Reduction of viral load and immune complex load on CD4+ lymphocytes as a consequence of highly active antiretroviral treatment (HAART) in HIV-infected hemophilia patients.

BACKGROUND AND OBJECTIVES: Human immunodeficiency virus (HIV)-induced immune complex load on circulating CD4+ blood lymphocytes is associated with dysfunction and depletion of CD4+ lymphocytes and with increased monocyte/macrophage function. It was investigated whether HAART reduces both the viral load in plasma and the number of immune complex-coated CD4+ lymphocytes in the blood, and whether CD4+ counts are associated with viral load and/or immune complex load. MATERIALS AND METHODS: Twelve HIV+ hemophilia patients before and after conversion to HAART (group 1); eight HIV+ hemophilia patients without antiretroviral therapy (group 2). HIV-1 RNA copies in plasma using NASBA/Nuclisens kits; CD4+ lymphocytes coated in-vivo with immune complexes using flowcytometry on whole blood samples; in-vitro responses of immune complex-coated T lymphocytes in cell culture assays. RESULTS: After conversion to HAART there was a significant reduction of viral load, CD4+ gp120+, CD4+ IgM+, and CD4+ IgG+ circulating blood lymphocytes and plasma neopterin, paralleled by a significant increase of CD4+ and CD8+ counts. The percentage of immune complex-coated CD4+ lymphocytes of converted patients was significantly associated with CD4+ counts, in-vitro responses to concanavalin A (Con A), pokeweed mitogen (PWM), phytohaemagglutinin (PHA), anti-CD3 and pooled allogeneic stimulator cells, and with plasma neopterin levels. CONCLUSION: HAART reduces viral load and HIV-induced immune complex load on circulating CD4+ blood lymphocytes. The results of this study can be interpreted to suggest that HAART increases CD4+ lymphocyte counts in part by counteracting HIV-induced autoimmune phenomena.     

Micronutrient levels and HIV disease status in HIV-infected patients on highly active antiretroviral therapy in the Nutrition for Healthy Living cohort

BACKGROUND: Low serum micronutrient levels were common before widespread use of highly active antiretroviral therapy (HAART) and were associated with adverse outcomes. Few data are available on micronutrient levels in subjects taking HAART. OBJECTIVE: To determine the prevalence of low serum retinol, alpha-tocopherol, zinc, and selenium in HIV-infected subjects taking HAART and to assess the association of micronutrient levels with HIV disease status. DESIGN: Cross-sectional. SETTING: Nutrition for Healthy Living (NFHL) study. PARTICIPANTS: HIV-infected subjects on HAART. METHODS: Retinol, alpha-tocopherol, zinc, and selenium were determined in frozen serum samples from 171 men and 117 women. Low serum levels were defined as retinol <30 microg/dL, selenium <85 microg/L, alpha-tocopherol <500 microg/dL, and zinc <670 microg/L. Association of micronutrient quartiles with CD4 cell count, CD4 count <200 cells/mm, HIV viral load (VL), and undetectable VL was assessed using adjusted multivariate regression. RESULTS: Five percent of men and 14% of women had low retinol, 8% of men and 3% of women had low selenium, and 7% of men and no women had low alpha-tocopherol. Forty percent of men and 36% of women had low zinc, however. Subjects in the upper quartiles of zinc had lower log VL levels than those in the lowest quartile (significant for women). Subjects in the upper quartiles of selenium also tended to have lower VL levels compared with those in the lowest quartile. Surprisingly, women in the upper quartiles of retinol had higher log VLs than those in the lowest quartile. There was no significant association of any micronutrient with CD4 cell count or likelihood of CD4 count <200 cells/mm. The level of CD4 cell count influenced the association of retinol with log VL in men, however. In men with CD4 counts >350 cells/mm, those with higher retinol had higher log VLs compared with the lowest quartile, whereas in men with CD4 counts <350, those with higher retinol levels had lower log VLs compared with the lowest quartile. CONCLUSIONS: Low retinol, alpha-tocopherol, and selenium are uncommon in HIV-infected subjects on HAART. Zinc deficiency remains common, however. Decreased retinol levels in women and in men with CD4 counts >350 cells/mm and increased zinc and selenium levels in both genders may be associated with improved virologic control.     

