HIV-1 insertions targeting BACH2 or MLK2 are enriched and persist for decades in hematopoietic cells from patients under combination antiretroviral therapy. However, it is unclear how these ...insertions provide such selective advantage to infected cell clones. Here, we show that in 30/87 (34%) patients under combination antiretroviral therapy, BACH2, and STAT5B are activated by insertions triggering the formation of mRNAs that contain viral sequences fused by splicing to their first protein-coding exon. These chimeric mRNAs, predicted to express full-length proteins, are enriched in T regulatory and T central memory cells, but not in other T lymphocyte subsets or monocytes. Overexpression of BACH2 or STAT5B in primary T regulatory cells increases their proliferation and survival without compromising their function. Hence, we provide evidence that HIV-1-mediated insertional activation of BACH2 and STAT5B favor the persistence of a viral reservoir in T regulatory cells in patients under combination antiretroviral therapy.HIV insertions in hematopoietic cells are enriched in BACH2 or MLK2 genes, but the selective advantages conferred are unknown. Here, the authors show that BACH2 and additionally STAT5B are activated by viral insertions, generating chimeric mRNAs specifically enriched in T regulatory cells favoring their persistence.
Vacc-4x, a therapeutic HIV vaccine candidate has previously induced a significant reduction in viral load (VL) set-point compared to placebo upon interruption of combination anti-retroviral therapy ...(ART) (2007/1 study). This study, (2012/1), explored the potential to maintain Vacc-4x effect by re-boosting eligible 2007/1 study participants.
Participant inclusion required 2007/1 participants to have completed all Vacc-4x immunizations and interrupted ART for up to 26 weeks. At weeks (wk)0 and 2, participants received intradermal (i.d.) Vacc-4x booster immunizations (1.2mg) on ART with GM-CSF (60μg) i.d. as a local adjuvant. ART was interrupted for up to 16 weeks (wk12-wk28). Participants were then followed on ART until wk36. VL set-point, total proviral DNA (pvDNA) and immunogenicity assessed by IFN-γ ELISPOT, T-cell proliferation and delayed type hypersensitivity (DTH) reactions were compared to participants' values in the 2007/1 study where available.
This open, multicenter, clinical study enrolled 33 participants from 9 clinical trial sites in the US and Europe. In the per-protocol (PP) population, the VL set-point geometric mean (GM) 18162 copies/mL was not significantly changed compared to the 2007/1 study (GM VL 22035 copies/mL), (p = 0.453, n = 18). For participants with available preART VL values, the VL set-point (GM 26279 copies/mL) remained significantly lower than the preART VL set-point (GM 74048 copies/mL, p = 0.021, n = 13). A statistically significant reduction in pvDNA (49%) from baseline to wk4 was observed (p = 0.03, n = 26). DTH responses (wk4) increased significantly from baseline (p = 0.006, n = 30) and compared to the 2007/1 study (p = 0.022, n = 29) whilst the proportion of participants with ELISPOT and T-cell proliferation responses was similar between the two studies.
Vacc-4x booster immunizations safely maintained the mean VL set-point at that established following primary Vacc-4x therapeutic immunization. The reduction in pvDNA during ART supports the potential for Vacc-4x immunization to reduce HIV reservoirs and thereby contribute to combination HIV cure strategies.
A natural monkeypox virus infection may not induce sufficient neutralizing antibody responses in a subset of healthy individuals. The aim of this study was to evaluate monkeypox virus-neutralizing ...antibodies six months after infection and to assess the virological factors predictive of a poor immunological response. Antibodies were assessed using a plaque reduction neutralization test at six months from mpox infection; mpox cutaneous, oropharyngeal, and anal swabs, semen, and plasma samples were tested during infection. Overall, 95 people were included in the study; all developed detectable antibodies. People who were positive for the monkeypox virus for more days had higher levels of antibodies when considering all tested samples (
= 0.029) and all swabs (
= 0.005). Mpox cycle threshold values were not predictive of antibody titers. This study found that the overall days of monkeypox virus detection in the body, irrespective of the viral loads, were directly correlated with monkeypox virus neutralizing antibodies at six months after infection.
(mpxv) started to spread to Europe and North America at the beginning of the current outbreak in May 2022, and the World Health Organization (WHO) declared Human Monkeypox (mpox) as a public health ...emergency of international concern (PHEIC) in July 2022. The aim of this observational analysis is to describe demographical data, symptoms presentation and clinical course till outcome of individuals diagnosed with mpox, between May and October 2022, at our open-access Sexual Health Clinic in IRCCS San Raffaele Hospital in Milan, Italy.
