Activated Phenotype Of Naive B Cells In Hiv
It has recently been described that naive B cells activated in a B-cell receptor âindependent fashion may be the source of hypergammaglobulinemia in chronic viral infections. We analyzed the expression of 2 activation/differentiation markers on naive B cells from HIV-1âinfected and uninfected subjects. In healthy individuals, the expression of CD70 is up-regulated in naive B cells recently stimulated by an antigen while the expression of LAIR-1 is down-regulated throughout the process of terminal differentiation into plasma cells. In the HIV-1âinfected individuals we observed the appearance of a subset of naive B cells with an up-regulated expression of CD70 that is barely detectable in healthy subjects . The percentage of CD70+ naive B cells was positively correlated with the plasma IgG . Similarly, we also found that a significant proportion of the naive B cells from patients down-regulated the expression of LAIR-1 as compared with healthy subjects , suggesting that these cells are activated and more differentiated. However, the percentage of LAIR-1+ or CD70+ naive B cells was not correlated to CD4+ T-cell count or HIV-1 plasma load .
Why Does The Immune System Fail To Fight The Hiv Virus
There are various reasons which can contribute to the failure of the immune system to control HIV infection and prevent AIDS development. By infecting CD4+ T cells, HIV is able to replicate predominantly in activated T cells and paralyse one of the main components of adaptive immune system. HIV can also establish latent infection in CD4+ T cells and remain invisible to CD8+ T cells and therefore replication can occur later in the infection and generate new virions. Antigenic mutation within the T-cell epitopes can affect the binding capacity of MHC molecules to the viral peptides, resulting in the inability of the TCRs to recognise the MHC-peptide complex. Finally, HIV is able to hide from anti-HIV antibodies by expressing non-immunogenic glycans on key antibody epitopes.
Function Of Cd8+ T Cells In Hiv Infection
During chronic infection, once viral set point is established, the other functions of CD8+ T cells may become more important, although lytic potential may still be essential . In patients who control virus well, the T cells are more quiescent than in acute infection. Many studies have shown that T cells in those who control HIV-1 well are polyfunctional, showing not only cytolytic potential but also have the capacity to produce cytokines and chemokines , although it is not clear whether this is cause or effect. Prolonged antigen stimulation in the absence of excessive activation and exhaustion, as occurs in slow progressors, could favor expression of multiple functions. Production of IL-2 may be important in the long term persistence of CD8+ T cells and can be provided by the CD8+ T cell itself or by CD4+ T cells, which survive much better in those whose disease progresses slowly . Similar observations have been made in HIV-2 infection in which elite controllers are relatively common . These findings are entirely consistent with data in CD4+ T-cell-depleted mice that show the importance of IL-2 in the maintenance of long-term CD8+ T-cell memory .
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Review Of The Immune System
a. What is a T cell? A lymphocyte that is produced or processed by the thymus gland and actively participating in the immune response.
b. What varieties of T cell exist? How are they functionally different? Cytotoxic T cell- they attack foreign cells of body cells infected by viruses. Theyre involved with cell-mediated immunity Helper T cell-stimulate the activation and function of both t cells and b cells. Suppressor t cell- they inhibit the activation and function of both t cells and b cells. The interplay between suppressor and helper helps establish and control the sensitivity of the immune response.
c. What are their roles in the human body? Read above.
d. How is each T cell variety differentiated from the others ? Class 1 MHC-CD8, cytotoxic, memory, suppressor Class 2 MHC- CD4, helper
Cell Preparation And Culture
Peripheral blood mononuclear cells from HIV-1âinfected and healthy subjects were purified from 30 mL to 40 mL of EDTA âtreated whole blood by centrifugation over a Ficoll-Hypaque density gradient. Plasma samples were collected and stored at â70Â°C until analysis.
