Biomarkers for progressive multifocal leukoencephalopathy: emerging data for use of JC virus DNA copy number in clinical trials.

Progressive multifocal leukoencephalopathy is a rare but devastating demyelinating disease caused by the JC virus (JCV), for which no therapeutics are approved. To make progress towards addressing this unmet medical need, innovations in clinical trial design are needed. Quantitative JCV DNA in CSF has the potential to serve as a valuable biomarker of progressive multifocal leukoencephalopathy disease and treatment response in clinical trials to expedite therapeutic development, as do neuroimaging and other fluid biomarkers such as neurofilament light chain. Specifically, JCV DNA in CSF could be used in clinical trials as an entry criterion, stratification factor, or predictor of clinical outcomes. Insights from the investigation of candidate biomarkers for progressive multifocal leukoencephalopathy might inform approaches to biomarker development for other rare diseases.

Impact of predicted HLA class I immunopeptidome on viral reservoir in a cohort of people living with HIV in Italy.

The class I HLA genotype has been widely recognized as a factor influencing HIV disease progression in treatment-naïve subjects. However, little is known regarding its role in HIV disease course and how it influences the size of the viral reservoir once anti-retroviral therapy (ART) is started. Here, leveraging on cutting-edge bioinformatic tools, we explored the relationship between HLA class I and the HIV reservoir in a cohort of 90 people living with HIV (PLWH) undergoing ART and who achieved viral suppression. Analysis of HLA allele distribution among patients with high and low HIV reservoir allowed us to document a predominant role of HLA-B and -C genes in regulating the size of HIV reservoir. We then focused on the analysis of HIV antigen (Ag) repertoire, by investigating immunogenetic parameters such as the degree of homozygosity, HLA evolutionary distance and Ag load. In particular, we used two different bioinformatic algorithms, NetMHCpan and MixMHCpred, to predict HLA presentation of immunogenic HIV-derived peptides and identified HLA-B*57:01 and HLA-B*58:01 among the highest ranking HLAs in terms of total load, suggesting that their previously reported protective role against HIV disease progression might be linked to a more effective viral recognition and presentation to Cytotoxic T lymphocytes (CTLs). Further, we speculated that some peptide-HLA complexes, including those produced by the interaction between HLA-B*27 and the HIV Gag protein, might be particularly relevant for the efficient regulation of HIV replication and containment of the HIV reservoir. Last, we provide evidence of a possible synergistic effect between the CCR5 ∆32 mutation and Ag load in controlling HIV reservoir.

Association of high-risk sexual behaviours with sexually transmitted infections among men who have sex with men living with HIV.

OBJECTIVES: To explore different sexual behaviours as risk factors for STI among men who have sex with men (MSM) living with HIV. METHODS: This is a cross-sectional study on MSM living with HIV followed at the Infectious Diseases Unit of San Raffaele Hospital, Milan, with at least one diagnosis of gonorrhoea, syphilis, chlamydia or anal human papilloma virus (HPV), between July 2016 and February 2021. We conducted a survey on high-risk sexual behaviours with regard to (1) mean number of partners per month, (2) estimated percentage of condom use and (3) most frequent type of sexual intercourse during 2016-2021. Data on these variables were grouped as follows: (1a) ≤5 vs >5, (1b) >10 vs ≤10, (2a) 0% vs >0%, (2b) ≤50% vs >50%, (2c) 100% vs <100%, (3a) ≥50% vs <50% receptive, (3b) 100% vs <100% insertive, and (3c) 100% vs <100% receptive. A high-risk group was defined as >5 partners, <100% use of condom and ≥50% receptive intercourse. Univariate logistic regressions were applied to assess the association between sexual behaviours and the risk of each STI. RESULTS: Out of 1051 MSM with at least one STI diagnosis, 580 (55%) answered the survey. The risk of chlamydia was lower among individuals with ≤5 partners (≤5 partners vs >5 partners: OR=0.43, 95% CI 0.28 to 0.66, p=0.001) and among those using condoms more frequently (≤50% use of condom vs >50% use of condom: OR=1.55, 95% CI 1.06 to 2.27, p=0.025; 100% vs <100%: OR=0.35, 95% CI 0.20 to 0.59, p=0.001). Individuals using condoms more frequently also had lower risk of gonorrhoea (100% use of condom vs <100% use of condom: OR=0.37, 95% CI 0.17 to 0.79, p=0.011). The risks of chlamydia (OR=3.07, 95% CI 1.92 to 4.90, p<0.001) and gonorrhoea (OR=2.05, 95% CI 1.12 to 3.75, p=0.020) were higher among individuals belonging to the high-risk group. CONCLUSIONS: Chlamydia and gonorrhoea are more likely associated with high-risk sexual behaviours than syphilis and anal HPV among MSM living with HIV.

Outcome of Progressive Multifocal Leukoencephalopathy Treated by Interleukin-7.

OBJECTIVE: Restoring anti-JC virus (JCV) immunity is the only treatment of progressive multifocal leukoencephalopathy (PML). Interleukin-7 is a cytokine that increases number and function of T cells. We analyzed a population of PML patients who received recombinant human IL-7 (rhIL-7) to estimate survival and its determinants. METHODS: After exclusion of patients with missing data or receiving other immunotherapies, findings from 64 patients with proven PML who received rhIL-7 between 2007 and 2020 were retrospectively analyzed. Logistic regression was used to analyze variables associated with one-year survival. RESULTS: Underlying conditions were HIV/AIDS (n = 27, 42%), hematological malignancies (n = 16, 25%), primary immunodeficiencies (n = 13, 20%), solid organ transplantation (n = 4, 6%) and chronic inflammatory diseases (n = 4, 6%). One-year survival was 54.7% and did not differ by underlying condition. Survival was not associated with baseline characteristics, but with a >50% increase in blood lymphocytes (OR 4.1, 95%CI 1.2-14.9) and CD4+ T cells (OR 5.9, 95%CI 1.7-23.3), and a > 1 log copies/mL decrease in cerebrospinal fluid JCV DNA (OR 7.6, 95%CI 1.6-56.1) during the first month after rhIL-7 initiation. Side effects were mainly local and flu-like symptoms (n = 8, 12.5%) and PML-immune reconstitution inflammatory syndrome (IRIS) (n = 5, 8%). INTERPRETATION: In this non-controlled retrospective study, survival did not differ from that expected in HIV/AIDS patients, but might have been improved in those with hematological malignancies, primary immunodeficiencies and transplant recipients. RhIL-7 might have contributed to the increase in blood lymphocytes and decrease in CSF JCV replication that were associated with better survival. ANN NEUROL 2022;91:496-505.

Acquisition of human immunodeficiency virus infection in a patient with multiple sclerosis: could these conditions positively influence each other's course?

Patients with human immunodeficiency virus (HIV) infection have a decreased risk of developing multiple sclerosis (MS) and MS patients very rarely contract HIV infection. We report on a 35-year-old woman with relapsing-remitting MS, who acquired HIV infection 8 years after MS onset. During 7 years of follow-up without combined antiretroviral therapy (cART), CD4+ counts decreased and HIV viremia increased progressively, but slightly. These trends reverted after starting cART, with optimal viro-immunological control. While the patient had many MS relapses before acquiring HIV infection, she had then only one relapse, shortly after HIV infection, despite irregular or no MS therapy. This case contributes to the discussion about MS and HIV potential interactions and describes for the first time the effects of the MS-targeting drug natalizumab in an HIV-positive patient.