Bone marrow plasma cells are a primary source of serum HIV-1-specific antibodies in chronically infected individuals.

Several potent and broadly neutralizing Abs to HIV-1 have been isolated recently from peripheral blood B cells of infected individuals, based on prescreening of Ab activity in the serum. However, little is known regarding the cells that make the Abs that circulate in the blood. Accordingly, we investigated the most likely source, the bone marrow, of chronically HIV-1-infected individuals who were not receiving antiretroviral therapy. Increased frequencies of plasma cells, as well as B cell precursors, namely preB-I and preB-II, and decreased frequencies of mature B cells were observed in bone marrow aspirates of these individuals compared with HIV-negative counterparts. Increased frequencies of bone marrow plasma cells are consistent with known hallmarks of HIV-1 infection, namely hypergammaglobulinemia and increased frequencies of peripheral blood plasmablasts. Levels of HIV-1 envelope (Env)-binding and HIV-1-neutralizing Abs were measured in serum, and corresponding frequencies of Ab-secreting or Env-binding cells were measured in the blood (plasmablasts and memory B cells) and in the bone marrow (plasma cells). A strong correlation was observed between serum HIV-1-specific Abs and Env-specific bone marrow-derived plasma cells, but not circulating plasmablasts or memory B cells. These findings demonstrate that, despite HIV-1-induced phenotypic and functional B cell dysregulation in the peripheral blood and secondary lymphoid tissues, bone marrow plasma cells remain a primary source for circulating HIV-1-specific Abs in HIV-1-infected individuals.

Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir.

Several highly potent and broadly neutralizing monoclonal antibodies against HIV have recently been isolated from B cells of infected individuals. However, the effects of these antibodies on the persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We show that several HIV-specific monoclonal antibodies--in particular, PGT121, VRC01, and VRC03--potently inhibited entry into CD4(+) T cells of HIV isolated from the latent viral reservoir of infected individuals whose plasma viremia was well controlled by ART. In addition, we demonstrate that HIV replication in autologous CD4(+) T cells derived from infected individuals receiving ART was profoundly suppressed by three aforementioned and other HIV-specific monoclonal antibodies. These findings have implications for passive immunotherapy as an approach toward controlling plasma viral rebound in patients whose ART is withdrawn.

Long COVID in Cancer: A Matched Cohort Study of 1-year Mortality and Long COVID Prevalence Among Patients With Cancer Who Survived an Initial Severe SARS-CoV-2 Infection.

OBJECTIVES: The long-term effects of severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) infection in patients with cancer are unknown. We examined 1-year mortality and prevalence of long COVID in patients with and without cancer after initial hospitalization for acute COVID-19 infection. METHODS: We previously studied 585 patients hospitalized from March to May 2020 with acute COVID-19 infection at Weill Cornell Medicine (117 patients with cancer and 468 age, sex, and comorbidity-matched non-cancer controls). Of the 456 patients who were discharged, we followed 359 patients (75 cancer and 284 non-cancer controls) for COVID-related symptoms and death, at 3, 6, and 12 months after initial symptom onset. Pearson χ 2 and Fisher exact tests were used to determine associations between cancer, postdischarge mortality, and long COVID symptoms. Multivariable Cox proportional hazards models adjusting for potential confounders were used to quantify the risk of death between patients with and without cancer. RESULTS: The cancer cohort had higher mortality after hospitalization (23% vs 5%, P < 0.001), a hazard ratio of 4.7 (95% CI: 2.34-9.46) for all-cause mortality, after adjusting for smoking and oxygen requirement. Long COVID symptoms were observed in 33% of patients regardless of cancer status. Constitutional, respiratory, and cardiac complaints were the most prevalent symptoms in the first 6 months, whereas respiratory and neurological complaints (eg, "brain fog" and memory deficits) were most prevalent at 12 months. CONCLUSIONS: Patients with cancer have higher mortality after hospitalization for acute severe acute respiratory syndrome coronavirus 2 infections. The risk of death was highest in the first 3 months after discharge. About one-third of all patients experienced long COVID.

Maturational characteristics of HIV-specific antibodies in viremic individuals.

Despite the rare appearance of potent HIV-neutralizing mAbs in infected individuals requiring prolonged affinity maturation, little is known regarding this process in the majority of viremic individuals. HIV-infected individuals with chronic HIV viremia have elevated numbers of nonconventional tissue-like memory (TLM) B cells that predominate in blood over conventional resting memory (RM) B cells. Accordingly, we investigated affinity maturation in these 2 memory B cell populations. Analysis of IgG-expressing TLM B cells revealed a higher number of cell divisions compared with RM B cells; however, TLM B cells paradoxically displayed significantly lower frequencies of somatic hypermutation (SHM). To assess Ab reactivity in TLM and RM B cells, single-cell cloning was performed on HIV envelope CD4-binding site-sorted (CD4bs-sorted) B cells from 3 individuals with chronic HIV viremia. Several clonal families were present among the 127 cloned recombinant mAbs, with evidence of crosstalk between TLM and RM B cell populations that was largely restricted to non-VH4 families. Despite evidence of common origins, SHM frequencies were significantly decreased in TLM-derived mAbs compared with SHM frequencies in RM-derived mAbs. However, both cell populations had lower frequencies of SHMs than did broadly neutralizing CD4bs-specific mAbs. There was a significant correlation between SHM frequencies and the HIV-neutralizing capacities of the mAbs. Furthermore, HIV neutralization was significantly higher in the RM-derived mAbs compared with that seen in the TLM-derived mAbs, and both SHM frequencies and neutralizing capacity were lowest in TLM-derived mAbs with high polyreactivity. Thus, deficiencies in memory B cells that arise during chronic HIV viremia provide insight into the inadequacy of the Ab response in viremic individuals.