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.     

Anemia prevalence and associated risk factors in a single-center ambulatory HIV clinical cohort

The prevalence of anemia in HIV-infected persons has not been well characterized in the HAART era. In a single-center, retrospective study, anemia prevalence and risk factors, including use of HAART, were assessed in an ambulatory clinical cohort of 758 HIV-infected patients for the calendar year 2000. The relationships between anemia (hemoglobin level less than 12.5 g/dL) and demographic variables, antiretroviral treatment regimens, and disease markers were analyzed. Mean baseline patient characteristics were hemoglobin level, 13.7 +/- 1.9 g/dL; CD4+ cell count, 405 +/- 293/microL; and HIV RNA level, 77,841 +/- 148,394 copies/mL. Overall anemia prevalence was 30.3%. Multivariate logistic regression analysis demonstrated that anemia was associated with a CD4+ cell count below 50/microL, female sex, black race, a viral load above 100,000 copies/mL, zidovudine use, and older age. Severe anemia was less prevalent in this study population than in historical comparators; however, mild to moderate anemia rates remain high.     

Multiple relapses of human cytomegalovirus retinitis during HAART in an AIDS patient with reconstitution of CD4+ T cell count in the absence of HCMV-specific CD4+ T cell response.

BACKGROUND: While in the past human cytomegalovirus (HCMV) represented the major viral opportunistic pathogen in patients with AIDS, incidence of HCMV disease in HIV-infected patients drastically dropped after introduction of highly active antiretroviral therapy (HAART). However, cases of HCMV disease in HIV-infected patients treated with HAART have been reported. OBJECTIVE: A 38-year-old HIV-infected patient developed HCMV retinitis in May 1999 after reaching a nadir of 69 CD4(+) T cells/microl. HAART and anti-HCMV treatments with parenteral ganciclovir (GCV) were started, resulting in HIV viremia suppression, rise in CD4(+) T cell count to >300 cells/microl and recovery from retinitis. Notwithstanding the apparent immune reconstitution, every attempt to discontinue GCV maintenance treatment was followed by a relapse of retinal lesions. Thus, HCMV-specific CD4(+) cellular immune response was investigated. RESULTS: Lymphoproliferation assay and cytokine flow cytometry analysis were performed repeatedly from November 1999 showing absolute lack of HCMV specific CD4(+) T cell response, in the presence of an efficient lymphoprolipherative response against another pathogen (Candida) or a mitogen (Phytohemoagglutinin). CONCLUSION: In some patients, immune reconstitution after HAART may be only partial, since lack of pathogen-specific CD4(+) T cell response may persist even in the case of a significant rise in the absolute CD4(+) T cell count. This case suggests that immunologic assays investigating specific immune response against HCMV in HIV infected patients may be more useful than the CD4(+) T cell count alone in assessing immune function reconstitution after HAART and in deciding interruption of anti-HCMV secondary prophylaxis.     

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.     

Impact of weight on immune cell counts among HIV-infected persons

Prior studies have shown that weight may impact immune cell counts. However, few data exist about the relationship of weight and immune cell counts among HIV-infected patients. We examined documented HIV seroconverters (mean window, 15.7 months) in a prospective U.S. Military HIV Natural History Study (1 January 1986 to 20 January 2010). We estimated the association of the time-updated body mass index (BMI) category with changes in immune cell counts from HIV diagnosis across time (mean follow-up of 5.1 years) using multiply adjusted longitudinal linear mixed-effects models. Of 1,097 HIV seroconverters, 448 (41%) were overweight and 93 (8%) were obese at HIV diagnosis. Immune cell counts at HIV diagnosis did not significantly differ by BMI category. In the longitudinal models for those diagnosed before the advent of the highly active antiretroviral therapy (HAART) era, mean postdiagnosis decreases in the white cell count, total lymphocyte count, CD4 count, CD4 percentage, and CD4/CD8 ratio were less as the BMI category increased (all with P values of <0.05). Among HIV seroconverters diagnosed in the HAART era, obese compared to normal-weight patients had significantly smaller increases in CD4 counts, CD4 percentages, and the CD4/CD8 ratio (all with P values of <0.05). Similar findings were also noted among underweight versus normal-weight patients. In conclusion, although BMI was not associated with immune cell levels at the time of HIV diagnosis, weight appears to affect immune cells counts over the course of infection. In the HAART era, being either underweight or obese was associated with smaller increases in several important immune cell levels, including the CD4/CD8 ratio.     