Spontaneous IgG secretion by cultured PBMCs was analyzed in 41 HIV-1âinfected patients and 20 healthy subjects. PBMCs were cultured in complete RPMI 1640 medium at a concentration of 0.5 Ã 106 cells/mL for 7 days when culture supernatants were collected and analyzed by IgG enzyme-linked immunosorbent assay .
In order to evaluate whether polyclonal B-cell activation in HIV-1âinfected subjects was strictly dependent on cell-to-cell contact, we isolated B cells by magnetic sorting from 12 HIV-infected patients. Unfractionated PBMCs were cultured at a cell concentration of 1 Ã 106 cells/mL. The purified B cells were cultured in Transwell plates with polycarbonate membrane with pore size 5.0 Î¼m as follows. B-cellâdepleted PBMCs were layered in the bottom chamber and in the upper chamber purified B cells were added at the same proportion present in unfractionated PBMCs. A similar number of purified B cells present in the total PBMCs were also cultured in parallel. Cells were cultured in RPMI 1640 supplemented with 10% fetal calf serum and antibiotics. Supernatants for IgG secretion measurement were collected after 7 days in culture.
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Effects Of Early Initiation Of Art On B Cells
Few comprehensive studies have looked at B-cell numbers and function in HIV-infected individuals who initiate ART during the acute phase of infection. There are indications that B-cell functions, including memory B-cell responses, are impaired early after HIV infection,,. Suggestions that the early initiation of ART might reverse immune defects remain anecdotal, although early initiation of ART does seem to reverse one defect of chronic HIV infection, the low frequency of IgM+ memory B cells. Whether the restoration of normal numbers of IgM+ memory B cells translates into an improved responsiveness to T-cell-independent immunogens remains to be determined, as does the broader issue regarding the impact of early initiation of ART on the preservation of the immune system.
Expression Of Apoptosis Markers
To determine the frequency of apoptotic cells, we analyzed two major events during apoptosis using flow cytometry: cleavage of caspase 3 and the exposure of phosphatidylserine on the outer leaflet of the cell membrane . Cryopreserved PBMCs from 10 healthy controls and 10 chronically infected patients were analyzed for the frequency of apoptotic cells within the different B cell subsets . PBMCs were stained for 30 min with antibodies against surface markers including CD19 biotin , CD21 PE , CD27 PE-CF594 , IgD PE-Cy7 , and the apoptosis markers cleaved caspase 3 inhibitor FITC-C6-DEVD-FMK . Subsequently, live/dead near-infrared dye and streptavidin BV421 staining was performed for 30 min followed by staining with Annexin V APC according to the manufacturers protocol. Samples were analyzed on either a FACS Aria III or a BD FACS Verse immediately after staining and analyzed with FlowJo version 10. Apoptotic cells were defined as double positive for Annexin V and FITC-C6-DEVD-FMK after dead cell exclusion using live/dead near-infrared dye.
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Future Directions: Toward A Unified Explanation For Hiv Pathogenesis
A unified view of HIV pathogenesis is emerging, but there remain many unknowns, and a better understanding will undoubtedly require an integrated analysis of innate and adaptive immune responses, host genetics, and viral genetics. Although both viral load and CD4+ cell count predict disease progression, we remain convinced that the adaptive immunologic response is also predictive of the subsequent course. Clear signals are there: CD8+ T cells are associated with initial control, depletion of these cells in animal models of AIDS leads to an increase in viremia, virus is evolving to escape detection by CTLs, specific functions mediated by CD8+ T cells have demonstrable antiviral effects in vivo, the effect of HLA far outweighs any other genetic factors, CD8+ and CD4+ T-cell dysfunction is associated with lack of viral control, and immune-induced mutations reduce viral fitness and likely contribute to the antiviral efficacy of the CD8+ T-cell response. But important questions remain, and in particular questions regarding the actual functional profile of CD8+ T cells that might lead to long-term control of HIV, or prevention of disseminated infection. And the extent to which such data will be important to vaccine design remains unclearalthough animal models suggest that CD8+ T cells may be able to prevent progressive systemic dissemination of infection and even reduce the level of virus to barely detectable levels .
