Long-term Highly Active Antiretroviral Therapy Research Articles

Immune reconstitution in the sigmoid colon after long-term HIV therapy

Early and profound CD4+ T-cell depletion in gut-associated lymphoid tissue (GALT) may drive Human Immunodeficiency Virus (HIV) immunopathogenesis, and GALT immune reconstitution on highly active antiretroviral therapy (HAART) may be suboptimal. Blood and sigmoid colon biopsies were collected from HAART-treated individuals with undetectable blood HIV RNA for ⩾4 years and from uninfected controls. HIV proviral levels and T-cell phenotype/function were examined in both compartments. CD4+ T-cell reconstitution in the sigmoid, including CD4+ T cells expressing CCR5, exceeded that in blood and did not differ from uninfected controls. Sigmoid HIV proviral load was not correlated with CD4+ reconsitution, but was correlated with the degree of mucosal CD8+ T-cell immune activation. Colonic Gag-specific T-cell responses were common, but were not associated with proviral load or immune activation. In this select study population, long-term HAART was associated with complete CD4+ T-cell reconstitution in sigmoid colon. However, colonic immune activation may drive ongoing HIV replication.

Non-AIDS-defining malignancies among HIV-infected patients in the highly active antiretroviral therapy era

In the highly active antiretroviral therapy (HAART) era, the incidence of AIDS-defining malignancies (ADMs) has declined significantly. On the other hand, the incidence of other malignancies not known to be associated with immunosuppression (non-ADMs) has not changed and remains significantly higher than in the general population. Some recent controlled studies even suggest that the incidence of selected non-ADMs has increased in the HAART era. These trends warrant a high index of suspicion for malignancies among HIV care providers and a renewed focus on understanding the mechanisms underlying the increased rates. Potential explanations for the higher non-ADM rates include longer survival of patients with HIV on HAART, with only partial immune recovery achieved in most patients; high incidence of human papillomavirus, Epstein-Barr virus, and hepatitis C virus coinfection in patients with HIV infection; and potential oncogenicity of long-term HIV infection or of long-term HAART.

Restoration of the CD4 T Cell Compartment after Long-Term Highly Active Antiretroviral Therapy without Phenotypical Signs of Accelerated Immunological Aging

It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery. In addition to measuring T cell activation and proliferation markers, CD4 T cell generation and aging of the CD4 T cell compartment were assessed by measuring TCR excision circles and the fraction of CD31-expressing naive CD4 T cells. In all children and in adults with relatively high CD4 T cell counts at start of therapy (>200 cells/microl), total CD4 T cell numbers normalized within 1 year of therapy. After long-term HAART (4.4-9.6 years), naive CD4 T cell counts had normalized in both groups. Although in adults with low baseline CD4 T cell counts (<200 cells/microl) total CD4 T cell numbers normalized eventually after at least 7 years of HAART, naive CD4 T cell counts had still not recovered. TCR excision circle data showed that thymic T cell production contributed to naive T cell recovery at all ages. The fraction of CD31-expressing naive CD4 T cells was found to be normal, suggesting that the CD4 T cell repertoire was diverse after long-term HAART. Hence, under sustained viral suppression during long-term HAART, the T cell compartment has the potential to fully recover by generating new naive T cells both in children and in adults with high baseline CD4 T cells counts. Irrespective of baseline CD4 T cell counts, reconstitution occurred without a significant effect on T cell aging as reflected by markers for replicative history.

Clonal evolution of CD8+ T-cell expansions in HIV-infected patients on long-term HAART.

HIV-1 continually replicates in spite of long-term highly active anti-retroviral therapy (HAART) and therefore, it is conceivable that the low level, persistent viral activity could continue to stimulate the hosts immune system despite remaining below the detection limit of the current assays. In this study, we performed a longitudinal analysis of the CD8+ T-cell receptor Vbeta repertoire in HAART-treated and untreated HIV patients. HAART-mediated control of viremia, for up to 18 months, did not prevent similar perturbations within the CD8+ Vbeta repertoire in both study groups as defined by CDR3 spectratyping. Oligoclonal Vbeta expansions, with new dominant CDR3 lengths, were observed throughout the study period. Our findings are compatible with antigen-driven CD8+ immune responses to bursts of replication from a continuously changing viral reservoir, regardless of HAART-mediated suppression of HIV-1 viremia.

