In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments on pharmacogenomic (PGx) tools ...for treatment selection in depression.
The literature was reviewed for new clinical trials and meta-analyses, published from 2017 to 2022, of studies using PGx tools for treatment selection in depression. The blinding and control conditions, as well as primary and secondary outcomes and post hoc analyses, were summarized.
Eleven new clinical trials and five meta-analyses were identified; all studies had primary outcome measures related to speed or efficacy of treatment response. Three trials (27%) demonstrated efficacy on the primary outcome measure with statistical significance; the three studies used different PGx tools; one study was open-label and the other two were small single-blind trials. Five trials (45%) did not detect efficacy with statistical significance on either primary or secondary outcome measures. Only one trial (9%) used adverse events as a primary outcome measure. All studies had significant limitations; for example, none adopted a fully blinded study design, only two studies attempted to blind the treating clinician, and none incorporated measures to estimate the effectiveness of the blinds or the influence of lack of blinding on the study results.
The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder. Priority efforts for future studies and the development and testing of effective tools include fully blinded study designs, inclusion of promising genetic variants not currently included in any commercially available tests, and investigation of other uses of pharmacogenomics, such as estimating the likelihood of rare adverse drug effects, rather than increasing the speed or magnitude of drug response.
Freshly isolated PBMC are broadly used as effector cells in functional assays that evaluate antibody-dependent cell mediated cytotoxicity (ADCC) and NK activity; however, they introduce ...natural-individual donor-to-donor variability. Cryopreserved PBMC provide a more consistent source of effectors than fresh cells in cytotoxicity assays. Our objective was to determine the effects of cryopreservation of effector PBMC on cell frequency, and on the magnitude and specificity of ADCC and NK activity. Fresh, frozen/overnight rested and frozen/not rested PBMC were used as effector cells in (51)Cr-release and CD107a degranulation assays. Frozen/overnight rested PBMC had higher ADCC and NK activity in both assays when compared to fresh PBMC; however, when using frozen/not rested PBMC, ADCC and NK activities were significantly lower than fresh PBMC. Background CD107a degranulation in the absence of target cell stimulation was greater in PBMC that were frozen/not rested when compared to fresh PBMC or PBMC that were frozen overnight and rested. The percentages of CD16(+)CD56(dim) NK cells and CD14(+) monocytes were lower in PBMC that were frozen and rested overnight than in fresh PBMC. CD16 expression on CD56(dim) NK cells was similar for all PBMC treatments. PBMC that were frozen and rested overnight were comparable to fresh PBMC effectors. PBMC that were frozen and used immediately when evaluating ADCC or NK activity using either a (51)Cr-release assay or a CD107a degranulation assay had the lowest activity. Clinical studies of antibodies that mediate ADCC would benefit from using effector cells that have been frozen, thawed and rested overnight prior to assay.
The reason co-morbid methamphetamine use and HIV infection lead to more rapid progression to AIDS is unclear. We used a model of methamphetamine self-administration to measure the effect of ...methamphetamine on the systemic immune system to better understand the co-morbidity of methamphetamine and HIV. Catheters were implanted into the jugular veins of male, Sprague Dawley rats so they could self-administer methamphetamine (n=18) or be given saline (control; n=16) for 14 days. One day after the last operant session, blood and spleens were collected. We measured serum levels of pro-inflammatory cytokines, intracellular IFN-γ and TNF-α, and frequencies of CD4+, CD8+, CD200+ and CD11b/c+ lymphocytes in the spleen. Rats that self-administered methamphetamine had a lower frequency of CD4+ T cells, but more of these cells produced IFN-γ. Methamphetamine did not alter the frequency of TNF-α-producing CD4+ T cells. Methamphetamine using rats had a higher frequency of CD8+ T cells, but fewer of them produced TNF-α. CD11b/c and CD200 expression were unchanged. Serum cytokine levels of IFN-γ, TNF-α and IL-6 in methamphetamine rats were unchanged. Methamphetamine lifetime dose inversely correlated with serum TNF-α levels. Our data suggest that methamphetamine abuse may exacerbate HIV disease progression by activating CD4 T cells, making them more susceptible to HIV infection, and contributing to their premature demise. Methamphetamine may also increase susceptibility to HIV infection, explaining why men who have sex with men (MSM) and frequently use methamphetamine are at the highest risk of HIV infection.