Nih Scientists Suspect Process Aims To Curb Immune
- NIH/National Institute of Allergy and Infectious Diseases
- For the first time, scientists have shown that in certain people living with HIV, a type of antibody called immunoglobulin G3 stops the immune system’s B cells from doing their normal job of fighting pathogens. This phenomenon appears to be one way the body tries to reduce the potentially damaging effects of immune-system hyperactivity caused by the presence of HIV, according to the investigators, but in so doing, it also impairs normal immune function.
For the first time, scientists have shown that in certain people living with HIV, a type of antibody called immunoglobulin G3 stops the immune system’s B cells from doing their normal job of fighting pathogens. This phenomenon appears to be one way the body tries to reduce the potentially damaging effects of immune-system hyperactivity caused by the presence of HIV, according to the investigators, but in so doing, it also impairs normal immune function.
The research was led by scientists in the Laboratory of Immunoregulation and the Laboratory of Immunogenetics at the National Institute of Allergy and Infectious Diseases , part of the National Institutes of Health.
The Intersection Of Viral Fitness And Immune Control
Although most of the focus on immune control and lack of control has been on CD8+ T-cell function and differential induction of negative immunoregulatory molecules, an increasing body of data suggests that immune-mediated mutations within CD8+ T-cell epitopes lead to reduced viral fitness. These data include assays in which replication of virus containing a B57-selected mutation is out-competed by wild-type virus , evidence of reduced viral fitness in Gag-PR in persons who control virus spontaneously , and evidence of compensatory mutations leading to restoration of fitness . Importantly, mutations in Env do not lead to reduced fitness, suggesting that structural constraints are likely key to this effect . More recent studies have shed further light on this, by demonstrating that there are multidimensional constraints on HIV evolution because certain combinations of mutations must occur in a coordinated manner to maintain virus viability, and thus constrain immune escape pathways . Persons who spontaneously control HIV without medications preferentially target sites that are most constrained, providing further evidence that the specific sites targeted by the immune system may have a major impact on overall control .
Ctl Responses In Acute Infection
Despite the narrowness of the acute phase CD8+ T-cell response, it is associated with a dramatic decline in initial viremia, suggesting that these early, presumably narrowly directed responses are at least partially effective. Although functional studies of early CTL responses are few , evidence of CD8+ T-cell efficacy is suggested by detailed analysis of viral genomes during these early phases of infection, and by modeling studies. 80% of acute infections are established by a single founder virus, which first begins to diversify at around the time of peak infection . By single genome amplification one can detect viral evolution at sites of CTL pressure as early as peak viremia , clear indication that there is effective pressure being applied because it can lead to a wholesale turnover in the replicating virus population. This has been modeled, suggesting that 15%35% of infected cells can be killed by CTLs of a single specificity per day in vivo during acute infection . This CD8+ T-cell-mediated immune pressure is also apparent in population studies, which have shown clear HLA-associated signature mutations following acute infection , persisting in the chronic phase of infection , and transmission and reversion of CTL escape variants .
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Correlates Of A Strong B
Currently, there is relatively little evidence that HIV-specific B-cell and antibody responses restrict viral replication and/or prevent disease progression in infected individuals, especially given numerous reports that development of bNAbs is associated with high HIV viremia and low or decreasing CD4+ T cell counts . However, there are reports that either dispute these observations or suggest a more complex picture. For example even in the studies reporting that bNAbs are associated with high HIV viremia, there are suggestions that reduced immunologic function may explain why a majority of individuals do not develop bNAbs . We explore these ideas in this last section in hope of providing a view of potential correlates of a strong B-cell and antibody response, as reported in certain studies investigating HIV-infected individuals and as should be sought in an effective antibody-based vaccine. We focus on B-cell and T-cell responses in the peripheral blood and lymphoid tissues, but refer to reviews xx in this series for insight into the role of Fc-mediated effector functions of antibodies in restricting or protecting against HIV infection.
