Restored antioxidant capacity parallels the immunologic and virologic improvement in children with perinatal human immunodeficiency virus infection receiving highly active antiretroviral therapy.

CD3+CD4+ T-lymphocyte numbers, viral load, and serum antioxidant capacity were evaluated in 20 children with perinatal human immunodeficiency virus (HIV) infection one month (T = -1) and one day (T = 0) before and one month (T = 1) and two months (T = 2) after a treatment switch to highly active antiretroviral therapy (HAART). Antioxidant capacity micromol/L) was evaluated by measuring the cuprous ion deriving from a known amount of cupric ion. Compared to control values (998 +/- 113 micromol/L), values in HIV-infected children were lower before HAART (T = -1, 848 +/- 211 micromol/L, P = 0.008; T = 0, 732 +/- 131 micromol/L, P < 0.0001), but similar during HAART (T = 1, 914 +/- 121 micromol/L, P = 0.089; T = 2; 957 +/- 155 micromol/L, P = 0.528; T = 1 and T = 2 vs T = 0, P < 0.0001). Immunologic and virologic improvement paralleled the restored antioxidant capacity. HAART may restore antioxidant capacity suppressing HIV, which inhibits antioxidant capacity. A positive feedback may be triggered since restored antioxidant capacity counterbalances the oxidative stress, which enhances lymphocyte apoptosis and HIV replication.     

Dissociation of immunologic and virologic responses to highly active antiretroviral therapy

OBJECTIVE: Immunologic markers, levels of HIV DNA, and infectious HIV were compared in partial responders (PR) to HAART who had high plasma HIV RNA levels but stable or increasing levels of CD4+ peripheral blood mononuclear cells (PBMC), and patients with complete failure (CF) who had very low or decreasing levels of CD4+ PBMC and high plasma HIV RNA levels. DESIGN AND METHODS: CD4 and CD8 levels were monitored by flow cytometry. Beta2-microglobulin (beta2M) and neopterin levels were measured by quantitative enzyme immunoassays. Plasma and PBMC from 11 PR and 13 CF were analyzed for infectious HIV levels in limiting dilution cultures. Polymerase chain reaction (PCR) assays were used to quantify cellular HIV DNA and plasma HIV RNA. RESULTS: In comparison with CF, PR had little or no CD4+ cell loss, a substantial increase in CD8+ cells, significantly fewer positive plasma HIV cultures (p = .03), lower frequencies of infectious HIV in total PBMC (p = .005) and in CD4+ PBMC (p < .001), and lower frequencies of HIV DNA in CD4+ PBMC (p = .007). CONCLUSIONS: Lower levels of infectious HIV and a lower frequency of CD4+ PBMC that contain "productive" HIV DNA in PR as compared with CF may contribute to the stable or increasing CD4+ PBMC levels of the PR. However, HAART may also have effects on lymphocyte homeostasis independent of its antiviral activity.     

Immunity to human immunodeficiency virus (HIV) in children with chronic HIV infection receiving highly active antiretroviral therapy

Our objective was to describe the CD4-mediated human immunodeficiency virus (HIV)-specific cell-mediated immunity (CMI) and its virologic and immunologic correlates in children with chronic HIV infection on highly active antiretroviral therapy (HAART). Twelve HIV-infected children on stable antiretroviral therapy with a median level of CD4+ lymphocytes (CD4%) of 25.5% and a median viral load (VL) of 786 HIV RNA copies/ml were enrolled in this study. Nine of these children were also cytomegalovirus (CMV) seropositive. Blood mononuclear cells, stimulated with HIV and CMV antigens, were used to measure lymphocyte proliferation and to enumerate gamma interferon (IFN-gamma)-producing CD4+ cells. HIV CMI and CMV CMI were detected in similar proportions of patients and correlated with each other, although the HIV responses were less robust. HIV lymphocyte proliferation significantly increased with lower HIV VL and showed a trend to increase with higher CD4% and longer time on HAART. The in vitro IFN-gamma response to HIV or CMV was not affected by CD4%, VL, or HAART. Pediatric patients with established HIV infection on HAART frequently exhibit HIV CMI despite undetectable HIV replication. We concluded that the association between HIV CMI and CMV CMI indicates that the same factors govern responsiveness to either antigen.     