Individuals infected with HIV-1 and nearly everyone vaccinated with HIV-1 vaccines will, in time, generate antibodies against viral proteins. These antibodies do not resolve natural infection, and ...vaccine candidates that successfully stimulate the production of high titers of neutralizing antibodies have failed to protect against infection. In spite of this, antibodies continue to be a focus of vaccine research. One reason for the continued interest in antibodies is the failure of a vaccine engineered to generate cell-mediated immunity against HIV. Successful protective immunity against most intracellular pathogens involves several arms of the immune response. A successful vaccine should also stimulate both protective cell-mediated immunity and specific antibody. Efforts should be directed toward making a vaccine that will stimulate the production of 1) more antibody, 2) more broadly cross-reactive neutralizing antibody (broadly neutralizing antibodies), and 3) antibody with a particular functional activity (antibody-dependent cell-mediated cytotoxicity; catalytic antibodies).
Antibodies that mediate human immunodeficiency virus (HIV)-specific antibody-dependent cell-mediated cytotoxicity (ADCC) are present in the cervical fluid of many HIV-positive women; however, the ...role that these antibodies play in host defense against HIV is not known. To understand the contribution of ADCC in cervical secretions as a protective mechanism against HIV, we evaluated ADCC titers in paired serum and cervical-lavage (CVL) samples from >300 HIV-1-positive women who participated in the multicenter Division of AIDS Treatment Research Initiative Study 009. The present study demonstrates that women with CVL ADCC activity had lower genital viral loads than did women with serum ADCC activity only. Women with CVL ADCC activity were likely to have HIV-1 gp120-specific immunoglobulin (Ig) G, but not IgA, in their cervical fluid. This finding suggests that specific IgG in cervical fluid can mediate ADCC activity that inversely correlates with genital viral load.
We compared TLR responsiveness in PBMC from HIV-1-infected and uninfected individuals using the TLR agonists: TLR7 (3M-001), TLR8 (3M-002), and TLR7/8 (3M-011). Activation and maturation of ...plasmacytoid dendritic cells (pDC) were measured by evaluating CD86, CD40, and CD83 expression and myeloid dendritic cell (mDC) activation was measured by evaluating CD40 expression. All agonists tested induced activation and maturation of pDC in PBMC cultures of cells from HIV
+ and HIV
− individuals. The TLR7 agonist induced significantly less pDC maturation in cells from HIV
+ individuals. Quantitative assessment of secreted IFN-α and pro-inflammatory cytokines at the single cell level showed that pDC from HIV
+ individuals stimulated with TLR7 and TLR7/8 induced IFN-α. TLR8 and TLR7/8 agonists induced IL-12 and COX-2 expression in mDC from HIV
+ and HIV
− individuals. Understanding pDC and mDC activation and maturation in HIV-1 infection could lead to more rational development of immunotherapeutic strategies to stimulate the adaptive immune response to HIV-1.
Recent studies suggest that HIV-specific antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies contribute to protective immunity against HIV. An important characteristic of future HIV ...vaccines will, therefore, be the ability to stimulate production of these antibodies in both men and women. Early studies suggest that men may have a better ADCC antibody response against HIV than women. Our objective was to determine whether men and women differ with respect to their ADCC response to HIV-1 gp120. HIV-positive, asymptomatic untreated men and women were matched for race, age, CD4(+) T cell number, HIV-1 viral load, and treatment and HIV-1 gp120 ADCC antibody titers were compared. A standard (51)Cr-release assay was used to determine HIV-1 gp120 ADCC antibody titers in HIV-1-seropositive individuals from the Multicenter AIDS Cohort Study (MACS; n=32) and the Women's Interagency HIV Study (WIHS; n=32). Both sexes had high ADCC titers against HIV-1 gp120: 34.4% (n=11) and 40.6% (n=13) of men and women, respectively, had titers of 10,000; 62.5% (n=20) and 56.3% (n=18) had titers of 100,000. Groups did not differ in percent specific release (% SR), lytic units (LU), correlations of titer to viral load, or titer to CD4(+) T cells in men or women. Both groups also had similar cross-clade ADCC antibody responses (p>0.5 for % SR and LU). Comparable groups of asymptomatic HIV-1-infected men and women had comparable HIV-1 gp120 ADCC antibodies. Both sexes had significant cross-clade reactivity. Differences between men and women may become evident as disease progresses; this should be evaluated at later stages of HIV-1 infection.