Lack of Evidence for Prolonged Double-Long Terminal Repeat Episomal HIV DNA Stability In Vivo

Lack of Evidence for Prolonged Double-Long Terminal Repeat Episomal HIV DNA Stability In Vivo

Persistence of Neuropsychologic Deficits Despite Long-Term Highly Active Antiretroviral Therapy in Patients With HIV-Related Neurocognitive Impairment

Although highly active antiretroviral therapy (HAART) can reverse HIV-related neurocognitive impairment (NCI), neuropsychologic (NP) deficits may persist in a substantial proportion of patients despite antiretroviral treatment. We assessed the prevalence and predictors of persistent NP deficits despite long-term HAART in patients with HIV-related NCI. A group of 94 patients with HIV-related NCI underwent 2 to 7 serial NP batteries, neurologic examination, and brain imaging studies. Patients received HAART for a mean of 63 (range: 6-127) months. According to NP assessment results, patients were considered to have reversible or persistent NP deficits. Kaplan-Meier analyses and Cox proportional hazards models were used to analyze time to first evidence of NP deficit reversion. Persistent NP deficits were observed in 59 (62.8%) patients. Age, gender, Centers for Disease Control and Prevention stage, risk category, CD4 cell count, plasma viral load, and use of central nervous system-penetrating drugs were not associated with persistent NP deficits. By contrast, patients with persistent NP deficits were less educated and showed poorer baseline performances in NP measures exploring concentration and speed of mental processing, memory, and mental flexibility. In multivariable analyses, only the baseline severity of NCI, as measured by the composite NPZ8 global score (odds ratio = 3.07, 95% confidence interval: 1.54 to 6.08; P = 0.001) remained significantly associated with persistent NP deficits. The severity of NCI at HAART initiation seems to be the strongest predictor of persistent NP deficits despite long-term HAART. Our data indicate that HAART should be initiated as soon as NCI is diagnosed to avoid potentially irreversible neurologic damage.

When To Initiate HIV Antiretroviral Therapy

When To Initiate HIV Antiretroviral Therapy

Impact of highly active antiretroviral therapy on plasma MCP-1 and MSP in AIDS patients

To study the effect of highly active antiretroviral therapy (HAART) on plasma levels of MSP and MCP-1 in AIDS patients. Forty Chinese AIDS patients were treated with HAART for 3 months and 84 German AIDS patients with HAART for 3 to 6 years. The pre-treatment and post-treatment plasma levels of MSP and MCP-1 were measured by enzyme-linked immunosorbent assay (ELISA), and their correlations with CD4+ cell counts and viral loads were analyzed. The mean levels of MCP-1 were significantly higher and MSP were significantly lower in HIV-infected patients compared with the HIV-negative controls (P <0.01). After HAART for three months, there were no significant changes in the levels of these cytokines. But after long-term HAART (for 3 to 6 y), the level of MCP-1 was increased and that of MSP decreased significantly (P<0.01). There was a negative correlation between MSP and MCP-1 levels, and the same for MSP level and CD4+ cell counts; while there was a positive correlation between MCP-1 levels and CD4+ cell counts. The changed plasma levels of MSP and MCP-1 are associated with HIV-1 infection and HAART may reverse the levels of these two cytokines.

Current Therapy for Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome

Antiretroviral treatments with highly active antiretroviral therapy (HAART) have shown remarkable progress in the past decade and resulted in impressive improvements in life expectancy and quality of life for patients infected with human immunodeficiency virus 1 (HIV-1). Despite the clinical benefits, the management of HIV infection faces many problems. Although HAART is able to suppress the viral load in the plasma, it is unable to eradicate it, and once HAART is initiated, treatment needs to be continued over a lifetime. The side effects of long-term HAART, such as lipodystrophy, lactic acidosis, insulin resistance, and hyperlipidemia, are negative impacts for patients who receive HAART. In addition, patients need to demonstrate high adherence to the therapy to achieve viral suppression and prevent the development of a drug-resistant virus. This review discusses currently recommended antiretroviral treatment strategies, the difficulties with antiretroviral treatments, and current issues regarding HIV management.