gammadelta T-cell anergy in human immunodeficiency virus-infected persons with opportunistic infections and recovery after highly active antiretroviral therapy

gammadelta T lymphocytes recognize non-peptidic microbial antigens without antigen processing and major histocompatibility complex (MHC) restriction, representing an early defence mechanism against invading pathogens. As a defective response to non-peptidic antigens was observed in human immunodeficiency virus-positive (HIV+) persons, the aims of this study were twofold: to analyse the incidence of gammadelta T-cell anergy in HIV+ positive patients with opportunistic infections/co-infections (HIV-OIC), and to investigate the role of highly active antiretroviral therapy (HAART) on gammadelta T-cell functions. Peripheral gammadelta T-cell distribution and in vitro reactivity to a non-peptidic mycobacterial antigen, isopentenyl pyrophosphate (IPP), were analysed. gammadelta T-cell subset distribution was altered more in HIV-OIC patients than in asymptomatic HIV+ subjects (HIV-ASY). Specifically, the Vdelta2/Vdelta1 ratio was inverted as a consequence of a decrease in Vdelta2 T-cell number. Moreover, IPP-stimulated Vdelta2 T cells from the HIV-OIC group displayed a major defect in interferon-gamma (IFN-gamma) production. Interestingly, HAART induced a sustained recovery of naive CD45RA+ and CD62L+ T cells and restored gammadelta T-cell function. Accordingly, in vitro CD45RA depletion resulted in gammadelta T-cell hyporesponsiveness. Altogether, the incidence of gammadelta T-cell anergy was increased in HIV-OIC patients and dependent on CD45RA helper function. Moreover, HAART was able to restore gammadelta T-cell reactivity, extending the immune recovery to non-peptide microbial antigens.     

Immunovirologic characteristics of human immunodeficiency virus-infected patients consisting mainly of injecting drug users on highly active antiretroviral treatment with prolonged virologic failure

Immunovirologic parameters of 24 heavily antiretroviral drug-pretreated patients with prolonged virologic treatment failure under highly active antiretroviral therapy, and who harbored highly resistant human immunodeficiency virus (HIV) isolates, were studied in this retrospective cross-sectional study. Most of the patients were injecting drug users (71%) and male (88%). All patients were studied for CD4(+) cell count, HIV viral load, resistance mutations, and viral phenotype. The patients showed a high accumulation of resistance-associated mutations, their CD4(+) cell count and viral load directly correlated with their respective values at initiation of therapy, and the presence of K103N was inversely associated with lower viral load. On the other hand, patients with K103N had the same level of CD4(+) cell count compared with patients without this mutation. Among the patients, a majority with a specific viral phenotype was not present. Rather, a dual-tropic virus was found most frequently, suggesting a preferential suppression of X4-specific strains and less cytopathogenicity during antiretroviral therapy and a greater proportion of R5X4 viruses due to an adaptation to that pressure.     

Psychiatric illness and virologic response in patients initiating highly active antiretroviral therapy

BACKGROUND: Mental illness (MI) and substance abuse (SA) are common in HIV-positive patients. MI/SA consistently predict poorer antiretroviral adherence, suggesting that affected patients should be at higher risk of poor virologic and immunologic response to highly active antiretroviral therapy (HAART). PARTICIPANTS: 198 HAART-naive patients initiated HAART at an academic medical center serving a heterogeneous population. METHODS: Participants were assigned a predicted probability from 0 to 1 of having each of the following: (1) any mood, anxiety, or substance use disorder; (2) clinically relevant depression; (3) alcohol abuse/dependence; and (4) drug abuse/dependence. Probabilities were based on responses to questions on an MI/SA screening instrument (Substance Abuse and Mental Illness Symptoms Screener [SAMISS]) and other clinical and sociodemographic characteristics and were derived using predictive logistic regression modeling from a separate validation study of the SAMISS compared with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnoses. Using survival analysis techniques, we assessed baseline predicted probability of psychiatric illness as a predictor of time from HAART initiation to virologic suppression (first viral load [VL] <400 copies/mL), from HAART initiation to overall virologic failure (first VL >or=400 copies/mL after suppression, time set to 0 for patients never achieving suppression), from virologic suppression to virologic rebound (first VL >or=400 copies/mL), and from HAART initiation to immunologic failure (first CD4 cell count lower than baseline). RESULTS: A higher predicted probability of any psychiatric disorder was associated with a slower rate of virologic suppression (adjusted hazard ratio [aHR] = 0.86 per 25% increment, 95% confidence interval [CI]: 0.75 to 0.98) and a faster rate of overall virologic failure (aHR = 1.22, 95% CI: 1.06 to 1.40). Associations with other outcomes were consistent in direction but not statistically significant. Predicted probability of depression was associated with slower virologic suppression (aHR = 0.79, 95% CI: 0.63 to 0.98), and predicted probabilities of alcohol and drug abuse/dependence was associated with faster overall virologic failure (aHR = 1.37, 95% CI: 1.08 to 1.74 and aHR = 1.18, 95% CI: 1.00 to 1.39, respectively). CONCLUSIONS: These results are consistent with an inferior virologic response to first HAART among patients with concurrent mood, anxiety, and substance use disorders, suggesting a clinical benefit to identification and treatment of psychiatric illness among patients initiating antiretroviral therapy.     

