In humans, the interaction of the natural killer group 2 member D (NKG2D)-activating receptor on natural killer (NK) and CD8(+) T cells with its major histocompatibility complex class I-related chain (MIC) and UL16 binding protein (ULBP) ligands (NKG2DLs) promotes recognition and elimination of stressed cells, such as tumor or infected cells. Here, we investigated the capacity of HIV-1 to modulate NKG2DL expression and escape NGK2D-mediated immunosurveillance. In CD4(+) T lymphocytes, both cell surface expression and release of MICA, MICB, and ULBP2 were up-regulated >2-fold by HIV-1 infection. In HIV-infected CD4(+) T lymphocytes or Jurkat T-cell lines, increased shedding of soluble NKG2DLs (sNKG2DLs) was impaired by a matrix metalloproteinase inhibitor (MMPI). Moreover, naive HIV(+) patients displayed increased plasma sMICA and sULBP2 levels and reduced NKG2D expression on NK and CD8(+) T cells compared to patients receiving highly active antiretroviral therapy (HAART) or healthy donors. In individual patients, HAART uptake resulted in the drop of sNKG2DL and recovery of NKG2D expression. Finally, sNKG2DLs in patients' plasma down-regulated NKG2D on NK and CD8(+) T cells and impaired NKG2D-mediated cytotoxicity of NK cells. Thus, NKG2D detuning by sNKG2DLs may promote HIV-1 immune evasion and compromise host resistance to opportunistic infections, but HAART and MMPI have the potential to avoid such immune dysfunction.

Background: We tested whether pre-HAART viraemia affects the achievement and maintenance of virological success in HIV-1-infected patients starting modern firstline therapies. Methods: A total of 1,430 patients starting their first HAART (genotype-tailored) in 2008 (median; IQR: 2006-2009) were grouped according to levels of pre-HAART viraemia (≤30,000, 30,001-100,000, 100,001-300,000, 300,001-500,000 and >500,000 copies/ml). The impact of pre-therapy viraemia on the time to virological success (viraemia ≤50 copies/ml) and on the time to virological rebound (first of two consecutive viraemia values >50 copies/ml after virological success) were evaluated by Kaplan-Meier curves and Cox regression analyses. Results: Median pre-HAART viraemia was 5.1 log 10 copies/ml (IQR 4.5-5.5), and 53% of patients had viraemia >100,000 copies/ml. By week 48, the prevalence of patients reaching virological success was >90% in all pre-HAART viraemia ranges, with the only exception of range >500,000 copies/ml (virological success =83%; P<0.001). Higher pre-HAART viraemia was tightly correlated with longer median time to achieve virological success. Cox multivariable estimates confirmed this result: patients with pre-HAART viraemia >500,000 copies/ml showed the lowest hazard of virological undetectability after adjusting for age, gender, pre-HAART CD4 + T-cell count, transmitted drug resistance, calendar year and third drug administered (adjusted hazard ratio [95% CI]: 0.27 [0.21, 0.35]; P<0.001). Pre-HAART viraemia >500,000 copies/ml was also associated with higher probability of virological rebound compared with patients belonging to lower viraemia strata at weeks 4, 12 and 24 (P=0.050). Conclusions: At the time of modern HAART, and even though an average >90% of virological success, high pre-HAART viraemia remains an independent factor associated with delayed and decreased virological success. Patients starting HAART with >500,000 copies/ml represent a significant population that may deserve special attention.HAART has significantly extended the time to development of AIDS and to death in HIV-infected individuals [1,2]. Its efficacy in suppression of plasma HIV-1 RNA to undetectable levels, and in increasing CD4 + T-cell count, is well documented in several clinical trials [3][4][5][6].Despite years of great progress in treating AIDS, however, in some patients starting their first treatment; the effectiveness of HAART is still not sufficient, with consequent virological failures [7][8][9]. These failures can be caused by several factors, such as drug potency, drug