HIV Infection and Dementia in Older Adults

Human immunodeficiency virus (HIV) infection in older patients is becoming increasingly common as seropositive individuals live longer because of long-term antiretroviral treatment. Simultaneously, the development and expression of dementia among HIV-infected patients is evolving in the era of highly active antiretroviral therapy (HAART) and immune reconstitution. How long-term HAART interacts with chronic HIV infection and advanced age with regard to cognition is not fully understood. This article provides an overview of HIV cognitive impairment as it relates to aging and presents some emerging issues in the field. Particular emphasis is placed on describing the changing landscape of HIV-related cognitive impairment and discussing possible concerns regarding the long-term effects of antiretroviral treatment. A brief discussion of potential adjunctive therapies to reduce cognitive symptoms associated with HIV infection in older individuals is provided.

Long-Term Effects of Highly Active Antiretroviral Therapy in Pretreated, Vertically HIV Type 1-Infected Children: 6 Years of Follow-Up

Several studies of children with human immunodeficiency virus (HIV) type 1 infection have demonstrated sustained increases in CD4+ cell count, even when virological failure has occurred after receipt of highly active antiretroviral therapy (HAART), but these studies were of limited duration. Moreover, the CD4+ cell count threshold at which antiretroviral treatment should be initiated is still unsettled. The aim of this study was to define the long-term impact of HAART on CD4+ cell percentage and viral load according to CD4+ cell percentages before HAART was initiated. We conducted a retrospective study of 113 pretreated HIV-1-infected children stratified by pre-HAART CD4+ cell percentage (<5%, 5%-15%, 15%-25%, and >25%). The inclusion criteria were as follows: initiating HAART with a protease inhibitor, having 6 years of follow-up after starting HAART, having a CD4+ cell count or viral load recorded before initiation of HAART, and having received mono- or dual-nucleoside therapy before starting HAART. During the first 2 years of HAART, HIV-1-infected children experienced a significant increase in CD4+ cell percentage and a decrease in viral load (P<.05). During their last 4 years of receiving HAART, we found a significant decrease in viral load but not an increase in CD4+ cell percentage, because the CD4+ cell percentage reached a plateau after the second year of HAART. Moreover, children with CD4+ cell percentages of <5% at baseline did not achieve CD4+ cell percentages of >25% after 6 years of HAART. Children with CD4+ cell percentages of 5%-25% at baseline had a strong negative association with achieving CD4+ cell percentages of >30% for at least 6 and 12 months but not with achieving CD4+ cell percentages of >30% for at least 24 months. Long-term HAART allowed for restoration of CD4+ cell counts and control of viral loads in HIV-1-infected children. However, initiating HAART after severe immunosuppression has occurred is detrimental for the restoration of the CD4+ cell count.

Long-Term Highly Active Antiretroviral Therapy in Chronic HIV-1 Infection: Evidence for Reconstitution of Antiviral Immunity

In this study we investigated the long-term effect of highly active antiretroviral therapy (HAART) on HIV-specific CD4+ T-cell responses in comparison with virus-specific CD4+ T-cell responses against the persistent herpes viruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). To this end, HIV- and herpes virus-specific cellular immune responses were measured longitudinally in 10 seroconverters with long-term follow-up including 55 months of successful suppression of viral load by HAART. HIV- and CMV-specific CD4+ T cells producing interferon-gamma (IFNgamma) or interleukin-2 (IL-2) were analysed as well as proliferative capacity. EBV-specific CD4+ T cells were determined using a 12-day ex vivo assay. Initiation of HAART resulted in a transient increase of HIV-specific IL-2(+)IFNgamma(+)CD4(+) T cells and, to a lesser extent, IL-2(+)CD4(+) T cells. Long-term HAART resulted in an increase in HIV-, CMV- and EBV-specific CD4+ T-cell proliferative capacity. The increase in HIV- and herpes-virus-specific CD4+ T-cell proliferative capacity after 55 months of HAART suggests that the improved proliferative response is not specific for HIV, but reflects a more general improvement of antiviral immune responses, which is induced by HAART.

