R. Hoh

Multiomic and Spatial Profiling of Colorectal Tissue Reveals Viral Persistence and Immune Dysregulation in Long COVID

CD4 Count and CD4/CD8 Ratio Impact Antibody Responses to COVID-19 mRNA Booster Vaccination in People with HIV on Suppressive ART.

OBJECTIVE To evaluate the durability of SARS-CoV-2-specific humoral and cellular immune responses after booster vaccination in people living with HIV (PLWH) in a prospective longitudinal cohort study. METHODS We analyzed 46 PLWH with no prior history of SARS-CoV-2 infection who received a booster dose. Anti-receptor-binding domain (RBD) IgG concentrations, neutralization titers, and T cell responses were measured over time. The associations between CD4+ T cell count and CD4/CD8 ratio with antibody dynamics were assessed, adjusting for age, sex, and vaccine type. RESULTS Anti-RBD IgG and neutralization titers declined significantly over time. Participants with CD4+ T cell counts <500 cells/μL exhibited a 3-fold faster decline in anti-RBD IgG compared to those with ≥500 cells/μL. Neutralization capacity declined similarly across both groups, suggesting that CD4+ T cell count primarily influences antibody quantity rather than functional quality. A lower CD4/CD8 ratio was independently associated with reduced baseline IgG concentrations but did not influence the rate of antibody decay. In a subset of 30 participants, a lower CD4/CD8 ratio was also associated with altered follicular helper (Tfh) CD4+ T cell frequencies and faster decline of Spike-specific Tfh over time. CONCLUSIONS CD4+ T cell count influences antibody persistence, while the CD4/CD8 ratio affects initial antibody magnitude and Tfh cell frequencies, highlighting complementary roles in shaping vaccine responses in PLWH.

HIV DNA and transcription before and after ART in natural controllers compared to noncontrollers

ABSTRACT HIV-1 natural controllers can limit plasma HIV RNA levels in the absence of antiretroviral therapy (ART). Although controllers have less HIV DNA, it remains unclear how HIV transcription differs from noncontrollers, and whether ART further reduces HIV DNA or RNA in controllers. To address these questions, we quantified different HIV transcripts and HIV DNA regions/proviruses in longitudinal blood samples collected before ART and up to 3–5 years on suppressive ART from 10 controllers (5 “elite” and 5 viremic) and compared them to ART-suppressed noncontrollers. Compared to noncontrollers, controllers exhibited lower levels of most HIV DNA regions (but not intact proviruses) and lower total levels of initiated and completed HIV RNA, but paradoxically higher levels per provirus of initiated and 5′ elongated HIV transcripts. Controllers also showed a lower ratio of completed/elongated HIV RNA. After ART, controllers showed lower levels of multiply spliced HIV RNA and a lower ratio of multiply spliced/completed HIV RNA. These results suggest that natural controllers limit HIV infection frequency and selectively restrict HIV transcript completion and splicing. ART treatment of controllers led to further increases in CD4 counts and decreases in HIV DNA and some HIV transcripts, supporting the potential for clinical benefits in this population. IMPORTANCE Natural HIV controllers can suppress HIV-1 replication without antiretroviral therapy (ART) and serve as a model for an HIV functional cure, but the mechanisms are unclear. We found that natural control was associated with mechanisms that reduce levels of total HIV DNA and the HIV promoter regions to below the levels seen in ART-treated noncontrollers (NC), resulting in lower total levels of most HIV transcripts. When corrected for HIV DNA levels, natural controllers exhibited higher levels per provirus of short, prematurely terminated HIV transcripts but lower proportions of completed and spliced HIV transcripts. These findings suggest that the mechanisms of natural control do not only limit HIV infection frequency, but specifically limit production or increase clearance of infected cells making completed and spliced HIV transcripts. ART treatment of controllers led to further increases in CD4+ T-cell counts and decreases in HIV DNA and RNA, suggesting that ART should be offered to controllers. Natural HIV controllers can suppress HIV-1 replication without antiretroviral therapy (ART) and serve as a model for an HIV functional cure, but the mechanisms are unclear. We found that natural control was associated with mechanisms that reduce levels of total HIV DNA and the HIV promoter regions to below the levels seen in ART-treated noncontrollers (NC), resulting in lower total levels of most HIV transcripts. When corrected for HIV DNA levels, natural controllers exhibited higher levels per provirus of short, prematurely terminated HIV transcripts but lower proportions of completed and spliced HIV transcripts. These findings suggest that the mechanisms of natural control do not only limit HIV infection frequency, but specifically limit production or increase clearance of infected cells making completed and spliced HIV transcripts. ART treatment of controllers led to further increases in CD4+ T-cell counts and decreases in HIV DNA and RNA, suggesting that ART should be offered to controllers.