Normalized CD8+ but not CD4+ lymphocyte IL-2 expression is associated with early treatment with highly active antiretroviral therapy

CD4+ and CD8+ lymphocyte cytokine production in patients with HIV/AIDS and Controls, in response to stimulation with phorbol-12-myristate-13-acetate (PMA) and ionomycin was assessed using single cell flow cytometric methods. Sixty-eight patients with HIV were divided into those on no antiretroviral therapy and those on highly active antiretroviral therapy (HAART). Patients on HAART were analyzed further on the basis of gender, ethnicity, viral load (> or 100 or <100 cells/mm(3)) and CD4 count (>200 or <200 cells/mm(3)). Interferon gamma (IFNgamma) expression by CD4+ and CD8+ lymphocytes was elevated in HIV-infected groups as compared to Controls. This elevation was statistically significant for patients on HAART but not for those not on HAART. The most significant difference was seen when the CD4+ count reached >200 cells/mm(3) (p=0.018 for CD4+ IFNgamma production and p=0.004 for CD8+ IFNgamma production). CD4+ interleukin-2 (IL-2) expression was significantly lower in HIV patients as compared to Controls but did not significantly improve however good the response to HAART. IL-2 expression by CD8+ lymphocytes was also lower in HIV patients as compared to Controls. IL-2 expression by CD8+ lymphocytes significantly improved in all patients on HAART as compared to HIV patients on no HAART. IL-2 expression was not significantly different from that of the Controls when the HIV viral load was less than 50 copies/ml. These results demonstrate improvements in both CD4+ and CD8+ responsiveness with HAART. IFNgamma production was elevated in response to HAART and was maximal only with significant CD4 count recovery. In contrast, normalization of IL-2 production by CD8+ lymphocytes was seen early in patients receiving HAART even when there was only a small increase in CD4+ lymphocyte numbers.     

Regulatory dysfunction of the interleukin-7 receptor in CD4 and CD8 lymphocytes from HIV-infected patients--effects of antiretroviral therapy

Despite an increase in plasma IL-7 levels, the CD4 T-cell pool decrease progressively in HIV-infected patients. Here we report on our tests to check the hypothesis that defects in the IL-7 receptor system might be involved in this phenomenon. The cell surface expression of CD127 was measured ex vivo in CD4 and CD8 T lymphocytes drawn from 3 groups of HIV patients. IL-7 function was also followed in vitro by measuring IL-7-driven T-cell proliferation, the induction of the CD25 activation marker, and overexpression of the antiapoptotic molecule Bcl-2. Untreated viremic patients showed a slight but significant decrease in CD127 expression on the surface of their CD4 lymphocytes. By contrast, CD127 expression was substantially altered on the surface of CD8 T lymphocytes taken from untreated viremic patients. IL-7-induced overexpression of the antiapoptotic molecule Bcl-2 was dramatically altered in viremic patients, whereas IL-7-dependent CD25 induction and T-cell proliferation were reduced. Highly active antiretroviral therapy partially corrected these defects in patients with an undetectable viral load and CD4 counts of more than 400 cells/microL. The effects of HAART were less pronounced in patients with undetectable VL but low CD4 counts (<250 cells/microL). The IL-7 receptor is dysfunctional in the CD4 and CD8 lymphocytes of HIV-infected patients. This may be due to abnormal activation of the immune system in HIV-infected patients and may contribute to the reduced CD4 count and the altered function of the CD8 compartment.     

