Effect of analytical treatment interruption and reinitiation of antiretroviral therapy on HIV reservoirs and immunologic parameters in infected individuals

Therapeutic strategies aimed at achieving antiretroviral therapy (ART)-free HIV remission in infected individuals are under active investigation. Considering the vast majority of HIV-infected individuals experience plasma viral rebound upon cessation of therapy, clinical trials evaluating the efficacy of curative strategies would likely require inclusion of ART interruption. However, it is unclear what impact short-term analytical treatment interruption (ATI) and subsequent reinitiation of ART have on immunologic and virologic parameters of HIV-infected individuals. Here, we show a significant increase of HIV burden in the CD4+ T cells of infected individuals during ATI that was correlated with the level of plasma viral rebound. However, the size of the HIV reservoirs as well as immune parameters, including markers of exhaustion and activation, returned to pre-ATI levels 6–12 months after the study participants resumed ART. Of note, the proportions of near full-length, genome-intact and structurally defective HIV proviral DNA sequences were similar prior to ATI and following reinitiation of ART. In addition, there was no evidence of emergence of antiretroviral drug resistance mutations within intact HIV proviral DNA sequences following reinitiation of ART. These data demonstrate that short-term ATI does not necessarily lead to expansion of the persistent HIV reservoir nor irreparable damages to the immune system in the peripheral blood, warranting the inclusion of ATI in future clinical trials evaluating curative strategies

Cold-Stored Whole Blood: A Better Method of Trauma Resuscitation?

INTRODUCTION: Cold-stored whole blood (CWB) provides a balance of red blood cells, plasma, and platelets in less anticoagulant volume than standard blood component therapy (BCT). We hypothesize that patients receiving CWB along with BCT have improved survival compared to patients receiving only BCT. METHODS: We performed a dual-center case-match study of trauma patients who received CWB and BCT at two urban, Level-I Trauma Centers. Criteria to receive CWB included male age ≥16, female age \u3e50, SBPmmHg, and identifiable source of hemorrhage. We performed a 2:1 propensity match against any trauma patient who received ≥1u of packed red cells (PRBCs) during their initial trauma bay resuscitation. Endpoints included trauma bay mortality, 30-day mortality, laboratory values at 4 and 24 hours, and overall blood product utilization. Comparisons were made with Wilcoxon-ranked sum and Fisher\u27s exact test. P RESULTS: Between both institutions, a total of 107 patients received CWB during the study period with 91 being matched to 182 BCT patients for analysis. Hemodynamic parameters of the patients in both groups at the time of presentation were similar. CWB patients had higher mean hemoglobin (10±2 g/dL vs 11±2 g/dL;p CONCLUSION: CWB offers the benefit of a balanced resuscitation with improved trauma bay survival and higher mean hemoglobin at 24 hours. A larger, prospective study is needed to determine whether it has a longer-term survival benefit for severely injured patients. LEVEL OF EVIDENCE: III STUDY TYPE:: Therapeutic

Tracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine

Summary: Protective immunity following vaccination is sustained by long-lived antibody-secreting cells and resting memory B cells (MBCs). Responses to two-dose SARS-CoV-2 mRNA-1273 vaccination are evaluated longitudinally by multimodal single-cell analysis in three infection-naïve individuals. Integrated surface protein, transcriptomics, and B cell receptor (BCR) repertoire analysis of sorted plasmablasts and spike+ (S-2P+) and S-2P− B cells reveal clonal expansion and accumulating mutations among S-2P+ cells. These cells are enriched in a cluster of immunoglobulin G-expressing MBCs and evolve along a bifurcated trajectory rooted in CXCR3+ MBCs. One branch leads to CD11c+ atypical MBCs while the other develops from CD71+ activated precursors to resting MBCs, the dominant population at month 6. Among 12 evolving S-2P+ clones, several are populated with plasmablasts at early timepoints as well as CD71+ activated and resting MBCs at later timepoints, and display intra- and/or inter-cohort BCR convergence. These relationships suggest a coordinated and predictable evolution of SARS-CoV-2 vaccine-generated MBCs

Profiles of HIV-infected study participants.

<p>Profiles of HIV-infected study participants.</p

Immunologic parameters monitored for the duration of the trial.

<p>(<b>A</b>) CD4⁺ and (<b>B</b>) CD8⁺ T cell counts and percentages prior to treatment interruption (Pre-ATI), during ATI (ATI), and following reinitiation of ART (Post-ATI) and levels of (<b>C</b>) B cells, (<b>D</b>) NK cells, and (<b>E</b>) CD8⁺ T cells expressing CD38 and HLA-DR prior to treatment interruption (Pre-ATI), during ATI (ATI), and following reinitiation of ART (Post-ATI).</p

Impact of ATI and reinitiation of ART on HIV reservoirs.

<p>(<b>A</b>) Longitudinal measurements of plasma viremia (red triangles) and the frequency of CD4⁺ T cells carrying HIV DNA (blue triangles) from study participants are shown. The grey bars indicate duration of ATI. One participant (N04) self-administered antiretroviral drugs for 3 days during the ATI period. (<b>B</b>) Relationship between the level of peak plasma viremia and % increase of the frequency of CD4⁺ T cells carrying HIV DNA during the ATI phase over baseline. The % HIV DNA increase was calculated as follows: ((copy number of HIV DNA/10⁶ CD4⁺ T cells at ATI—copy number of HIV DNA/10⁶ CD4⁺ T cells at baseline)/copy number of HIV DNA/10⁶ CD4⁺ T cells at baseline)*100. (<b>C</b>) Kinetics of HIV DNA burden in CD4⁺ T cells of 10 study participants prior to ATI (Pre-ATI), during ATI (ATI), and after reinitiation of ART (Post-ATI). (<b>D</b>) Dynamics of cell-associated HIV RNA in CD4⁺ T cells of study participants prior to ATI (Pre-ATI) during ATI (ATI) and after reinitiation of ART (Post-ATI). (E) Ratios between the level of cell-associated HIV RNA and DNA. (<b>F</b>) Impact of ATI and reinitiation of ART on the level of CD4⁺ T cells carrying replication-competent HIV in 6 study participants in whom longitudinal leukapheresis was performed. Statistical significance was tested with Wilcoxon’s signed rank test for panels C, D, E, and F. A correlation was determined by the Spearman rank method for panel b. **<i>P</i> < 0.01, ns, not significant.</p