Pronounced lipoatrophy in HIV‐infected men receiving HAART for more than 6 years compared with the background population

To establish the prevalence and quantify the severity of body fat redistribution and dyslipidaemia in HIV-infected men after long-term highly active antiretroviral therapy (HAART) compared with the background population. In a cross-sectional study, we included 87 HIV-infected men who had received HAART for at least 6 years and 34 HIV-negative men. Regional body composition was assessed using dual-energy X-ray absorptiometry. Fasting metabolic parameters were obtained. Associations between regional body fat distribution and metabolic parameters were evaluated. HIV-infected patients and controls did not differ with regard to height and lean body mass. Compared with controls, HIV-infected men had reduced total fat mass (median 12.3 versus 19.2 kg, P<0.001), limb fat mass (4.3 versus 7.9 kg, P<0.001), and trunk fat mass (6.7 versus 10.8 kg, P<0.001) and higher trunk/limb fat ratio (1.7 versus 1.2, P<0.001). Also, patients without clinical lipodystrophy had reduced amounts of limb and trunk fat. In HIV-infected men, triglyceride levels were higher (2.0 versus 1.2 mmol/L, P<0.001), high-density lipoprotein (HDL)-cholesterol levels were lower (1.2 versus 1.3 mmol/L, P<0.05) and insulin levels were higher (40.8 versus 29.9 pmol/L, P<0.01) than in controls. All adverse metabolic parameters correlated with increased trunk/limb fat ratio, and insulin levels correlated positively with trunk fat mass (P<0.01). Peripheral as well as central fat loss is a general characteristic of HIV-infected men after long-term HAART. Although lipoatrophy was the dominant morphological presentation, the adverse metabolic parameters were mainly associated with the increased ratio of trunk/limb fat.

Individual Variation in CD4 Cell Count Trajectory among Human Immunodeficiency Virus-infected Men and Women on Long-term Highly Active Antiretroviral Therapy: An Application using a Bayesian Random Change-Point Model

The authors evaluated population- and individual-level CD4-positive T-lymphocyte (CD4 cell) count trajectories over a 7-year period (July 1995-March 2004) following initiation of highly active antiretroviral therapy (HAART) in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. The study population included 404 human immunodeficiency virus (HIV)-infected men and 609 HIV-infected women who 1) had a CD4 cell count measurement available from their last pre-HAART study visit, 2) provided at least four post-HAART CD4 cell count measurements, and 3) reported HAART usage for at least 80% of the post-HAART visits. The CD4 cell count trajectory was analyzed by means of a Bayesian random change-point model. The results indicated that CD4 cell count trajectories for long-term frequent HAART users can be well modeled with change points at both the population and individual levels. At the population level, regardless of CD4 cell count before HAART initiation, the gains in CD4 cell count ended approximately 2 years after HAART initiation in both men and women. At the individual level, 35% of men in the Multicenter AIDS Cohort Study versus 25% of women in the Women's Interagency HIV Study had a statistically significant change in CD4 cell count trajectory within 7 years after HAART initiation.

Reconstitution of EBV Latent but Not Lytic Antigen-Specific CD4+ and CD8+ T Cells after HIV Treatment with Highly Active Antiretroviral Therapy

The incidence of (EBV-related) malignancies in HIV-infected subjects has declined since the introduction of highly active antiretroviral therapy (HAART). To investigate the effect of HAART on EBV infection, we performed a longitudinal analysis of the T cell response to both a latent and a lytic Ag and EBV viral load in 10 subjects from early in HIV infection up to 5 years after HAART. All individuals responded to HAART by a decline in HIV viral load, a restoration of total CD4+ T cell numbers, and a decline in T cell immune activation. Despite this, EBV load remained unaltered, even after 5 years of therapy, although a decline in both CD4+ and CD8+ T cells specific for the lytic EBV protein BZLF1 suggested a decreased EBV reactivation rate. In contrast, latent EBV Ag EBNA1-specific CD4+ and CD8+ T cell responses were restored after 5 years of treatment to levels comparable to healthy individuals. In two individuals who were treated by HAART late during HIV progression, a lymphoma developed shortly after initiation of HAART, despite restoration of EBV-specific CD4+ and CD8+ T cells. In conclusion, long-term HAART does not alter the EBV DNA load, but does lead to a restoration of EBNA1-specific T cell responses, which might allow better control of EBV-infected cells when applied early enough during HIV infection.

2B4 expression on natural killer cells increases in HIV-1 infected patients followed prospectively during highly active antiretroviral therapy.