Excess apoptosis of mononuclear cells contributes to the depressed cytomegalovirus-specific immunity in HIV-infected patients on HAART

HIV-infected patients on highly active antiretroviral therapy (HAART) have persistently decreased cytomegalovirus (CMV)-specific proliferative responses [lymphocyte proliferation assay (LPA)] in spite of increases in CD4+ T cell counts. Here we demonstrate an association between apoptosis of unstimulated peripheral blood mononuclear cells (uPBMC) and decreased CMV-LPA. HAART recipients had more apoptosis of uPBMC than controls when measured by caspases 3, 8, and 9 activities and by annexin V binding. Patients with undetectable HIV replication maintained significantly higher apoptosis of CD4+ and CD14+ cells compared to controls. CMV-LPA decreased with higher apoptosis of uPBMC in patients only. This association was independent of CD4+ cell counts or HIV replication. Furthermore, rescuing PBMC from apoptosis with crmA, but not with TRAIL- or Fas-pathway blocking agents or with other caspase inhibitors, increased CMV-LPA in HAART recipients. This effect was not observed in uninfected controls, further indicating that the down regulatory effect of apoptosis on cell-mediated immunity (CMI) was specifically associated with the HIV-infected status.     

Decreased serum lipocalin-2 levels in human immunodeficiency virus-infected patients: increase during highly active anti-retroviral therapy

Although neutrophil gelatinase-associated lipocalin (NGAL) may play a pivotal role in the innate immune response, there are currently no data on NGAL levels in human immunodeficiency virus (HIV)-infected patients. In this study we aimed to examine the regulation of NGAL in HIV infection. The regulation of NGAL in HIV infection was examined by different experimental approaches, including studies in peripheral blood and mononuclear cells (MNC) from bone marrow aspirates before and during highly active anti-retroviral therapy (HAART). We found that: before initiating HAART, HIV-infected patients (n = 37) had significantly decreased serum NGAL levels compared with healthy controls (n = 26); (ii) during HAART, there was a gradual and significant increase in NGAL concentrations reaching levels comparable to those in healthy controls after 12 months; (iii) this increase was seen primarily in virological responders to HAART (HIV RNA level <200 copies/ml after 24 months); (iv) phytohaemagglutinin-stimulated NGAL release in MNC cells from bone marrow aspirates was decreased in untreated HIV-infected patients compared with healthy controls, but increased after 26 weeks on HAART; and (v) there was a significant positive correlation between neutrophil counts and NGAL levels at all time-points during HAART. We have shown decreased NGAL levels in HIV-infected patients, potentially reflecting decreased number and function of neutrophils as well as impaired bone marrow myelopoiesis. These abnormalities were reversed by successful HAART. Our findings underscore further the involvement of neutrophils and innate immunity in HIV-related immunodeficiency.     

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.     

HIV-infected children with moderate/severe immune-suppression: changes in the immune system after highly active antiretroviral therapy

The objective of this study was to monitor the changes in the immune system of HIV-infected children with moderate or severe immunodeficiency after highly active antiretroviral therapy (HAART), comprising a follow-up study in 14 HIV-infected children on HAART at two time points separated approximately by 11.8 +/- 0.4 (9.9; 15.4) months. HIV-infected children had significantly lower TREC levels than the control group, but 1 year after HAART the levels increased significantly (P < 0.05). In contrast, viral load (VL) did not change significantly. A positive correlation between T cell receptor excision circle (TREC) levels and both CD4(+) T cell absolute counts (r = 0.558; P = 0.05) and percentages (r = 0.625; P = 0.030) was found. During follow-up on HAART, the percentages and absolute counts of naive CD4(+) and CD8(+) T cell subsets were increased significantly (P < 0.05). CD4(+) CD45RA(hi+) CD62L(+), CD4(+) CD45RA(+) and CD4(+) CD38(+) percentages, and the CD8(+) CD45RA(hi+) CD62L(+) counts reached similar values to the control group. Also, CD8(+) CD45RO(+) CD38(+) and CD8(+) CD45RO(+) percentages, and CD8(+) CD45RO(+) CD38(+) absolute counts (P < 0.05) decreased with respect to the baseline. Lymphoproliferative responses to pokeweed mitogen (PWM) before HAART were lower in HIV-infected children than the control group, but they recovered to normal levels after a year on HAART. Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma production by PHA-activated peripheral blood mononuclear cells (PBMC) was lower before HAART (P < 0.001), but reached similar levels to the control group 1 year after HAART. In HIV-infected children IgG, IgG(1) and IgG(3) plasma levels decreased significantly after HAART. The immune system reconstitution induced by HAART in HIV-infected children seems to be the consequence of decreased immune system activation and naive T cell reconstitution, mainly of thymic origin.     

