Resistance to saquinavir (Ro 31-8959), an inhibitor of human immunodeficiency virus type 1 proteinase, was studied in peripheral blood mononuclear cell-derived proviral DNA from patients undergoing prolonged treatment. A Leu90→Met exchange was the predominant resistance mutation in vivo; Gly48→Val or doubly mutant virus was rarely observed. After 8–12 months of treatment with saquinavir alone (600 mg, 3 times/day) or in combination with zidovudine (200 mg, 3 times/day), ∼45% of all patients carried provirus with mutant proteinase; the incidence was lower (22%) in patients treated with a combination of saquinavir, zidovudine, and dideoxycytidine. There was a good relationship between genotypic analysis of saquinavir resistance and data from virus assays, confirming that Leu90→Met and Gly48→Val are the essential exchanges in the proteinase that determine loss of sensitivity to this inhibitor. Absence of genotypic resistance correlated with a sustained decrease in plasma viral RNA. There was a positive correlation between a Met90 mutation and some residues at natural polymorphic sites (positions 10, 36, 63, and 71).

Human herpesvirus 8 (HHV-8) has recently been implicated in the development of Kaposi sarcoma, primary effusion B-cell lymphoma, and multicentric Castleman disease of the plasma-cell type.^1-3 Its consistent detection in tissue lesions of Kaposi sarcoma and the results of epidemiological studies^4-7 confirm that HHV-8 is the cause of this neoplasm.

Hepatitis B virus (HBV) reactivation during immunosuppression can lead to severe acute hepatitis, fulminant liver failure, and death. Here, we investigated hepatitis B surface antigen (HBsAg) genetic features underlying this phenomenon by analyzing 93 patients: 29 developing HBV reactivation and 64 consecutive patients with chronic HBV infection (as control). HBsAg genetic diversity was analyzed by population‐based and ultradeep sequencing (UDS). Before HBV reactivation, 51.7% of patients were isolated hepatitis B core antibody (anti‐HBc) positive, 31.0% inactive carriers, 6.9% anti‐HBc/anti‐HBs (hepatitis B surface antibody) positive, 6.9% isolated anti‐HBs positive, and 3.4% had an overt HBV infection. Of HBV‐reactivated patients, 51.7% were treated with rituximab, 34.5% with different chemotherapeutics, and 13.8% with corticosteroids only for inflammatory diseases. In total, 75.9% of HBV‐reactivated patients (vs. 3.1% of control patients; P < 0.001) carried HBsAg mutations localized in immune‐active HBsAg regions. Of the 13 HBsAg mutations found in these patients, 8 of 13 (M103I‐L109I‐T118K‐P120A‐Y134H‐S143L‐D144E‐S171F) reside in a major hydrophilic loop (target of neutralizing antibodies [Abs]); some of them are already known to hamper HBsAg recognition by humoral response. The remaining five (C48G‐V96A‐L175S‐G185E‐V190A) are localized in class I/II–restricted T‐cell epitopes, suggesting a role in HBV escape from T‐cell‐mediated responses. By UDS, these mutations occurred in HBV‐reactivated patients with a median intrapatient prevalence of 73.3% (range, 27.6%‐100%) supporting their fixation in the viral population as a predominant species. In control patients carrying such mutations, their median intrapatient prevalence was 4.6% (range, 2.5%‐11.3%; P < 0.001). Finally, additional N‐linked glycosylation (NLG) sites within the major hydrophilic loop were found in 24.1% of HBV‐reactivated patients (vs. 0% of chronic patients; P < 0.001); 5 of 7 patients carrying these sites remained HBsAg negative despite HBV reactivation. NLG can mask immunogenic epitopes, abrogating HBsAg recognition by Abs. Conclusion: HBV reactivation occurs in a wide variety of clinical settings requiring immune‐suppressive therapy, and correlates with HBsAg mutations endowed with enhanced capability to evade immune response. This highlights the need for careful patient monitoring in all immunosuppressive settings at reactivation risk and of establishing a prompt therapy to prevent HBV‐related clinical complications. (Hepatology 2015;61:823–833)

The recent global COVID-19 public health emergency is caused by SARS-CoV-2 infections and can manifest extremely variable clinical symptoms. Host human genetic variability could influence susceptibility and response to infection. It is known that ACE2 acts as a receptor for this pathogen, but the viral entry into the target cell also depends on other proteins. The aim of this study was to investigate the variability of genes coding for these proteins involved in the SARS-CoV-2 entry into the cells. We analyzed 131 COVID-19 patients by exome sequencing and examined the genetic variants of TMPRSS2, PCSK3, DPP4, and BSG genes. In total we identified seventeen variants. In PCSK3 gene, we observed a missense variant (c.893G>A) statistically more frequent compared to the EUR GnomAD reference population and a missense mutation (c.1906A>G) not found in the GnomAD database. In TMPRSS2 gene, we observed a significant difference in the frequency of c.331G>A, c.23G>T, and c.589G>A variant alleles in COVID-19 patients, compared to the corresponding allelic frequency in GnomAD. Genetic variants in these genes could influence the entry of the SARS-CoV-2. These data also support the hypothesis that host genetic variability may contribute to the variability in infection susceptibility and severity.

To assess gender differences in the long-term clinical, virological and immunological outcomes during highly active antiretroviral therapy (HAART). This longitudinal observational multicentre study followed 2460 HIV-infected patients who had begun a protease inhibitor-based regimen for a median period of 43 months. Outcome measures were virological suppression (< 500 copies/ml), confirmed virological rebound after suppression, and death or new AIDS-defining illness (ADI). At baseline, 690 female patients (28.0%) had significantly lower age, higher prevalence of heterosexual contact and lower prevalence of intravenous drug use as risk factors for HIV infection compared with males. Furthermore, females had a lower number of AIDS-defining illnesses, higher CD4 cell counts and lower viral loads. No gender differences were reported in terms of proportion of patients achieving viral suppression or exhibiting rebound after achieving viral suppression. Female patients experienced reduced clinical progression during follow-up compared with males (P = 0.008) by Kaplan–Meier analysis; however this difference was not significant in an adjusted analysis. In a multivariate model, the interaction between gender and risk factor for HIV or viral load showed that female drug users and female patients with a baseline HIV RNA viral load of 104–105 copies/ml had a favourable clinical outcome compared with males (P = 0.035 and P = 0.015, respectively). No differences were found between genders in terms of virological and immunological outcomes during long-term HAART. Nevertheless, a lower risk of clinical progression was reported among female patients with intermediate baseline viral load than in males.