Older HIV-infected patients on antiretroviral therapy have B-cell expansion and attenuated CD4 cell increases with immune activation reduction.

BACKGROUND: The contribution of immune activation to accelerated HIV-disease progression in older individuals has not been delineated. METHODS: Prospective multicenter cohort of older (≥45 years) and younger (18-30 years) HIV-infected adults initiating 192 weeks of antiretroviral therapy (ART). Longitudinal models of CD4 cell restoration examined associations with age-group, thymic volume, immune activation, and viral load. RESULTS: Forty-five older and 45 younger adults (median age 50 and 26 years, respectively) were studied. Older patients had fewer naive CD4 cells (P<0.001) and higher HLA-DR/CD38 expression on CD4 (P=0.05) and CD8 cells (P=0.07) than younger patients at any time on ART. The rate of naive and total CD4 cell increase was similar between age groups, but older patients had a faster mean rate of B-cell increase (by +0.7 cells/week; P=0.01), to higher counts than healthy controls after 192 weeks (P=0.003). Naive CD4 increases from baseline were associated with immune activation reductions (as declines from baseline of %CD8 cells expressing HLA-DR/CD38; P<0.0001), but these increases were attenuated in older patients, or in those with small thymuses. A 15% reduction in activation was associated with naive gains of 29.9 and 6.2 cells/µl in younger, versus older patients, or with gains of 25.7, 23.4, and 2.1 cells/µl in patients with the largest, intermediate, and smallest thymuses, respectively (P<0.01 for interactions between activation reduction and age-group or thymic volume). CONCLUSION: Older patients had significant B-cell expansion, higher levels of immune activation markers, and significantly attenuated naive CD4 cell gains associated with activation reduction.

Factors associated with viral rebound in HIV-1-infected individuals enrolled in a therapeutic HIV-1 gag vaccine trial.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) vaccines directed to the cell-mediated immune system could have a role in lowering the plasma HIV-1 RNA set point, which may reduce infectivity and delay disease progression. METHODS: Randomized, placebo-controlled trial involving HIV-1-infected participants who received a recombinant adenovirus serotype 5 (rAd5) HIV-1 gag vaccine or placebo. Sequence-based HLA typing was performed for all 110 participants who initiated analytic treatment interruption (ATI) to assess the role of HLA types previously associated with HIV prognosis. Plasma HIV-1 gag and pol RNA sequences were obtained during the ATI. Virologic endpoints and HLA groups were compared between treatment arms using the 2-sample rank sum test. A linear regression model was fitted to derive independent correlates of ATI week 16 plasma viral load (w16 PVL). RESULTS: Vaccinated participants with neutral HLA alleles had lower median w16 PVLs than did vaccinated participants with protective HLA alleles (P = .01) or placebo participants with neutral HLA alleles (P = .02). Factors independently associated with lower w16 PVL included lower pre-antiretroviral therapy PVL, greater Gag sequence divergence from the vaccine sequence, decreased proportion of HLA-associated polymorphisms in Gag, and randomization to the vaccine arm. CONCLUSIONS: Therapeutic vaccination with a rAd5-HIV gag vaccine was associated with lower ATI week 16 PVL even after controlling for viral and host genetic factors. CLINICAL TRIALS REGISTRATION: NCT00080106.

AIDS clinical trials group 5197: a placebo-controlled trial of immunization of HIV-1-infected persons with a replication-deficient adenovirus type 5 vaccine expressing the HIV-1 core protein.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1)-specific cellular immunity contributes to the control of HIV-1 replication. HIV-1-infected volunteers who were receiving antiretroviral therapy were given a replication-defective adenovirus type 5 HIV-1 gag vaccine in a randomized, blinded therapeutic vaccination study. METHODS: HIV-1-infected vaccine or placebo recipients underwent analytical treatment interruption (ATI) for 16 weeks. The log(10) HIV-1 RNA load at the ATI set point and the time-averaged area under the curve served as co-primary end points. Immune responses were measured by intracellular cytokine staining and carboxyfluorescein succinimidyl ester dye dilution. RESULTS: Vaccine benefit trends were seen for both primary end points, but they did not reach a prespecified significance level of P < or = 25. The estimated shifts in the time-averaged area under the curve and the ATI set point were 0.24 (P=.04, unadjusted) and 0.26 (P=.07, unadjusted) log(10) copies lower, respectively, in the vaccine arm than in the placebo arm. HIV-1 gag-specific CD4(+) cells producing interferon-gamma were an immunologic correlate of viral control. CONCLUSION: The vaccine was generally safe and well tolerated. Despite a trend favoring viral suppression among vaccine recipients, differences in HIV-1 RNA levels did not meet the prespecified level of significance. Induction of HIV-1 gag-specific CD4 cells correlated with control of viral replication in vivo. Future immunogenicity studies should require a substantially higher immunogenicity threshold before an ATI is contemplated.