Long-term CD4+ lymphocyte response following HAART initiation in a U.S. Military prospective cohort

Background

Among HIV-infected persons initiating highly active antiretroviral therapy (HAART), early CD4+ lymphocyte count increases are well described. However, whether CD4+ levels continue to increase or plateau after 4-6 years is controversial.

Methods

To address this question and identify other determinants of CD4+ response, we analyzed data for 1,846 persons from a prospective HIV military cohort study who initiated HAART, who had post-HAART CD4+ measurements, and for whom HIV seroconversion (SC) date was estimated.

Results

CD4+ count at HAART initiation was ≤ 200 cells/mm³ for 23%, 201-349 for 31%, 350-499 for 27%, and ≥500 for 19%. The first 6 months post-HAART, the greatest CD4+ increases (93-151 cells) occurred, with lesser increases (22-36 cells/year) through the first four years. Although CD4+ changes for the entire cohort were relatively flat thereafter, HIV viral load (VL) suppressors showed continued increases of 12-16 cells/year. In multivariate analysis adjusting for baseline CD4+ and post-HAART time interval, CD4+ responses were poorer in those with: longer time from HIV SC to HAART start, lower pre-HAART CD4+ nadir, higher pre-HAART VL, and clinical AIDS before HAART (P < 0.05).

Conclusions

Small but positive long-term increases in CD4+ count in virally suppressed patients were observed. CD4+ response to HAART is influenced by multiple factors including duration of preceding HIV infection, and optimized if treatment is started with virally suppressive therapy as early as possible.     

Declining levels of rescued lymphoproliferative response to human cytomegalovirus (HCMV) in AIDS patients with or without HCMV disease following long-term HAART.

OBJECTIVE: To investigate the lymphoproliferative response (LPR) to human cytomegalovirus (HCMV) in two groups of AIDS patients undergoing long-term highly active antiretroviral therapy (HAART): group 1 ( n = 22) with nadir CD4(+) cell count <50/microl and no HCMV disease; group 2 ( n = 16) with <50/microl CD4(+) T-cell count and HCMV disease. All patients had previously undergone antiretroviral monotherapy or dual therapy before initiating HAART. STUDY DESIGN AND METHODS: The two groups of patients were tested prospectively for CD4(+) T cell count, HIV RNA load, HCMV viremia, and LPR to HCMV at baseline, and then after 3 and 4 years of HAART. A control group of 13 recently diagnosed treatment-naive AIDS patients with CD4(+) T-cell counts <100/microl was also investigated. RESULTS: No LPR to HCMV was found in any of the treatment-naive patients nor in any patient of the two groups examined at baseline, when HCMV viremia was 13.6% in the patient group without disease and 87.5% in the group with disease ( p <.0001). After 3 years of HAART, the frequency of patients who recovered an LPR to HCMV was not significantly different (81.8% in the group without HCMV disease, and 68.7% in the group with HCMV disease), whereas, compared with baseline, the HIV load decreased and the CD4(+) T-cell count increased significantly and to a comparable extent in the two groups of patients. In addition, the frequency of patients with HCMV viremia, although reduced, became comparable in both groups. After 4 years of HAART, the frequency of responders to HCMV without and with HCMV disease dropped to comparable levels (50.0 vs. 56.3%, respectively) in association with high median CD4(+) T-cell counts and low median HIV RNA plasma levels. In parallel, the frequency of patients with HCMV viremia did not change significantly. In addition, after between 3 and 4 years of HAART, although the frequency of stable responders and nonresponders remained unchanged (50%) in both groups, most of the remaining patients showed declining levels of responsiveness to HCMV. Although some patients from both groups were found to have CD4(+) T-cell counts >150/microl in the absence of LPR to HCMV, thus suggesting dissociation of specific and nonspecific immune reconstitution, a significant correlation was found between CD4(+) T-cell count and LPR to HCMV (r = 0.44; p <.001). From a clinical standpoint, anti-HCMV therapy could be safely discontinued in 8 patients with HCMV retinitis showing CD4(+) T-cell counts >150/microl, recovery of HCMV LPR, and no HCMV viremia. CONCLUSIONS: Declining levels of the previously recovered LPR to HCMV are often observed after long-term HAART. However, because the role of LPR in the evolution of HCMV infection and disease during HAART remains to be defined, the clinical impact of the declining LPR to HCMV must still be clarified in long-term prospective studies.     