Figure 1 The T Cell Response To Hiv
Adapted from the Immune Response to HIV wallchart, created by Nature Reviews Immunology in partnership with STEMCELL Technologies. Request a copy of the full Immune Response to HIV wallchart for your lab.
HIV-1 Vpu mediates HLA-C downregulation4 Cell Host & Microbe
CD8+ T cells are critical for effective antiviral responses, and viruses such as HIV-1 possess mechanisms to avoid or dampen these cells. Human leukocyte antigens , including HLA-A, HLA-B and HLA-C, present peptide antigens to CD8+ T cells, resulting in the activation of cytotoxic mechanisms to eliminate virus-infected cells. HIV-1 can cause the downregulation of HLA-A and HLA-B using the viral protein Nef. This study by Apps et al. showed that primary HIV-1 clones also downregulate HLA-C using the viral protein Vpu. As a result, HIV-1 escapes detection and elimination by CD8+ T cells to ensure its persistence.
Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction5 Nature Immunology
Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF6 Nature Medicine
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Antitetanus Toxoid Igg Antibodies
According to the Swedish vaccination program, all subjects in the study had received vaccination with TT. Anti-TT antibody levels were higher in the control group as compared with HIV-1âinfected subjects . HIV-1âinfected subjects with low memory B lymphocytes had a median anti-TT antibody level of 0.499 IU/mL that was lower as compared with both healthy controls and HIV-1âinfected individuals with normal memory B cells .
Lymphocyte Counts Before And After Art
Changes in lymphocyte counts over time after initiation of ART. Absolute numbers of CD19+ B cells , CD4+ , and CD8+ T cells in the peripheral blood were measured over time after initiation of ART at day 0. Each line represents the trajectory for 1 individual and was generated using regression from a minimum of 3 time points after initiation of ART. Left panels represent individuals treated early after infection and right panels represent individuals treated during the chronic stage of infection.
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Memory B Cells Are Decreased In Hiv
There is no significant difference between HIV patients and controls in absolute and relative B cell numbers . The percentages and absolute cell count of switched memory and non-switched memory B cells are significantly decreased . We found an increased frequency of circulating naive B cells in percentage , but not in absolute number . The increased percentage mainly represents the decrease in the other two populations . In addition to age-matched individuals, we compared all patients by stratifying them to age-defined groups to study the ontogenetic influence. Total B cell numbers do not show a significant difference at all, whereas percentages of all B cell subsets and absolute numbers of switched memory B cells show significant changes .
B cell differentiation compared among age-matched individuals, HIV-infected patients , and controls . Data expressed as percentage of total B cells , *p = 0.003, **p = 0.015, p< 0.001.
Antibody response to routine tetanus toxoid immunization was measured before initiation of ART . After initiation of ART , five of nine children already had increasing titers of antibodies without booster vaccine . Application of a booster regime provided all nine children with a protective immunity to tetanus.
Functional Analyses Of B
Finally, we considered whether the phenotypic changes in B cells after initiation of ART described in the previous section were associated with alterations in B-cell function. In a previous study, we identified tissue-like memory B cells in the peripheral blood of HIV-infected viremic individuals that were responsible for the majority of the HIV-specific response whereas classic memory B cells were responsible for the majority of responses against recall antigens as represented by influenza virus vaccine. However, as shown in , distinctions between these 2 subpopulations of B cells become increasingly difficult to evaluate over time after initiation of ART because tissue-like memory B cells decrease significantly in the peripheral blood after initiation of ART and are also more difficult to assess in early HIV-infected individuals given their lower frequency compared with chronically HIV-infected individuals. Given these limitations and the fact that resting memory B cells constitute the predominant antigen-experienced subpopulation within the peripheral blood after the initiation of ART , we restricted our functional analyses of responsiveness to specific antigens to CD27+ B cells.
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