Search

HIV infection significantly affects the frequencies and functions of immunoregulatory CD3 + CD4 - CD8 - double-negative (DN) T-cells, while the effect of early antiretroviral therapy (ART) initiation on these cells remains understudied. DN T-cell subsets were analyzed prospectively in 10 HIV+ individuals during acute infection and following early ART initiation compared to 20 HIV-uninfected controls. In this study, 21 Rhesus macaques (RMs) were SIV-infected, of which 13 were assessed during acute infection and 8 following ART initiation four days post-infection. DN T-cells and FoxP3 + DN Treg frequencies increased during acute HIV infection, which was not restored by ART. The expression of activation (HLA-DR/CD38), immune checkpoints (PD-1/CTLA-4), and senescence (CD28 - CD57 + ) markers by DN T-cells and DN Tregs increased during acute infection and was not normalized by ART. In SIV-infected RMs, DN T-cells remained unchanged despite infection or ART, whereas DN Treg frequencies increased during acute SIV infection and were not restored by ART. Finally, frequencies of CD39 + DN Tregs increased during acute HIV and SIV infections and remained elevated despite ART. Altogether, acute HIV/SIV infections significantly changed DN T-cell and DN Treg frequencies and altered their immune phenotype, while these changes were not fully normalized by early ART, suggesting persistent HIV/SIV-induced immune dysregulation despite early ART initiation.

People living with HIV (PLWH) can exhibit impaired immune responses to vaccines. Accumulating evidence indicates that PLWH, particularly those receiving antiretroviral therapy, mount strong antibody responses to COVID-19 vaccines, but fewer studies have examined cellular immune responses to the vaccinations. Here, we used an activation-induced marker (AIM) assay to quantify SARS-CoV-2 spike-specific CD4+ and CD8+ T cells generated by two and three doses of COVID-19 vaccines in 50 PLWH receiving antiretroviral therapy, compared to 87 control participants without HIV. In a subset of PLWH, T-cell responses were also assessed after post-vaccine breakthrough infections and/or receipt of a fourth vaccine dose. All participants remained SARS-CoV-2 infection-naive until at least one month after their third vaccine dose. SARS-CoV-2 infection was determined by seroconversion to a Nucleocapsid (N) antigen, which occurred in 21 PLWH and 38 control participants after the third vaccine dose. Multivariable regression analyses were used to investigate the relationships between sociodemographic, health- and vaccine-related variables, vaccine-induced T-cell responses, and breakthrough infection risk. We observed that a third vaccine dose boosted spike-specific CD4+ and CD8+ T-cell frequencies significantly above those measured after the second dose (all p < 0.0001). Median T-cell frequencies did not differ between PLWH and controls after the second dose ( p > 0.1), but CD8+ T-cell responses were modestly lower in PLWH after the third dose ( p = 0.02), an observation that remained significant after adjusting for sociodemographic, health- and vaccine-related variables ( p = 0.045). In PLWH who experienced a breakthrough infection, median T-cell frequencies increased even higher than those observed after three vaccine doses ( p < 0.03), and CD8+ T-cell responses in this group remained higher even after a fourth vaccine dose ( p = 0.03). In multivariable analyses, the only factor associated with an increased breakthrough infection risk was younger age, which is consistent with the rapid increase in SARS-CoV-2 seropositivity that was seen among younger adults in Canada after the initial appearance of the Omicron variant. These results indicate that PLWH receiving antiretroviral therapy mount strong T-cell responses to COVID-19 vaccines that can be enhanced by booster doses or breakthrough infection.

People living with HIV (PLWH) may be at risk for poor immunogenicity to certain vaccines, including the ability to develop immunological memory. Here, we assessed T-cell immunogenicity following three SARS-CoV-2 vaccine doses in PLWH versus uninfected controls. Blood was collected from 38 PLWH on antiretroviral therapy and 24 age-matched HIV-negative controls, pre-vaccination and after 1st/2nd/3rd dose of SARS-CoV-2 vaccines, without prior SARS-CoV-2 infection. Flow cytometry was used to assess ex vivo T-cell immunophenotypes and intracellular Tumor necrosis factor (TNF)-α/interferon(IFN)-γ/interleukin(IL)-2 following SARS-CoV-2-Spike-peptide stimulation. Comparisons were made using Wilcoxon signed-rank test for paired variables and Mann-Whitney for unpaired. In PLWH, Spike-specific CD4 T-cell frequencies plateaued post-2nd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose. PLWH had higher frequencies of TNFα+CD4 T-cells and lower frequencies of IFNγ+CD8 T-cells than seronegative participants post-3rd dose. Regardless of HIV status, an increase in naive, regulatory, and PD1+ T-cell frequencies was observed post-3rd dose. In summary, two doses of SARS-CoV-2 vaccine induced a robust T-cell immune response in PLWH, which was maintained after the 3rd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose.

Pulmonary dysbiosis may predispose people living with HIV (PLWH) to chronic lung disease. Herein, we assessed whether intrapulmonary HIV reservoir size and immune disruption are associated with reduced bacterial lung diversity in PLWH. Bacterial DNA was extracted and PCR-amplified from cell-free bronchoalveolar lavage (BAL) fluid from 28 PLWH and 9 HIV-negative controls. Amplicon sequence variant (ASV) relative abundances and taxonomic identities were analyzed using joint species distribution modeling. HIV-DNA was quantified from blood and pulmonary CD4+ T-cells using ultra-sensitive qPCR. Immunophenotyping of BAL T-cells was performed using flow cytometry. Lung microbiome diversity was lower in smokers than non-smokers and microbiome composition was more variable in PLWH than HIV-negative individuals. Frequencies of effector memory BAL CD4+ and CD8+ T-cells positively correlated with abundance of several bacterial families while frequencies of BAL activated CD4+ T-cells negatively correlated with abundance of most lung bacterial families. Higher HIV-DNA levels in blood, but not in BAL, as well as frequencies of senescent CD4+ T-cells were associated with reduced bacterial diversity. These findings suggest that HIV infection may weaken the relationship between the lung microbiome and smoking status. Viral reservoir and immune activation levels may impact the lung microbiome, predisposing PLWH to pulmonary comorbidities., Competing Interests: The authors declare no conflict of interest.