Among people who accessed our Sexual Health Clinic, we considered, as suspected diagnosis of mpox, individuals with consistent symptoms and epidemiological criteria. Following the physical examination, oropharyngeal, anal, genital and cutaneous swabs, plus plasma, urine and seminal fluid were collected as biological materials to detect mpxv DNA. We also performed a screening for sexually transmitted infections (STIs).
Overall, 140 individuals with mpox were included in this study. Median age was 37 (interquartile, IQR 33, 43) years old. Males were 137 (98%) and men who have sex with men (MSM) were 134 (96%). As risk factors, we detected travels abroad in 35 (25%) individuals and close contact with mpox cases in 49 (35%). There were 66 (47%) people living with HIV (PLWH). Most frequent symptoms were fever (59%), lymphadenopathy (57%), cutaneous (77%), genital (42%), anal (34%) and oral (26%) lesions, proctitis (39%), sore throat (22%) and generalized rash (5%). At mpox diagnosis, we also observed
in 18 (13%) cases, syphilis in 14 (10%) and
in 12 (9%). Two (1%) people received a concomitant diagnosis of HIV infection. We attended to 21 (15%) complications, with nine (6%) cases of hospitalization including six (IQR 3,7) median hospital days. Forty-five (32%) patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs), 37 (26%) with antibiotics and eight (6%) with antiviral drugs.
Similarly to other international cohorts, sexual transmission was most frequently present, and concomitant STIs were common. Symptoms were heterogenous, self-resolving and responsive to therapy. Hospitalization was necessary in few patients. There is uncertainty about the future development of mpox and further studies (e.g., potential disease reservoirs, other possible means of transmission, predictors of severe disease) are still needed.
The growing threat of antibiotic-resistant
, which causes gonorrhea, presents a current public health challenge. Over the years, the pathogen has developed resistance to different antibiotics, ...leaving few effective treatment options. High-level resistance to key drugs, including ceftriaxone, has become a concerning reality. This article primarily focuses on the treatment of gonorrhea and the current clinical trials aimed at providing new antibiotic treatment options. We explore ongoing efforts to assess new antibiotics, including zoliflodacin, and gepotidacin. These drugs offer new effective treatment options, but their rapid availability remains uncertain. We delve into two ongoing clinical trials: one evaluating the efficacy and safety of gepotidacin compared to the standard ceftriaxone-azithromycin combination and the other assessing the non-inferiority of zoliflodacin versus the combination therapy of ceftriaxone-azithromycin. These trials represent crucial steps in the search for alternative treatments for uncomplicated gonorrhea. Notably, gonorrhea has been included in the "WHO Priority Pathogens List for Research and Development of New Antibiotics". In conclusion, the urgent need for innovative treatment strategies is underscored by the rising threat of antibiotic resistance in
; collaboration among researchers, industries, and healthcare authorities is therefore essential.
To investigate the durability of the first integrase inhibitor-based regimen in a HIV geriatric multicentric prospective cohort and to explore the reasons of regimen discontinuation.
This is an ...analysis conducted on the Geriatric Patients Living with HIV/AIDS (GEPPO) cohort, an Italian prospective observational multicentre cohort of people living with HIV with 65 years of age or more.
The analysis was performed using R (version 4.0.2). The tests performed were two sided assuming a 5% significance level (Kruskal-Wallis test, Chi-squared test, log-rank test and a Cox Proportional Hazard model). The proportion of participants discontinuing the three regimens was displayed using cumulative curves.
Among 1531 patients enrolled between 2017 and 2019 in the GEPPO cohort, we included 822 participants in this analysis. At baseline, median age was 69.8, the immunovirological profile good, multimorbidity was present in 42.3% of participants, while 27.4% were on polypharmacy. Overall, 483, 243 and 96 participants received DTG, RAL and EVG/c respectively as first InSTI. At the end of the follow up 6.4%, 21.1% and 22.9% participants discontinued DTG, RAL and EVG/c respectively. Using a log-rank test, EVG showed a significantly lower durability than DTG (p<0.001) or RAL (p 0.05) or both, DTG and RAL (p<0.001). Among participants who discontinued their regimen we found 0 virological failure and 56.7% simplification/deprescription.
The three integrase inhibitors considered showed a good durability and no virological failures in geriatric patients such as those enrolled in the GEPPO cohort when used in a two or three drug regimen.
Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge.
Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing ...the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients.
In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/μL in raltegravir and 239 cells/μL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled.
Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/μL at week 48.
EUDRACT number: 2011-005973-21.