High prevalence of multiple human herpesviruses in saliva from human immunodeficiency virus-infected persons in the era of highly active antiretroviral therapy

Human immunodeficiency virus (HIV) infection is associated with an increased risk for human herpesviruses (HHVs) and their related diseases. Methods for limiting the transmission of HHVs require a better understanding of the prevalence and infectiousness of oral HHVs in HIV-infected patients. We performed quantitative PCR to investigate the prevalence, quantity, risk, and correlates of salivary HHVs from 58 HIV-seropositive individuals in a case control study. HHVs were significantly more prevalent in the salivas of HIV-seropositive persons than in those of the controls (odds ratios [ORs], 4.2 to 26.2; P相似文献   

Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV-infected children

Background

High dosage of intravenous immunoglobulin (IVIG) has been observed as a possible activator of HIV gene expression in latently infected resting CD4⁺ T-cells, leading to a substantial decrease in both the reservoir and the residual plasma viremia when added to effective ART. IVIG treatment has also been reported to expand T regulatory cells (Tregs). The aim of this study was to evaluate possible long-term effect of IVIG treatment on residual viremia and T-lymphocyte activation.

Methods

Nine HIV-infected subjects on effective ART included in a previously reported study on IVIG treatment were evaluated 48-104 weeks after therapy. In addition, 14 HIV-infected controls on suppressive ART were included. HIV-1 RNA was analyzed in cell-free plasma by using an ultrasensitive PCR-method with a detection limit of 2 copies/mL. T-lymphocyte activation markers and serum interleukins were measured.

Results

Plasma residual viremia rebounded to pre-treatment levels, 48-104 weeks after the initial decrease that was observed following treatment with high-dosage IVIG. No long-term effect was observed regarding T-lymphocyte activation markers, T-regulatory cells or serum interleukins. In a post-hoc analysis, a correlation between plasma HIV-1-RNA and CD4⁺ T-cell count was found in both IVIG-treated patients and controls.

Conclusions

These results indicate that the decrease in the latent HIV-1 pool observed during IVIG treatment is transient. Although not our primary objective, we found a correlation between HIV-1 RNA and CD4⁺ T-cell count suggesting the possibility that patients with a higher CD4⁺ T-cell count might harbor a larger residual pool of latently infected CD4⁺ T-cells.     

Response to superantigen stimulation in peripheral blood mononuclear cells from children perinatally infected with human immunodeficiency virus and receiving highly active antiretroviral therapy

Our understanding of the pathogenesis of perinatal human immunodeficiency virus (HIV) infection is still evolving. We sought to characterize the response to the bacterial superantigen Staphylococcus enterotoxin B (SEB) of lymphocytes from HIV-infected children receiving treatment with highly active antiretroviral therapy (HAART). Using the flow cytometric methodology, we quantified apoptosis, proliferation, cytokine production, and activation antigen upregulation in CD4 and CD8 T lymphocytes following in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with SEB. The levels of proliferation, CD4 interleukin-2 (IL-2) production, CD8 gamma interferon (IFN-gamma) production, and upregulation of CD69 expression by cells from HIV-infected children were indistinguishable from those by cells from controls. However, stimulation with SEB dramatically decreased the ratio of resting apoptotic cells to cycling apoptotic cells in the controls but not in the patients. In addition, unstimulated spontaneous apoptosis of CD4 T cells remained greater in the patients than in the controls. The percentages of IL-2-positive CD8 T cells and IFN-gamma-positive CD4 T cells following SEB stimulation were significantly lower in the patients than in the controls. Our multiparameter approach was able to demonstrate differences in lymphocyte superantigen responsiveness in HIV-infected children receiving HAART in comparison to that in uninfected controls, notably, an apoptotic versus a proliferative response to stimulation.     

Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy

BACKGROUND: The prognostic significance of a response to highly active antiretroviral therapy (HAART) that is immunologically and virologically discordant is not well understood. METHODS: Four hundred four antiretroviral-naive patients initiating HAART at an urban HIV outpatient clinic in 1995 to 2004 were analyzed. The association of treatment responses at 3 to 9 months after HAART initiation with time to development of an opportunistic infection (OI) or death was determined using Cox proportional hazards modeling. Logistic regression modeling was used to examine the association between discordant responses and patient characteristics. RESULTS: Of 404 patients, 70.5% experienced favorable concordant responses (CD4 cell count [CD4]+/viral load [VL]+: increase in CD4 count of >or=50 cells/microL and achievement of undetectable plasma HIV RNA level), 15.8% an immunologic response only (CD4+/VL(-)), 8.7% a virologic response only (CD4(-)/VL+), and 5.0% a concordant unfavorable response (CD4(-)/VL(-)). Both types of discordant responses (CD4+/VL(-) and CD4(-)/VL+), nonresponse (CD4(-)/VL(-)), and baseline CD4 cell count were significantly associated with earlier development of an OI or death (relative hazard [RH] = 2.81, 95% confidence interval [CI]: 1.31 to 3.97; RH = 4.83, 95% CI: 2.10 to 11.12; and RH = 0.93, 95% CI: 0.88 to 0.99, respectively). CD4+/VL(-) and CD4(-)/VL(-) were associated with nonwhite race in multivariate logistic regression models (adjusted OR = 2.83, 95% CI: 1.46 to 5.47 and adjusted OR = 6.50, 95% CI: 1.65 to 25.69, respectively). CONCLUSION: Discordant immunologic and virologic responses at 3 to 9 months after HAART initiation play important roles in predicting long-term clinical outcomes in treatment-naive patients.     

Anemia in HIV-infected patients receiving highly active antiretroviral therapy.

BACKGROUND: Anemia is common in HIV infection, particularly in advanced disease states. We wished to determine how highly active antiretroviral therapy (HAART) and other factors affected the level of hemoglobin in HIV infection. METHODS: We analyzed data from 905 patients receiving care at Johns Hopkins in Baltimore, Maryland after July 1, 1996. Analyses were done of hemoglobin levels obtained at baseline and during 1 year of follow-up in patients who received and did not receive a HAART regimen. Use of HAART and other demographic and clinical factors were examined. RESULTS: Eleven percent of patients had a hemoglobin count <10 g/dL, 27% had a hemoglobin count 10 to 12 g/dL, and 21% had a hemoglobin count of >14 g/dL at baseline before HAART was started. During 1 year of follow-up, use of HAART was associated with a hemoglobin levels >14 g/dL in 42% of patients, irrespective of use of zidovudine as part of HAART regimen, compared with 31% of patients who did not use HAART. In multivariate analysis, use of HAART was strongly associated with not having anemia during 1 year of follow-up, adjusting for patient gender, race, injection drug use history, baseline CD4 and HIV-1 RNA levels, and anemia treatments. CONCLUSIONS: HAART is an effective treatment of the anemia of HIV infection. Patients who continue to have symptomatic anemia while receiving HAART may need additional intervention.     

Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy

OBJECTIVE: To examine the independent association of discordant virologic and immunologic responses to highly active antiretroviral therapy (HAART) with mortality. METHODS: A population-based study of 1527 treatment-naive individuals initiating HAART used Cox proportional hazards modeling to determine the independent association of treatment response at 3 to 9 months with nonaccidental mortality. Logistic regression was used to examine associations with discordant responses. RESULTS: Viral load (VL)/CD4 discordant responses were seen in 235 (15.4%) of subjects, and VL/CD4 responses were seen in 179 (11.7%) of subjects. In adjusted Cox regression models, discordant responses were found to be independently associated with an increased risk of mortality (VL/CD4: relative hazard [RH] = 1.87, 95% confidence interval [CI]: 1.15 to 3.04; VL/CD4: RH = 2.47, 95% CI: 1.54 to 3.95). VL/CD4 discordance was found to be associated with increasing age, baseline HIV RNA load <100,000 copies/mL, baseline CD4 counts <50 cells/muL, the use of lamivudine (3TC)/zidovudine (ZDV), and poor adherence to therapy. VL/CD4 discordance was associated with younger age; injection drug use; baseline HIV RNA load >100,000 copies/mL; the use of 3TC/ZDV, didanosine (ddI)/3TC, or ddI/stavudine; and poor adherence to therapy. CONCLUSION: Discordant responses are independently associated with an increased risk of mortality and are, in turn, associated with poor adherence to therapy.     

Highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children: analysis of cellular immune responses

The present study analyzes the effect of highly active antiretroviral therapy (HAART) on restoration of cellular immunity in human immunodeficiency virus (HIV)-infected children over a 24-week period following initiation of HAART with ritonavir, nevirapine, and stavudine. The immunological parameters evaluated at four time points (at enrollment and at 4, 12, and 24 weeks of therapy) included cytokine production by monocytes as well as T-cell proliferation in response to mitogen, alloantigen, and recall antigens including HIV type 1 envelope peptides. Circulating levels of interleukin-16 (IL-16) were measured, in addition to CD4+ T-cell counts, plasma HIV RNA levels, and the delayed-type hypersensitivity (DTH) response. At enrollment the children exhibited defects in several immune parameters measured. Therapy increased CD4+ T-cell counts and decreased viral loads significantly. By contrast, the only immunological parameter that was significantly increased was IL-12 p70 production by monocytes; the DTH response to Candida albicans also showed a strong increase in patients becoming positive. In conclusion, these results demonstrate that HAART in HIV-infected children affects the dynamics of HIV replication and the CD4+ T-cell count over 24 weeks, similar to the pattern seen in HIV-infected adults. Furthermore, these data indicate improvement in antigen-presenting cell immunological function in HIV-infected children induced by HAART.     

Immunogenicity of 23-valent pneumococcal polysaccharide vaccine in children with human immunodeficiency virus undergoing highly active antiretroviral therapy.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (23PSV) has been recommended for children infected with human immunodeficiency virus (HIV); however, the efficacy of this vaccination in HIV-infected children undergoing highly active antiretroviral therapy (HAART) has not been studied. OBJECTIVE: To study the immunogenicity and immunologic protection of 23PSV in HIV-infected children after stable HAART. METHODS: Serotype-specific IgG antibodies to 12 pneumococcal capsular polysaccharides were analyzed before and after 23PSV vaccination in 41 HIV-infected children undergoing HAART and compared with 95 HIV-negative control children. Seropositivity, clinical protection, and additional clinical protection from 23PSV were calculated based on serotype specific IgG antibody levels and on the known incidence of these serotypes for causing invasive disease. RESULTS: Children with HIV infection undergoing HAART developed a significant increase in specific IgG levels to Streptococcus pneumoniae after 23PSV vaccination (0.95 vs 1.84 micro/gmL, P < .001). The HIV-infected children with CD4+ cell counts of 25% or higher at the time of vaccination developed a higher additional clinical protection gain from 23PSV vaccination than did children with a lower percentage of CD4+ cells. CONCLUSIONS: HIV-infected children undergoing stable HAART develop a significant immunologic response to 23PSV, especially those with higher T-cell counts and lower viral loads at the time of vaccination.     

Presence of HIV-specific CD4+ T-cell responses in HIV-infected subjects with sustained virologic control after highly active antiretroviral therapy

HIV-specific CD4+ T-helper cell responses in 40 subjects with chronic infection (CI) who had virus suppression after highly active antiretroviral therapy (HAART) were compared with those in 34 subjects treated during primary infection (PI). A CD4+ T-cell proliferative response to HIV p24 protein was present in 50% of these subjects compared with 79% of subjects treated during PI. The existence of a proliferative response in CI subjects was associated with a higher CD4+ T-cell count at initiation of HAART, a longer duration of virus suppression, and a higher CD4+ T-cell count at the time of analysis. These results show that an HIV-specific proliferative response is preferentially observed in treated CI subjects with CD4+ T-cell counts of >200/microL. However, in treated CI subjects with a significant degree of CD4+ T-cell depletion (<200/microL), it may also be observed in 35% provided that the duration of virus suppression is long enough, which may have implications for future therapeutic strategies.