Control of HIV-1 replication following nonsterilizing HIV-1 vaccination could be achieved by vaccine-elicited CD8؉ T-cell-mediated antiviral activity. To date, neither the functional nor the phenotypic profiles of CD8 ؉ T cells capable of this activity are clearly understood; consequently, little is known regarding the ability of vaccine strategies to elicit them. We used multiparameter flow cytometry and viable cell sorts from phenotypically defined CD8؉ T-cell subsets in combination with a highly standardized virus inhibition assay to evaluate CD8 ؉
T-cell-mediated inhibition of viral replication. Here we show that vaccination against HIV-1 Env and Gag-Pol by DNA priming followed by recombinant adenovirus type 5 (rAd5) boosting elicited CD8 ؉ T-cell-mediated antiviral activity against several viruses with either lab-adapted or transmitted virus envelopes. As it did for chronically infected virus controllers, this activity correlated with HIV-1-specific CD107a or macrophage inflammatory protein 1 (MIP-1) expression from HIV-1-specific T cells. Moreover, for vaccinees or virus controllers, purified memory CD8؉ T cells from a wide range of differentiation stages were capable of significantly inhibiting virus replication. Our data define attributes of an antiviral CD8 ؉ T-cell response that may be optimized in the search for an efficacious HIV-1 vaccine.
An intravenous solution of 99% pure globulin (hyperimmune IgG, HIVIG) was obtained from pooled plasma of selected human immunodeficiency virus (HIV-1)-seropositive asymptomatic donors with greater than 400 CD4+/microliters cells per microliter and a high titer of antibody to HIV-1 p24 protein. HIVIG had high titers of antibody to p24, glycoprotein 41 (gp41), and gp120, group-specific neutralizing activity, and binding to the gp120 hypervariable loop region. It inhibited syncytia formation. At low concentration, it enhanced viral production of HIV-1 in infected peripheral blood monocytes but was inhibitory at higher concentration. HIVIG directed group-specific antibody-dependent cellular cytotoxicity against HIV-infected targets. For a period of 6 to 28 months, plasma donors kept stable antibody titers and had a 1.0% decrease in CD4+ cells per month. One gram per kilogram HIVIG injected in two juvenile chimpanzees was well tolerated and did not transmit HIV, as measured by negative cell culture, IgM immune response to HIV proteins, and polymerase chain reaction. The mean half-life of HIV-1 p24 antibody was 15 days. These preliminary data suggest that HIVIG is a safe product suitable for clinical trial in HIV-1-infected individuals.
Chronic lymphocytic leukemia (CLL) is associated with physical dysfunction and low overall fitness that predicts poor survival following commencement of treatment. However, it remains unknown whether higher fitness in CLL patients provides anti-oncogenic effects. We identified ten fit (CLL-FIT) and ten less fit (CLL-UNFIT) treatment-naive CLL patients from 144 CLL patients who completed a set of physical fitness and performance tests. Patient plasma was used to determine its effects on in vitro 5-day growth/viability of three B-cell cell lines (OSU-CLL, Daudi and Farage). Plasma exosomal miRNA profiles, circulating lipids, lipoproteins, inflammation levels, and immune cell phenotypes were also assessed. CLL-FIT was associated with fewer viable OSU-CLL cells at Day 1 (p=0.003), Day 4 (p=0.001) and Day 5 (p=0.009). No differences between groups were observed for Daudi and Farage cells. Of 455 distinct exosomal miRNAs identified, 32 miRNAs were significantly different between groups. Of these, 14 miRNAs had ≤-1 or ≥1 log2 fold differences. CLL-FIT patients had 5 exosomal miRNAs with lower expression and 9 miRNAs with higher expression. CLL-FIT patients had higher HDL cholesterol, lower inflammation, and lower levels of triglyceride components (all p<0.05). CLL-FIT patients had lower frequencies of low-differentiated NKG2+/CD158a/bneg (p=0.015 and p=0.014) and higher frequencies of NKG2Aneg/CD158b+ mature NK-cells (p=0.047). Absolute numbers of lymphocytes including CD19+/CD5+ CLL-cells were similar between groups (p=0.359). Higher physical fitness in CLL patients is associated with altered CLL-like cell line growth in vitro, and with altered circulating and cellular factors indicative of better immune functions and tumor control.
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