Human immunodeficiency virus (HIV)-1 infection influences natural killer (NK) cell expression of inhibitory NK receptors and activating natural cytotoxicity receptors. It is unknown whether expression of the co-stimulatory NK cell receptor 2B4 (CD244) on NK cells and CD3+ CD8+ cells are affected by highly active antiretroviral therapy (HAART), low-level viraemia, proviral-DNA or immune activation in HIV-1 infected patients. A total of 101 HAART-treated HIV-1 infected patients with < or = 200 HIV-RNA copies/ml were followed prospectively for 24 months. HIV-RNA was investigated 3-monthly and 2B4 expression on CD3- CD16+ NK cells and CD3+ CD8+ cells, proviral-DNA and plasma soluble tumour necrosis factor receptor (sTNFr)-II were investigated 6-monthly. For comparison, 2B4 expression was investigated in 20 healthy individuals. The concentration of 2B4+ NK cells was initially reduced in HIV-1 infected patients (P < 0.001) but increased to a normal level during the 24 months' follow-up. The concentration of CD3+ CD8+ 2B4+ cells in HIV-1 infected patients was normal and did not change during follow-up. The relative fluorescence intensity (RFI) of 2B4 increased on both NK cells and CD3+ CD8+ cells during follow-up (both P < 0.001). Higher levels of proviral-DNA carrying cells and plasma sTNFrII were associated with reductions in the concentration of 2B4+ NK cells (all P < 0.05). HIV-RNA had no effect on 2B4 expression on NK cells or CD3+ CD8+ cells. These findings demonstrate that the concentration of 2B4+ NK cells normalizes during long-term HAART in HIV-1 infected patients. The finding that proviral-DNA and sTNFrII were associated negatively with the concentration of 2B4+ NK cells suggests that immune activation in HIV-1 infected patients receiving HAART influences the target cell recognition by NK cells.

Dysregulation of CD28 and CTLA‐4 expression by CD4 T cells from previously immunodeficient HIV‐infected patients with sustained virological responses to highly active antiretroviral therapy

Current guidelines recommend commencing highly active antiretroviral therapy (HAART) in HIV-infected patients when CD4 T-cell counts reach 350 cells/microL. However, late-presenting HIV-infected patients with CD4 T-cell counts<50 cells/microL are still common. The ability of long-term HAART to normalize immune dysregulation in severely immunodeficient HIV-infected patients remains unclear. Here we address indices of immune dysregulation in previously severely immunocompromised HIV-infected patients treated with long-term HAART who had achieved increased CD4 T-cell counts and complete suppression of HIV viraemia. We examined expression of CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and intracellular perforin by CD4 and CD8 lymphocytes from 25 highly selected HIV-infected patients [nadir CD4 T-cell counts <50 cells/microL, >4 years on HAART and >6 months of complete viral suppression (<50 HIV-1 RNA copies/mL)] and 18 HIV-seronegative age- and sex-matched controls. HIV-infected patients had lower percentages of CD28-expressing CD4 lymphocytes and higher percentages of CTLA-4-expressing CD4 lymphocytes than controls. The percentage of CTLA-4-expressing CD4 lymphocytes correlated inversely with that of CD28-expressing CD4 lymphocytes. The proportion of CD4 lymphocytes expressing perforin was generally low. However, more HIV-infected patients than controls had >1% of CD4 lymphocytes expressing perforin [11 of 25 (44%) vs. one of 18 (5.5%)]. The percentage of CD8 lymphocytes expressing perforin did not differ between HIV-infected patients and controls. Amongst HIV-infected patients, the percentage of perforin-expressing CD8 lymphocytes correlated inversely with nadir but not current CD4 T-cell count. Expression of CD28, CTLA-4 and perforin by CD4 lymphocytes remain dysregulated in HIV-infected patients with previous severe immunodeficiency, despite increased CD4 T-cell counts and control of HIV viraemia by HAART.