Oligodeoxynucleotides (ODN) with unmethylated deoxycytidyl-deoxyguanosine dinucleotides (CpG-ODNs) stimulate Toll-like receptor 9 (TLR9) in plasmacytoid dendritic cells (pDC) and B cells and activate ...innate and adaptive immunity. Three classes of synthetic CpG-ODNs, class A, B and C, activate cells through TLR9; our goal was to evaluate their effect on cells from human immunodeficiency virus (HIV)-1⁺ individuals. We compared the frequencies and the unstimulated activation status of immune effector cells in HIV-1⁺ and HIV-1⁻ individuals. Fewer pDC, myeloid dendritic cells (mDC), B cells, natural killer (NK) cells and invariant natural killer T cells (iNKT) were present in HIV-1⁺ peripheral blood mononuclear cells (PBMC) and their baseline activation status was higher than HIV-1⁻ PBMC. Exposure of HIV-1⁺ PBMC to all classes of CpG-ODNs led to activation and maturation of pDC based on CD86, CD80, and CD83 expression similar to that of cells from HIV-1⁻ individuals. The percentage of CpG-ODN stimulated pDC that express CD40 was dramatically higher when cells were obtained from HIV-1⁺ than from HIV-1⁻ individuals. B-lymphocytes were activated similarly in HIV-1⁺ and HIV-1⁻ individuals. mDC, NK and iNKT cell, which lack TLR9, were indirectly activated. Interferon-α (IFN-α) and interferon inducible protein 10 (IP-10) secretion was induced by class A or C but not class B CpG-ODN, but the concentrations were less than those produced by HIV-1⁻ PBMC. HIV-1 infected individuals have fewer innate effector cells that are chronically activated, but these cells can be further activated by CpG-ODN, which suggests that synthetic CpG-ODNs could be used to enhance the immune system in HIV-1 infected individuals.
Studies were designed to determine whether cervical antibodies in human immunodeficiency virus type 1 (HIV-1)-infected women participate in antibody-dependent cell-mediated cytotoxicity (ADCC). Serum ...and cervical lavage fluid (CVL) ADCC titers were compared with plasma virus load and CD4 cell number in 45 infected and 10 uninfected women from theWomen's Interagency HIV Study. Serum and CVL were incubated with normal peripheral blood lymphocytes and HIV-1 gp120-bearing target cells in a standard 51Cr-release assay. When stringent criteria were used to define ADCC activity, 63% had activity in ⩾1 fluid sample, 56% had serum titers, and 16%had CVL titers. Serum titers did not predict CVL titers. Three women with CVL ADCC had no serum ADCC, which suggests that ADCC antibodies may be produced locally. ADCC antibodies are present in the cervicovaginal fluids, which indicates that this form of innate immunity can contribute to mucosal defense against HIV-1.
PURPOSE OF REVIEWTo review recent progress in the development and evaluation of rapid CD4 cell assays needed to treat HIV-infected individuals in resource-poor countries.
RECENT FINDINGSField tests ...indicate that many simplified flow-based assays provide CD4 cell numbers comparable to the current standard, FACSCount, at a lower cost. Most are intended for use at centralized clinics, but some new assays are portable. The manual assays, Dynal T4 Quant and cyto-spheres, are useful when only a few tests are performed daily. Several new formats include a manual rosetting method that uses a unique anti-CD4 cell monoclonal antibody that does not bind to monocytes. Microchip digital imaging and immunochromatography assays are being developed with the goal of being less expensive, more portable and easier than current methods. Reagents that increase the stability of blood samples and clinical reagents in tropical climates are being field tested.
SUMMARYThe availability of antiretroviral medications increases the need for CD4 cell assays to monitor disease progression and the efficacy of therapy in resource-poor countries. Simplified flow cytometry is needed in centralized clinics, but there is a critical need for even less expensive easier methodology that can be used in smaller laboratories and in rural villages.
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