IP-10 and MIG are sensitive markers of early virological response to HIV-1 integrase inhibitors.

Background: Interferon-inducible protein-10 (IP-10) and monokine induced by interferon-gamma (MIG) are chemokines recognized as inflammatory biomarkers during HIV-1 infection. We assessed their early and long-term dynamics after initiation of antiretroviral treatment (ART). Methods: Persons with HIV-1 (PWH) aged>18 years starting their first ART in 2015-2021 in a prospective cohort (n=73) were included. IP-10 and MIG plasma levels were quantified using a multiplexed bead-based assay. Results: IP-10 and MIG plasma levels showed a significant and consistent reduction following ART (80% integrase inhibitor [INSTI]-based) initiation, starting at day 20 and maintained throughout the study period (48 months), paralleling the HIV-1 RNA decay and CD4+ count recovery (p<0·001). At baseline, PWH≥ 50 years, CDC stage C and CD4+ count<350cells/mm3 had higher levels of IP-10 (p=0·022, p=0·001 and p=0·002, respectively) and MIG (p<0·001, p=0·024 and p=0·069, respectively). All of them matched their counterparts several months following ART initiation. MIG levels showed a greater decrease at day 10 in those treated with INSTI (p=0·038). Low-level HIV-1 viremia did not impact MIG or IP-10 levels. Conclusion: Plasma IP-10 and MIG showed an early significant decline following ART initiation, with greater early declines in MIG levels in INSTI-based regimens. These findings suggest a strong impact of HIV-1 viremia on IP-10 and MIG levels.

HIV-1-specific T-cell responses and exhaustion profiles in people with HIV after switching to dual therapy vs. maintaining triple therapy based on integrase inhibitors.

BACKGROUND: Dual therapy (DT) has shown comparable results to triple therapy (TT) in efficacy and other immunological aspects. However, there are still some concerns about DT, including several immunological features. Therefore, we evaluated whether HIV-1-specific memory T-cell responses and exhaustion phenotypes are adversely influenced after simplification to DT. METHODS: HIV-1-specific CD4+ and CD8+ T-cell responses were assessed by intracellular cytokine and degranulation marker staining, and polyfunctionality indexes after stimulation with a Gag peptide pool. Exhaustion phenotypes were evaluated by PD-1, TIM-3, and LAG-3 expression in CD4+ and CD8+ T cells. RESULTS: Forty participants in the TRIDUAL trial (ClinicalTrials.gov: NCT03447873) who were randomized to continue integrase inhibitor-based TT (n = 20) or to switch to DT (dolutegravir or darunavir/cobicistat plus lamivudine) (n = 20). After 96 weeks, the magnitude of CD4+ and CD8+ T-cell responses was similar in both treatment arms (p = 0.221 and p = 0.602, respectively). The CD4+ polyfunctionality index decreased in the TT arm (p = 0.013) and remained stable in the DT arm, while the polyfunctionality of CD8+ T cells was unchanged in both arms. There was a significant decrease in the expression of PD-1, TIM-3, and the co-expression of PD-1+TIM-3+LAG-3+, and PD-1 +TIM-3 + in both CD4+ and CD8+ T cells. However, the decrease in the expression of exhaustion markers did not improve HIV-1-specific T-cell responses. CONCLUSIONS: Our results suggest that simplification to DT does not negatively influence the HIV-1-specific T-cell response or the exhaustion phenotype after 96 weeks of follow-up.

Decay kinetics of HIV-1-RNA in seminal plasma with dolutegravir/lamivudine versus dolutegravir plus emtricitabine/tenofovir alafenamide in treatment-naive people living with HIV.

BACKGROUND: This was a substudy of a Phase IV, randomized clinical trial (ClinicalTrials.gov identifier: NCT04295460) aiming to compare the activity of dolutegravir/lamivudine versus dolutegravir plus tenofovir alafenamide/emtricitabine (DTG + TAF/FTC) in the male genital tract. METHODS: Participants were asymptomatic adults without sexually transmitted diseases, treatment-naive people living with HIV (PLWH), with CD4+ T cell counts >200 cells/mm3 and plasma HIV-1-RNA levels >5000 and <500 000 copies/mL, randomized (1:1) to DTG + TAF/FTC or dolutegravir/lamivudine. Blood plasma (BP) and seminal plasma (SP) were collected at baseline and Weeks 4, 8, 12 and 24. HIV-1-RNA was measured in BP and SP using the Cobas 6800 system (Roche Diagnostics) with a lower detection limit of 20 copies/mL. The primary efficacy endpoint was the proportion of subjects with undetectable SP HIV-1-RNA at Week 12 by intention-to-treat analysis. RESULTS: Fifteen participants in the DTG + TAF/FTC and 16 in the dolutegravir/lamivudine arms were analysed, with basal SP viral load of 4.81 (4.30-5.43) and 4.76 (4.09-5.23), P = 0.469, respectively. At Week 12, only one participant in each treatment arm had a detectable SP HIV-1-RNA (DTG + TAF/FTC, 141 copies/mL; dolutegravir/lamivudine, 61 copies/mL). Based on the estimated means, there was no significant difference in the decay of HIV-1-RNA in both BP and SP over time between the two arms of treatment (F = 0.452, P = 0.662, and F = 1.147, P = 0.185, respectively). CONCLUSIONS: After 12 weeks of treatment, there were no differences in the percentage of undetectable SP HIV-1-RNA in naive PLWH who started dolutegravir/lamivudine compared with DTG + TAF/FTC.

Humoral and cellular immunity to SARS-COV-2 after vaccination with mRNA vaccines in PLWH with discordant immune response. Influence of the vaccine administered.

Background: Data on SARS-CoV-2 mRNA vaccine immunogenicity in people living with human immunodeficiency virus (PLWH) and discordant immune response (DIR) are currently limited. Therefore, we compare the immunogenicity of these vaccines in DIR and immunological responders (IR). Methods: A prospective cohort that enrolled 89 participants. Finally, 22 IR and 24 DIR were analyzed before vaccination (T0), one (T1) and six months (T2) after receiving BNT162b2 or mRNA-1273 vaccine. Additionally, 10 IR and 16 DIR were evaluated after a third dose (T3). Anti-S-RBD IgG, neutralizing antibodies (nAb), neutralization activity, and specific memory B cells were quantified. Furthermore, specific CD4+ and CD8+ responses were determined by intracellular cytokine staining and polyfunctionality indexes (Pindex). Results: At T1, all participants developed anti-S-RBD. 100% IR developed nAb compared to 83.3% DIR. Spike-specific B cells were detected in all IR and 21/24 DIR. Memory CD4+ T cells responded in 5/9 IR and 7/9 DIR, mainly based on the expression of IFN-γ and TNF-α, with a higher Pindex in DIR. Memory CD8+ T cells responded in only four participants in each group. At T2, anti-S-RBD and nAb titers were higher in DIR than in IR. In both groups, there was an increase in specific B memory cells, higher in DIR. Six IR and five DIR maintained a specific memory CD4+ response. Memory CD8+ response was preserved in IR but was lost in DIR. In a multivariate linear regression analysis, receiving mRNA-1273 instead of BNT162b2 played a prominent role in the results. Conclusions: Our data suggest that PLWH with DIR can mount an immune response similar to those with higher CD4+, provided they receive the mRNA-1273 vaccine instead of others less immunogenic.