The effect of aging on T-regulatory cell frequency in HIV infection.

T-regulatory cell (T-reg) frequency is increased in HIV infection and with aging. We evaluated the effect of age on total, memory and naïve T-reg percentages in untreated HIV infection. Older HIV(+) subjects had a total T-reg percent that is 2.8% (p=0.02) higher than among younger HIV(+), older HIV(-) and younger HIV(-) subjects. In HIV(+) subjects, the total T-reg percentage is inversely correlated with the lymphocyte proliferative responses to tetanus (r=-0.45, p=0.002) and Candida (r=-0.43, p=0.003) antigens. Similar correlations were seen between memory T-reg percentages and the lymphocyte proliferative response to tetanus and Candida in HIV(+) subjects. T-reg percentages did not correlate consistently with markers of immune activation. T-reg percentages are increased in the older HIV(+) population and may play a role in the accelerated disease progression seen in older HIV-infected persons.

Evidence that intermittent structured treatment interruption, but not immunization with ALVAC-HIV vCP1452, promotes host control of HIV replication: the results of AIDS Clinical Trials Group 5068.

BACKGROUND: The ability to control human immunodeficiency virus (HIV) replication in vivo in the absence of antiretroviral therapy (ART) is a measure of the efficiency of antiviral immunity. In a study of patients with chronic, ART-suppressed HIV infection, AIDS Clinical Trials Group 5068 investigated the effects of immunization with an exogenous HIV vaccine and pulse exposure to the subject's unique viral epitopes, by means of structured treatment interruptions (STIs), on the dynamics of viral rebound during a subsequent analytical treatment interruption (ATI). METHODS: Ninety-seven subjects receiving stable ART with an HIV-1 RNA load <50 copies/mL and CD4(+) T lymphocyte count >400 cells/mm(3) were randomized to undergo continued ART, STIs, ALVAC-HIV vCP1452 immunization, or STIs and ALVAC-HIV vCP1452 immunization. RESULTS: Subjects in the 2 STI arms had a significantly longer median doubling time in the period of the initial rise of viral load, a significantly lower median peak viral load, a significantly lower median end-of-ATI viral load set point, and a greater proportion of subjects with an end-of-ATI viral load set point <1,000 copies/mL, compared with the subjects in the 2 arms without STIs. With an immunization schedule of 3 sets of 3 weekly injections, ALVAC-HIV vCP1452 did not affect viral load measures. CONCLUSIONS: In this randomized, controlled study of intermittent STI as a therapeutic autoimmunization strategy, evidence of enhanced immunologic control of HIV replication was demonstrated.

Serum neopterin, an immune activation marker, independently predicts disease progression in advanced HIV-1 infection.

BACKGROUND: CD4+ T lymphocyte (CD4) counts and plasma human immunodeficiency virus (HIV) type 1 RNA concentrations predict clinical outcome in HIV-1 infection. Our objective was to assess the independent prognostic value for disease progression of soluble markers of immune system activation. METHODS: This retrospective marker-validation study utilized previously obtained clinical and laboratory data, including CD4+ cell counts, and made use of stored frozen serum samples to assay for levels of beta2-microglobulin, neopterin, endogenous interferon, triglycerides, interleukin-6, soluble tumor necrosis factor- alpha receptor II, and HIV-1 RNA, and to determine HIV genotypic reverse-transcriptase inhibitor resistance. The 152 patients who participated in this study represented a subsample of participants in AIDS Clinical Trials Group (ACTG) 116B/117, a randomized trial that demonstrated the clinical benefit of didanosine over zidovudine monotherapy in persons with advanced HIV-1 infection. Marker data were analyzed in relation to protocol-defined clinical disease progression, using Cox proportional hazards models. RESULTS: The median duration of follow-up was 344 days. Elevated baseline values for neopterin (P=.0009), endogenous interferon (P=.00039) and interleukin-6 (P=.0007) were each associated with greater subsequent risk of clinical disease progression. In a head-to-head comparison that was adjusted for CD4+ cell count (P=.0165) and HIV-1 RNA level (P=.1220), we found that elevated values for neopterin (P=.0002) and, to a lesser extent, endogenous interferon (P=.0053) were the strongest predictors of increased risk of clinical disease progression 6 months later. CONCLUSIONS: Soluble markers of immune activation add prognostic information to CD4 counts and viral load for risk of disease progression in advanced HIV-1 infection. The robust performance of neopterin, an inexpensive and reliably measured serum marker, supports its potential suitability for patient monitoring, particularly in resource-limited settings.