BackgroundThe aim of our work was to evaluate the potential impact of the European policy of testing for HIV all individuals presenting with an indicator disease, to prevent late diagnosis of HIV. We report on a retrospective analysis among individuals diagnosed with HIV to assess whether a history of certain diseases prior to HIV diagnosis was associated with the chance of presenting late for care, and to estimate the proportion of individuals presenting late who could have been diagnosed earlier if tested when the indicator disease was diagnosed.MethodsWe studied a large cohort of individuals newly diagnosed with HIV infection in 13 counselling and testing sites in the Lazio Region, Italy (01/01/2004-30/04/2009). Considered indicator diseases were: viral hepatitis infection (HBV/HCV), sexually transmitted infections, seborrhoeic dermatitis and tuberculosis. Logistic regression analysis was performed to estimate association of occurrence of at least one indicator disease with late HIV diagnosis.ResultsIn our analysis, the prevalence of late HIV diagnosis was 51.3% (890/1735). Individuals reporting at least one indicator disease before HIV diagnosis (29% of the study population) had a lower risk of late diagnosis (OR = 0.7; 95%CI: 0.5-0.8) compared to those who did not report a previous indicator disease. 52/890 (5.8%) late presenters were probably already infected at the time the indicator disease was diagnosed, a median of 22.6 months before HIV diagnosis.ConclusionsOur data suggest that testing for HIV following diagnosis of an indicator disease significantly decreases the probability of late HIV diagnosis. Moreover, for 5.5% of late HIV presenters, diagnosis could have been anticipated if they had been tested when an HIV indicator disease was diagnosed.However, this strategy for enhancing early HIV diagnosis needs to be complemented by client-centred interventions that aim to increase awareness in people who do not perceive themselves as being at risk for HIV.

Data on COVID-19 boosting vaccination in people living with HIV (PLWH) are scant. We investigated the immunogenicity and safety of the BNT162b2 homologous boosting vaccination. Anti-SARS-CoV-2 spike antibodies (LIAISON® SARS-CoV-2 S1/S2 IgG test, DiaSorin®), CD4+, CD8+ and viraemia were monitored at T0 (pre-vaccination), T1 (4 weeks after the second dose), T2 (pre-booster) and T3 (4 weeks after the booster dose). Humoral responses were evaluated according to sex, age, BMI, nadir and baseline CD4+ counts, as well as type of cART regimen. Forty-two subjects were included: the median age was 53 years (IQR: 48–61); the median time since HIV was 12.4 years (IQR: 6.5–18.3); the median nadir and baseline CD4+ counts were 165 (IQR: 104–291) and 687 cells/mm3 (IQR: 488–929), respectively. The booster dose was administered at a median of 5.5 months after the second dose. Median anti-SARS-CoV-2 IgG concentration had significantly decreased at T2 compared to T1 (107 vs. 377, p < 0.0001). Antibody levels elicited by the booster dose (median: 1580 AU/mL) were significantly higher compared with those of all the other time points (p < 0.0001). None of the investigated variables significantly affected antibody response induced by the booster dose. Local and systemic side-effects were referred by 23.8% and 14.3% of the subjects, respectively. One patient developed sensorineural hearing loss (SNHL) 24 h after boosting. He recovered auditory function upon endothympanic administration of corticosteroids. The BNT162b2 boosting vaccination in PLWH is safe and greatly increased the immune response with respect to the primary vaccination.

BackgroundImmunological non-responders (INRs) lacked CD4 increase despite HIV-viremia suppression on HAART and had an increased risk of disease progression. We assessed immune reconstitution profile upon intensification with maraviroc in INRs.MethodsWe designed a multi-centric, randomized, parallel, open label, phase 4 superiority trial. We enrolled 97 patients on HAART with CD4+<200/µL and/or CD4+ recovery ≤25% and HIV-RNA<50 cp/mL. Patients were randomized 1:1 to HAART+maraviroc or continued HAART. CD4+ and CD8+ CD45+RA/RO, Ki67 expression and plasma IL-7 were quantified at W0, W12 and W48.ResultsBy W48 both groups displayed a CD4 increase without a significant inter-group difference. A statistically significant change in CD8 favored patients in arm HAART+maraviroc versus HAART at W12 (p=.009) and W48 (p=.025). The CD4>200/µL and CD4>200/µL + CD4 gain ≥25% end-points were not satisfied at W12 (p=.24 and p=.619) nor at W48 (p=.076 and p=.236). Patients continuing HAART displayed no major changes in parameters of T-cell homeostasis and activation. Maraviroc-receiving patients experienced a significant rise in circulating IL-7 by W48 (p=.01), and a trend in temporary reduction in activated HLA-DR+CD38+CD4+ by W12 (p=.06) that was not maintained at W48.ConclusionsMaraviroc intensification in INRs did not have a significant advantage in reconstituting CD4 T-cell pool, but did substantially expand CD8. It resulted in a low rate of treatment discontinuations.Trial Registration ClinicalTrials.gov NCT00884858 http://clinicaltrials.gov/show/NCT00884858

