Nef in a group of patients characterized by different disease progression rates. HIV-1 sequences were collected from 19 Long term non progressor patients (LTNPs), 9 slow progressors (SPs), and 11 rapid progressors (RPs). Phylogenetic trees were estimated by MEGA 6. Differences in amino acid variability among sequences belonging to the 3 groups have been evaluated by amino acid divergence, Shannon entropy analysis, and the number of amino acid mutations (defined as amino acid variations compared with HxB2). The involvement of amino acid mutations on epitope rich regions was also investigated. The population was mainly composed of males (74.3%) and HIV-1 subtype B strains (B: 92.32%, CRF_12BF, A1, C: 2.56% each). Viral load (log₁₀ copies/mL) and CD4⁺T cell count (cells/mm³) were 3.9 (3.5–4.2) and 618 (504–857) in LTNPs, 3.3 (2.8–4.7) and 463 (333–627) in SPs, and 4.6 (4.3–5.3) and 201 (110–254) in RPs. Gp41 and C2–V3 amino acid divergence was lower in LTNP and SP strains compared to RPs (median value: 0.085 and 0.091 vs. 0.114, p?=?0.005 and 0.042) and a trend of lower variability was observed for Nef (p?=?0.198). A lower entropy value was observed at 10, 3, and 7 positions of Gp41, C2–V3, and Nef belonging to LTNPs and at 7, 3, and 1 positions of Gp41, C2–V3, and Nef belonging to SPs compared with RPs (p?<?0.05). Focusing on epitope rich regions, again a higher degree of conservation was observed in Gp41 and C2–V3 sequences belonging to LTNPs and SPs compared to those belonging to RPs. This study shows that the extent of amino acid variability correlates with a different HIV-1 progression rate. This variability also involves CTL epitope rich regions, thus suggesting its involvement in the immune escape process modulation.     

HIV-1 B-subtype capsid protein: a characterization of amino acid’s conservation and its significant association with integrase signatures

The HIV-1 pre-integration phase and the subsequent integration of viral genome to the host of nuclear chromosomes are not well analyzed so far. Many studies are discussing the question of pre- and post-nuclear viral entry which is to support the assumption that HIV-1 integrase (IN) is maintained in the volume of intact conical structure’s capsids through HIV entry. The aim of the current study is to identify the prevalence of capsid’s (CA) signatures among drug-naïve and antiretroviral (ARV)-treated patients in a cohort of 827 HIV-1 B-subtype-infected individuals, and subsequently the relationship between IN and CA amino acid’s changes was evaluated. These analyses suggest a conceivable co-evolution of IN–CA sequences, especially in relation to steps of nuclear viral entry. The frequency of mutations was calculated, and statistically has been compared between treatment-naïve and ARV-treated patients. The binomial correlation coefficient was used to assess covariation among CA and IN mutations; then, the average linkage hierarchical agglomerative clustering was performed. The results show a detailed conservation of HIV-1 CA protein both in drug-naïve and in ARV-treated patients. Moreover, the specific CA substitutions are significantly associated with different IN signatures at the amino acid level and the topology of the dendrogram has revealed the existence of two strong sub-clusters associated with hypothetical different mutational pathways. The in vitro and in vivo studies are necessary to exclude the hypothetical statistical false positive results and in order to confirm that some CA amino acid signatures are going to establish specific and precise implication in the HIV life cycle.     

gp41 sequence variability in HIV type 1 non-B subtypes infected patients undergoing enfuvirtide pressure

Enfuvirtide is the first of a new class of antiretroviral drugs that inhibits HIV entry. It is a 36 amino acid synthetic peptide that mimics the HR2 region of the HIV-1 gp41, preventing the fusion of viral and cellular membranes. Up to now, enfuvirtide was designed based on the HIV-1 B-subtype gp41, and resistance mutations to the fusion inhibitor have been investigated primarily in individuals infected with this subtype. To fill the gap, we analyzed the full length gp41 protein sequence of HIV-1 non-B strains from individuals receiving enfuvirtide-containing regimens. No primary resistance to the enfuvirtide binding domain (36-45 residues) was found. Resistance mutations were detected at follow-up visits and were comparable to those described among B-subtype HIV-1-infected patients; no sequence changes were detected in crucial HR1/HR2 gp41 sites such as the cytotoxic T lymphocyte epitope, cysteine loop, ectodomain, and 5-helix interaction and binding region.     

Myocardial signal intensity decay after gadolinium injection: a fast and effective method for the diagnosis of cardiac amyloidosis

Late Gadolinium Enhancement (LGE) pattern of cardiac amyloidosis (CA) at cardiac magnetic resonance (CMR) examination is absent in approximately 30 % of patients. We tested whether the evaluation of myocardial gadolinium signal intensity (SI) decay (SID) has a higher diagnostic accuracy for CA. CMR was performed in 59 patients with systemic AL amyloidosis (36 males, 69 ± 10 years, mean ± SD), and 20 age/sex-matched healthy controls. LGE images were acquired every minute up to 8 min after gadolinium injection (time of inversion 250 ms). SI regions of interest were plotted in SI/time curves for endocardial (Endo) and epicardial layer of interventricular septum, cavity, and skeletal muscle as reference. SID (a negative exponential function described by the parameter T_SID) was expressed as number of heart beats (HB) from each ROI. The typical LGE pattern for CA was detected in 42 patients (Ty-LGE), while 17 showed either absent LGE or an atypical pattern (ATy-LGE). A definite CA diagnosis was confirmed in all Ty-LGE patients and in 10/17 ATy-LGE patients. At ROC analysis Endo-T_SID was the most accurate parameter to distinguish Ty-LGE and ATy-LGE patients from controls. A 269 HB threshold (mean + 2 SD Endo-T_SID measured in controls) identified 51/52 patients with definite CA diagnosis, with 98 % sensitivity, 93 % specificity, and 96 % diagnostic accuracy. A direct relation was found between the extracellular volume and Endo-T_SID in CA patients (r 0.72, 95 % CI 0.37–089, p < 0.001). the analysis of myocardial SID after gadolinium injection improves the accuracy of CMR for CA diagnosis.     

Cardiovascular magnetic resonance for the diagnosis and management of heart failure with preserved ejection fraction

Heart Failure Reviews - Heart failure with preserved ejection fraction (HFpEF) is characterized by an impaired ventricular filling resulting in the development of dyspnea and other HF symptoms....