TTV Viral Load As a Marker for Immune Reconstitution After Initiation of HAART in HIV-Infected Patients

Abstract

Purpose: To investigate whether TT virus (TTV) viral load may be used as a surrogate marker for functional immune reconstitution in HIV-infected patients receiving highly active antiretroviral therapy (HAART). Method: Fifteen protease inhibitor-naÏve HIV-infected patients were included in a longitudinal study. From each patient, three serum samples taken before HAART initiation and three samples taken during HAART were analyzed. TTV was detected by polymerase chain reaction (PCR) and was quantitated by competitive PCR. TTV viral heterogeneity was determined by restriction fragment length polymorphisms (RFLPs) and sequencing. Results: All 15 HIV-infected patients were TTV positive. No significant change in HIV RNA or TTV viral load was observed at the three time points before HAART initiation. Even though HAART lead to an immediate and significant reduction in HIV RNA (p = .0001), a significant reduction in TTV viral load (p = .0002) was not observed until after 3-5 months of HAART. Four patients did not have an increase in CD4+ T cell count after 1 year of HAART; however, a decrease in TTV viral load was still observed, and three of these patients had a reduction in HIV RNA. RFLPs and sequencing revealed that TTV is represented as a heterogeneous population of virus in HIV-infected patients. Conclusion: This pilot study suggests that HAART leads to improved immunological responses, even in patients who do not have an increase in CD4+ T cell counts. We propose that the change in TTV viral load may be useful in the evaluation of cellular immune response at a functional level in HIV-infected patients who receive HAART.     

CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater

OBJECTIVE: CD4 cell count changes in therapy-naive patients were investigated during 7 years of highly active antiretroviral therapy (HAART) in an observational cohort. METHODS: Three endpoints were studied: (1) time to >or=800 CD4 cells/mm in 5299 therapy-naive patients starting HAART, (2) CD4 cell count changes during 7 years of uninterrupted HAART in a subset of 544 patients, and (3) reaching a plateau in CD4 cell restoration after 5 years of HAART in 366 virologically suppressed patients. RESULTS: Among patients with <50, 50 to 200, 200 to 350, 350 to 500, and >or=500 CD4 cells/mm at baseline, respectively, 20%, 26%, 46%, 73%, and 87% reached >or=800 CD4 cells/mm within 7 years of starting HAART. Periods with HIV RNA levels >500 copies/mL and age >or=50 years were associated with lesser increases in CD4 cell counts between 6 months and 7 years. Having reached >or=800 CD4 cells/mm at 5 years, age >or=50 years, and >or=1 HIV RNA measurement >1000 copies/mL between 5 and 7 years were associated with a plateau in CD4 cell restoration. CONCLUSIONS: Restoration to CD4 cell counts >or=800 cells/mm is feasible within 7 years of HAART in most HIV-infected patients starting with >or=350 cells/mm and achieving sufficient suppression of viral replication. Particularly in patients >or=50 years of age, it may be beneficial to start earlier than current guidelines recommend.     