A survey of HIV coreceptor usage in cerebrospinal fluid (CSF) samples, peripheral blood mononuclear cells (PBMCs), and plasma samples from naïve seropositive patients was conducted. One hundred patients were enrolled in this study. Of the 100 patients, 36 had a primary or recent infection (P-RI), 31 had an early chronic infection (>350 CD4 cells) (ECI), and 33 had a late chronic infection (LCI). All 3 compartments were sampled in a subset of 33 participants, while the remaining 67 patients provided plasma samples and PBMCs only. Seventy-seven patients harbored the R5 virus in plasma samples and had a significantly higher median and percentage of CD4 ؉ T cells than patients with X4 virus (437 and 281 cells/l, respectively; P ‫؍‬ 0.0086; 20.6% and 18.6%, respectively). The X4 strain was detected more frequently in patients with LCI than in patients with P-RI or ECI (39.3%, 19.4%, and 9.6%, respectively; P ‫؍‬ 0.0063). PBMC and plasma tropism was concordant in 90 patients, and 73 had the R5 strain. Among patients with discordant results, 4 had the R5 virus in their plasma and the X4 virus in PBMCs; 6 showed the opposite profile. Plasma, PBMC, and CSF tropism determinations were concordant in 26/33 patients (21 patients had R5, and 5 had X4). The tropism was discordant in 5/33 patients, with the X4 virus in plasma and R5 in CSF; the HIV tropism in PBMCs was X4 in 3 patients. The remaining 2/33 patients had the R5 virus in plasma and PBMCs and the X4 virus in CSF; one of these patients had a P-RI. The discordant tropism in CSF and blood may have implications for chemokine (C-C motif) receptor 5 (CCR5) antagonist use in patients with limited response to antiretroviral therapy (ART) or in responding patients evaluated for simplification of treatment.

Low levels of plasma viremia (below 50 copies/ml of HIV-1 RNA) can be detected in the majority of HIV+ subjects successfully treated with HAART. Aim of our study was to evaluate the impact of different antiretroviral regimens on this residual viremia and on proviral HIV-1 DNA in HAART-treated subjects with plasma HIV RNA <400 cp/ml and no history of virological failure. To this purpose, a cross-sectional analysis of 319 HIV-positive patients on HAART with plasma HIV RNA <400 cp/ml was performed. Subjects had been on HAART for a median of 3.6 years: the current regimen included two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI) in 104 (32.6%) cases, of which 73 treated with a boosted PI; two NRTIs plus a non-NRTI (NNRTI) were prescribed in 166 (52.2%) cases, and NRTIs-only in 49 cases (15.4%). Patients treated with PI had the lowest nadir CD4 cell count (237+191 cells/microl) compared to patients treated with NNRTI (384+192 cells/microl) or NRTIs-only (387+222 cells/microl). Cell-associated HIV-1 DNA was measured in 231 subjects. Residual viremia was measured in 238 subjects with plasma HIV-1 RNA levels < 50 copies/ml. Multivariate analysis showed that the use of NNRTI was independently associated to low levels of residual viremia and high levels of HIV-1DNA, whereas the use of PI was independently associated to low levels of HIV-1 DNA. The better virological performance of NNRTI in terms of low residual viremia is consistent with specific literature data, whereas the greater impact of PI on the viral reservoirs is noteworthy and needs further investigations.

Please cite this article in press as: Svicher, V., et al., HIV-1 dual/mixed tropic isolates show different genetic and phenotypic characteristics and response to maraviroc in vitro.