A phase II, double-masked, randomized, placebo-controlled evaluation of a human monoclonal anti-Cytomegalovirus antibody (MSL-109) in combination with standard therapy versus standard therapy alone in the treatment of AIDS patients with Cytomegalovirus retinitis.

ACTG 266 was designed as a randomized study to evaluate two doses of the human monoclonal antibody directed against CMV gH (MSL-109) versus placebo, each in combination with standard antiviral therapy for the treatment of newly diagnosed Cytomegalovirus (CMV) retinitis in AIDS patients. A total of 82 subjects were enrolled and received either placebo (n = 28), or MSL-109 at 15 mg (n = 26) or 60 mg (n = 28) every 2 weeks until disease progression was diagnosed. The primary endpoint, disease progression, was determined by masked reading of retinal photographs taken every 4 weeks read by a single investigator. The median time to progression was 8.0, 8.3, and 12.1 weeks in the placebo, MSL-109 15mg and MSL-109 60 mg cohorts, respectively (P = 0.087, placebo versus 60 mg cohort). There were 22 deaths during the study period (9, 9, and 4 in the placebo, MSL-109 15 mg and MSL-109 60 mg cohorts, respectively (P = 0.0058, placebo versus 60 mg cohort)). MSL-109 was well tolerated with no significant adverse events attributable to study medication. The unexplained survival advantage in the higher dose cohort was discordant with the findings of the parallel Studies of Ocular Complications of AIDS Research Group (SOCA)-Monoclonal Anti-CMV Retinitis Trial (MACRT), which was prematurely halted because of increased mortality in subjects treated with high-dose MSL-109, recognizing that A266 enrolled subjects with newly diagnosed, whereas the MACRT enrolled subjects with relapsed, CMV retinitis.

Granulocyte-macrophage colony-stimulating factor induces modest increases in plasma human immunodeficiency virus (HIV) type 1 RNA levels and CD4+ lymphocyte counts in patients with uncontrolled HIV infection.

BACKGROUND: Studies have reported that plasma human immunodeficiency virus type 1 (HIV-1) RNA levels and CD4+ lymphocyte counts in HIV-infected patients improved after treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: In AIDS Clinical Trials Group Protocol 5041, 116 patients were enrolled in a double-blind, randomized, placebo-controlled clinical trial of 16 weeks of 250 microg of GM-CSF administered subcutaneously 3 times/week, followed by open-label treatment for an additional 32 weeks. Patients had stable baseline plasma HIV-1 RNA levels of > or =1500 copies/mL and received constant antiretroviral regimens through at least the first 16 weeks of the study. RESULTS: After 16 weeks, the GM-CSF group tended to have greater, though clinically insignificant, increases in plasma HIV-1 RNA levels, compared with the placebo group (median change, +0.048 vs. -0.103 log copies/mL; P=.036, in a post hoc analysis). There were trends toward progressive modest increases in CD4+ lymphocyte counts with GM-CSF treatment at 16 weeks (median change, +14 vs. -6 cells/mm3; P=.06) and beyond. CONCLUSIONS: GM-CSF does not have an antiviral effect in patients with ongoing HIV replication but may increase CD4+ lymphocyte counts.

Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: association of age and HIV infection with naive CD8+ cell depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic volumes.

Older age is a strong predictor of accelerated human immunodeficiency virus (HIV) disease progression. We investigated the possible immunologic basis of this interaction by comparing older (>/=45 years) and younger (

A study of the immunology, virology, and safety of prednisone in HIV-1-infected subjects with CD4 cell counts of 200 to 700 mm(-3).

Adult Clinical Trials Group Study 349 examined the immunology, virology, and safety of 40 mg/d prednisone as an adjunct to antiretroviral therapy in 24 HIV-infected subjects with >200 CD4+ T cells/mm in a randomized placebo-controlled trial. After 8 weeks, median lymphocyte and CD4+ cell numbers increased >40% above baseline values (p =.08). No effect was observed on markers of cell activation or apoptosis, although the proportion of CD28+ CD8+ T cells increased (p =.006). Prednisone inhibited monocyte TNFalpha production without affecting T-cell responses to antigens or mitogens. Two subjects assigned to prednisone were subsequently found to have asymptomatic osteonecrosis of the hip. Many questions remain regarding the role of activation-induced sequestration and apoptosis as causes of progressive CD4+ T-cell loss in AIDS. The potential role of corticosteroids as tools to examine this question will be limited by concerns regarding their toxicity; however, further studies of other agents to limit cellular activation in AIDS are warranted.