Human immunodeficiency virus type 1 (HIV) transmission mostly occurs through the genital and intestinal mucosae. Although HIV-1 transmission has been extensively investigated, gaps remain in ...understanding the initial steps of HIV entry through the colonic mucosa. We previously showed that HIV can selectively trigger mononuclear phagocytes (MNP) to migrate within colonic epithelial cells to sample virions. Mucosal exposure to human seminal plasma (HSP), rich in pro- and anti-inflammatory cytokines, chemokines and growth factors, may as well induce alterations of the colonic mucosa and recruit immune cells, hence, affecting pathogen sampling and transmission.
Here, we studied the role of HSP on the paracellular intestinal permeability by analyzing the distribution of two proteins known to play a key role in controlling the intestinal barrier integrity, namely the tight junctions-associated junctional adhesion molecule (JAM-A) and the adherents junction associated protein E-cadherin (E-CAD), by immunofluorescence and confocal microscopy. Also, we evaluated if HSP promotes the recruitment of MNP cells, specifically, the CD11c and CD64 positive MNPs, to the apical side of the human colonic mucosa. At this scope, HSP of HIV-infected and uninfected individuals with known fertility status was tested for cytokines, chemokines and growth factors concentration and used in an
polarized colonic tissue culture system to mimic as closely as possible the physiological process.
HSP showed statistically significant differences in cytokines and chemokines concentrations between the three groups of donors, i.e. HIV infected, or uninfected fertile or randomly identified. Nevertheless, we showed that in the
tissue culture HSP in general, neither affected the morphological structure of the colonic mucosa nor modulated the paracellular intestinal permeability. Interestingly, CD11c+ MNP cells migrated to the apical surface of the colonic epithelium regardless, if incubated with HIV-infected or -uninfected HSPs, while CD64+ MNP cells, did not change their distribution within the colonic mucosa.
In conclusion, even if HSP did not perturb the integrity of the human colonic mucosa, it affected the migration of a specific subset of MNPs that express CD11c towards the apical side of the colonic mucosa, which in turn may be involved in pathogen sampling.
Pre-exposure prophylaxis (PrEP) is effective for HIV prevention and is mostly used by men who have sex with men (MSM). The aim of this study was to describe the characteristics of a cohort of PrEP ...users at first PrEP counselling visits (baseline, BL).
Cross-sectional study of a cohort of MSM receiving PrEP (Centro San Luigi, CSL-PrEP Cohort).
Secondary-level sexually transmitted infections (STI) centre in Milan, Italy, from May 2017 to May 2022.
Overall, 624 MSM PrEP users were included; most users were Caucasian (97%), attended university (64%), with a median BL age of 34.5 years.
Overall, 45% choose the daily-based PrEP regimen, 55% the event-based one. An increasing trend in PrEP counselling visits was observed (p=0.024). The majority had between 10 and 19 partners in the 3 months before BL and 41% were chemsex users. All had a HIV Incidence Risk Index for MSM (HIRI-MSM)>10, 54% between 20 and 29. Overall, 50% had ≥1 previous STI and 22% ≥1 BL STI. BL chlamydia (10%) was often more frequent than in the past (7%). The number of sexual partners was associated with BL chlamydia (p<0.001), gonorrhoea (p=0.002) and syphilis (p=<0.001), HIRI-MSM with chlamydia (p=0.001) and gonorrhoea (p=0.008), chemsex use with chlamydia (p=0.003) and gonorrhoea (p=0.030).
We observed an unbalanced access to PrEP in respect to all key populations which might benefit from PrEP, with a similar choice for event-based or daily-based regimens. High-risk behaviours and STIs were frequently observed. History of chlamydia was very frequently high in asymptomatic MSM at BL, compared with what observed before access to PrEP. High-risk behaviours and HIRI-MSM were associated with most of STIs.
Vaccination prevents 2-3 million deaths worldwide every year. Nevertheless, vaccine-preventable diseases (VPDs) still cause a considerable number of deaths especially in subjects belonging to "risk ...groups." These are represented by older adults, immunocompromised individuals and all subjects with underlying chronic medical conditions (cardiovascular, pulmonary, renal and liver chronic diseases, diabetes, immunodeficiency disorders). They have a weaker immune system and, if infected, are more likely to develop severe complications of their condition or of the preventable-infectious disease. This document summarizes the recommendations for vaccination of the main Global Institutional Organizations and analyses the risks of comorbidities associated with infectious disease and the benefits of vaccination for each specific group. The document provides a clear, practical and authoritative guide to adult vaccination.
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