Influence of hepatitis C and hepatitis G virus co-infection on viral and cellular dynamics in patients infected with human immunodeficiency virus following interruption of highly active anti-retroviral therapy

This study describes the influence of hepatitis C virus (HCV) and hepatitis G virus (HGV) co-infection on CD4 cell count decline and plasma human immunodeficiency virus (HIV) viral load in HIV-infected patients during a 1-year period following interruption of highly active anti-retroviral therapy (HAART) guided by CD4 count. CD4 cell count decline and plasma HIV viral load did not differ between HIV mono-infected patients and those patients co-infected with HCV and HGV. HCV genotype 1 had no apparent influence on the cellular and viral dynamics in HIV-infected patients compared with other HCV genotypes, although the unbalanced groups make larger studies desirable.     

Polyneuropathies in patients treated with HAART in Bobo-Dioulasso hospital, Burkina Faso

Peripheral neuropathies (PN) represent the most common neurological manifestation in patients with HIV infection. Introduction of highly active antiretroviral therapy (HAART) had a significant impact on the epidemiology of HIV-associated neuropathies even in poor-resources countries. HIV-infected patients were followed up over a 2-years period from January 2002 to December 2003. PN was clinically diagnosed based on abnormalities of ankle reflexes or vibratory perception and if patients described pain, paresthesia or numbness. Electromyography was not performed in this study Among the 133 HIV-infected patients treated with HAART 31 patients (23 females and 8 males) with 38.8 of mean age were followed up for PN. 95.5% among them were HIV1-infected. According to the availability of the antiretroviral therapy, 9 patients were treated with protocol A including lamivudine + stavudine + nevirapine, 12 patients with protocol B including combination of stavudine + lamivudine + efavirenz, and 10 patients with protocol C with other combinations of antiretroviral therapies. Average CD4 cell count was 229.3/microl and 60% of the sample had < 200 CD4 cell counts at the time of diagnosis. PN occurred within 5.6 months from the institution of the HAART and 80% less than 3 months after the beginning of the treatment. Burning feet syndrome was found in 16.1% of the sample. 45.2% of polyneuropathies occurred in late stage of HIV infection (< 200 CD4/microl). The presence of PN was related to decreased CD4 cells counts and neurotoxic antiretroviral therapy Introduction of HAART has modified the course and the prognosis of HIV infection even in poor resources setting. The incidence of toxic neuropathies is increasing with longer patients' life expectancy and represents a major factor in treatment limitation and the neurological side effects of HAART should be well identified by physicians.     

Immune-specific immunoglobulin G-mediated enhancement of human immunodeficiency virus-induced IFN-alpha production.

Interferon-alpha (IFN-alpha) is synthesized as an integral part of innate immunity to viral infection. We previously provided preliminary evidence that antibody-containing serum from HIV-infected individuals enhanced HIV-induced production of IFN-alpha. Subsequently, preparations of pooled human immunoglobulin G (IgG) have also been shown to enhance poliovirus (PV)-induced IFN-alpha production. The current work establishes IgG as the serum mediator that enhances induction of IFN-alpha by HIV. Our studies also establish the ability of sera from individual subjects to enhance PV-induced IFN-alpha production. HIV-induced IFN-alpha production was enhanced maximally by >4000-fold and by an average of 25-fold. Sera from 74 people enhanced PV- induced IFN-alpha from undetectable levels to an average of 615 units (range 7-4679 units). The ability of individual sera to enhance IFN-alpha production by HIV and PV persisted undiminished in patients with AIDS. IgG-mediated enhancement of IFN-alpha production was similar to that induced by IgG and PV and was blocked by IgG Fc fragments. Demonstration of the selective enhancement of HIV-induced IFN-alpha production by IgG from HIV-seropositive individuals provides further evidence for the existence of antigen-specific upregulation of a critical component of innate antiviral immunity by the adaptive Th2 immune response.