Detection and quantification of proviral HIV-1 184M/V in circulating CD4 + T cells of patients on HAART with a viremia less than 1000 copies/ml

Background Highly active anti-retroviral therapy (HAART) effectively reduces HIV replication but does not completely hinder it. Sub-optimal therapy leads to HIV resistance to the drugs administered. However, the role of low-level viremia (viral-load less than 1000 copies/ml) on mutation genesis and incorporation of resistant forms in the long-lived CD4 + T cellular DNA compartment is not clear. Objective To investigate the relationship between lamivudine associated mutant-type 184V and the wild-type 184M proviral forms in the circulating CD4 + T cells of patients and low-level viremia. Study design Cross-sectional study of 50 patients on long-term HAART, with a viremia of less than 1000 copies/ml. Patients were stratified into three groups; on lamivudine, group I (viral load <20 copies/ml), group II (viral load 20–1000 copies/ml) and as lamivudine experienced, group III (viral load <1000 copies/ml). 184M and 184V proviral HIV-1 was detected and quantified by a specific and sensitive assay combining a TaqMan real-time PCR analysis with the amplification-refractory mutation system (ARMS) principle. Results Fifty-six percent of patients with low-level viremia had 184V in the CD4 + T cellular DNA compartment as compared to only 8% in those with undetectable viremia. The presence of 184V was significantly associated with a higher viral load ( P = 0.001). Patients with low-level viremia without 184V in the CD4 + T cellular DNA compartment, had a median plasma viral load of 135 copies/ml, while patients harbouring 184V had a median viral load of 498 copies/ml ( P = 0.006). No significant differences between the groups were observed in proviral HIV-1 DNA load. Conclusions The frequency of the 184V mutation was significantly lower, in the CD4 + T cellular compartment of patients with a viral load of less than 20 copies/ml as compared to patients with a viremia of 20–1000 copies/ml. Viremia, sustained below 20 copies/ml may prevent the appearance of 184V mutation in this reservoir and therefore should be the objective of treatment.

Gender differences in clinical progression of HIV-1-infected individuals during long-term highly active antiretroviral therapy

To assess gender differences in the long-term clinical, virological and immunological outcomes during highly active antiretroviral therapy (HAART). This longitudinal observational multicentre study followed 2460 HIV-infected patients who had begun a protease inhibitor-based regimen for a median period of 43 months. Outcome measures were virological suppression (< 500 copies/ml), confirmed virological rebound after suppression, and death or new AIDS-defining illness (ADI). At baseline, 690 female patients (28.0%) had significantly lower age, higher prevalence of heterosexual contact and lower prevalence of intravenous drug use as risk factors for HIV infection compared with males. Furthermore, females had a lower number of AIDS-defining illnesses, higher CD4 cell counts and lower viral loads. No gender differences were reported in terms of proportion of patients achieving viral suppression or exhibiting rebound after achieving viral suppression. Female patients experienced reduced clinical progression during follow-up compared with males (P = 0.008) by Kaplan-Meier analysis; however this difference was not significant in an adjusted analysis. In a multivariate model, the interaction between gender and risk factor for HIV or viral load showed that female drug users and female patients with a baseline HIV RNA viral load of 10(4)-10(5) copies/ml had a favourable clinical outcome compared with males (P = 0.035 and P = 0.015, respectively). No differences were found between genders in terms of virological and immunological outcomes during long-term HAART. Nevertheless, a lower risk of clinical progression was reported among female patients with intermediate baseline viral load than in males.

Partial immune reconstitution following highly active antiretroviral therapy: can adjuvant interleukin-2 fill the gap?

Highly active antiretroviral therapy (HAART) induces a substantial control of HIV viral replication, but it allows for only a partial immune reconstitution, thus prompting the rationale for the adjuvant use of immunomodulants. Based on its in vitro action as a major T cell growth factor, interleukin (IL)-2 has now been extensively investigated for its potential to correct the HIV-driven immune deficiencies, possibly translating into immunological control over HIV infection. Specific immunological end points have thus far been addressed within extensive Phase I/II trials, disclosing a broad insight into several aspects of the IL-2-mediated immune reconstitution allowing for interesting clinical speculation. Indeed, preliminary results indicate that adjuvant IL-2 induces a significant CD4 cell rescue in patients with no immune recovery following long-term HAART, thus standing as a valid and safe therapeutic option for these patients. Furthermore, in these patients, the IL-2-mediated immune reconstitution is characterized by a rise in both peripheral turnover and de novo T cell synthesis, with reversion of the skewed HIV-driven immunophenotypic pattern, a substantial increase in IL-7 production and in several markers of immune function. Combined, these findings indicate IL-2 has a beneficial effect in correcting the severe disruption in T cell homeostasis induced by HIV, through the interaction with T cells and cytokine microenvironment. However, whether or not these immunological effects translate into an actual immunological competency and therefore clinical benefit, still awaits demonstration from ongoing large, controlled clinical studies.