Innate, T-, and B-Cell Responses in Acute Human Zika Patients.

Background: There is an urgent need for studies of viral persistence and immunity during human Zika infections to inform planning and conduct of vaccine clinical trials. Methods: In 5 returned US travelers with acute symptomatic Zika infection, clinical features, viral RNA levels, and immune responses were characterized. Results: Two pregnant, flavivirus-experienced patients had viral RNA persist in plasma for >44 and >26 days. Three days after symptom onset, transient increases in proinflammatory monocytes began followed at 5 days by transient decreases in myeloid dendritic cells. Anti-Zika virus immunoglobulin M was detected at day 7 after symptom onset, persisted beyond 103 days, and remained equivocal through day 172. Zika virus-specific plasmablasts and neutralizing antibodies developed quickly; dengue virus-specific plasmablasts and neutralizing antibodies at high titers developed only in flavivirus-experienced patients. Zika virus- and dengue virus-specific memory B cells developed in both flavivirus-naive and -experienced patients. CD4+ T cells were moderately activated and produced antiviral cytokines after stimulation with Zika virus C, prM, E, and NS5 peptides in 4/4 patients. In contrast, CD8+ T cells were massively activated, but virus-specific cells that produced cytokines were present in only 2/4 patients assessed. Conclusions: Acute infections with Zika virus modulated antigen-presenting cell populations early. Flavivirus-experienced patients quickly recalled cross-reactive MBCs to secrete antibodies. Dengue virus-naive patients made little dengue-specific antibody but developed MBCs that cross-reacted against dengue virus. Zika virus-specific functional CD4+ T cells were readily detected, but few CD8+ T cells specific for the tested peptides were found.

Baseline Levels of Influenza-Specific B Cells and T Cell Responses Modulate Human Immune Responses to Swine Variant Influenza A/H3N2 Vaccine.

The cellular immune responses elicited by an investigational vaccine against an emergent variant of influenza (H3N2v) are not fully understood. Twenty-five subjects, enrolled in an investigational influenza A/H3N2v vaccine study, who received two doses of vaccine 21 days apart, were included in a sub-study of cellular immune responses. H3N2v-specific plasmablasts were determined by ELISpot 8 days after each vaccine dose and H3N2v specific CD4+ T cells were quantified by intracellular cytokine and CD154 (CD40 ligand) staining before vaccination, 8 and 21 days after each vaccine dose. Results: 95% (19/20) and 96% (24/25) subjects had pre-existing H3N2v specific memory B, and T cell responses, respectively. Plasmablast responses at Day 8 after the first vaccine administration were detected against contemporary H3N2 strains and correlated with hemagglutination inhibition HAI (IgG: p = 0.018; IgA: p < 0.001) and Neut (IgG: p = 0.038; IgA: p = 0.021) titers and with memory B cell frequency at baseline (IgA: r = 0.76, p < 0.001; IgG: r = 0.74, p = 0.0001). The CD4+ T cells at Days 8 and 21 expanded after prime vaccination and this expansion correlated strongly with early post-vaccination HAI and Neut titers (p ≤ 0.002). In an adult population, the rapid serological response observed after initial H3N2v vaccination correlates with post-vaccination plasmablasts and CD4+ T cell responses.

RXR-induced TNF-alpha suppression is reversed by morphine in activated U937 cells.

Deficiency in vitamin A has been associated with adverse clinical outcomes in drug users with HIV-1 infection. Retinoids have been demonstrated to suppress proinflammatory cytokine production by immune cells in vitro. These effects are induced by ligand-mediated activation of the retinoid receptors--retinoic acid receptor (RAR) and retinoid X receptor (RXR). In these studies, the effects of all-trans-retinoid acid (ATRA, a RAR agonist), 9-cis-retinoic acid (9cis RA; RAR and RXR agonist), LG101305 (RXR agonist), LG100815 (RAR antagonist) and LG101208 (RXR antagonist) on TNF-alpha production by phytohemagglutanin-activated U937 cells and the modulation of these effects by morphine were examined. TNF-alpha production was suppressed in all cultures exposed to retinoid agonist and antagonist agents. For cells exposed to RXR agonists or RAR antagonist, incubation with morphine resulted in the reversal of TNF-alpha suppression and this effect was inhibited by naloxone. These data suggest that interactions between RXR and morphine are involved in the immune effects of retinoids on TNF-alpha production by activated U937 cells. Such information may be important for understanding interactions between drugs of abuse and immune function in individuals with chronic proinflammatory states such as HIV-1 infection.

Probable deceleration of progression of Simian AIDS affected by opiate dependency: studies with a rhesus macaque/SIVsmm9 model.

OBJECTIVES: To determine effects of opiate dependency on development of simian AIDS. DESIGN: Assessments of viral, immune, and clinicopathological status were conducted on rhesus macaques before and after establishment of opiate dependency and Simian Immunodeficiency Virus, sooty mangabey, strain-9 (SIVsmm9) infection. Controls received saline. METHODS: Blood was collected at baseline, before opiate dependencies, and viral infections were established and then after SIVsmm9 infection, longitudinally, through 216 weeks. Plasma viral titers were assessed using the branched chain DNA assay and CD4 and CD8 counts via cytofluorometry. Clinicopathological assessments of AIDS were founded on Centers for Disease Control and Prevention and other selected criteria. RESULTS: AIDS progression rates seemed to be decelerated and survival times increased by opiate dependency. Mean viral titers were unaffected by opiate exposure. Opiate-dependent monkeys that evidenced high initial viral titers survived significantly longer than controls. Several opiate-dependent monkeys maintained high viral titers for atypically extended durations. Several (5/19) opiate-dependent monkeys died or were removed early from the study due to "non-AIDS" causes. CONCLUSIONS: Long-term opiate dependency seemed to decelerate the rate of progression to AIDS in the SIVsmm9 monkey model. This effect was most evident in monkeys with high initial viral titers/set points. "Non-AIDS" morbidities and mortalities were noted as potential confounds of epidemiological assessments of the role of opiates in HIV/AIDS.

Does reduced DNA repair capacity play a role in HIV infection and progression in the lymphocytes of opiate addicts?

Opiate use in vivo and in vitro reduces the ability of human peripheral lymphocytes to repair DNA damage caused by both the physical and chemical mutagens that produce single-strand adducts. This decrease in repair leads to increased genetic damage to the individual cell as measured by cytogenetic damage, including sister chromatid exchanges and formation of micronuclei. The expected consequences of this increase in damage can also be established by increases in host cell mutation rate and rate of apoptosis. The effect of this increase in genetic damage can be expected to have significant consequences for HIV-1 or simian immunodeficiency virus infecting those lymphocytes. For example, DNA damaging agents have long been known to induce lentiviral growth and propagation, and this has been found to be true for HIV-1 following ultraviolet light treatment of lymphocytes. However, to date, no one has fully explored the consequences of increased host mutation rate on HIV growth and maintenance. Recent reports have demonstrated the role of viral mutation in such key physiologic processes as resistance to highly active antiretroviral therapy (HAART). Beyond the effects of random mutations in the viral genome, specific mutations in the HIV-1 transcriptase and protease lead to increased accumulation of mutant viruses and the gradual failure of HAART. It therefore remains to be tested whether changes in host cell mutation rate will also predict changes in susceptibility to drug therapy. This also leads to questions about whether the higher rate of viral mutation in HIV-infected drug addicts might be the basis for higher rates of neuroAIDS in this population. It would be attractive to speculate that the increase in the heterogeneity of the virus in addicts produces mutants with a greater capacity to attack neuronal tissue and a high affinity to replicate there.