Short communication: Does interleukin-28B single nucleotide polymorphisms influence the natural history of hepatitis B?

Single nucleotide polymorphisms (SNP) nearby the IL28B gene have been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in both monoinfected and HIV-coinfected patients. However, its impact on spontaneous clearance of HBV (the pathogenesis of which is also related to interferon) is less known. A case-control study was performed. Cases were 49 HIV(+) patients with chronic hepatitis B (HBsAg(+) for more than 6 months) who had been genotyped for the rs12979860 SNP (protective CC genotype). One control for each case was chosen among HIV patients with anti-HBs and anti-HBc. Controls were matched for gender and coinfection with HCV. Most patients were male (90%) and the median (IQR) age was 42.6 (39-46.7) years. Eighteen (36.7%) were also coinfected by HCV. Among HBsAg(+) patients, 19 (41.3%) were HBeAg(+) and 13 (26.5%) were also infected with hepatitis delta (HDV). No differences were found in the distribution of the CC genotype between patients with chronic hepatitis B and those who spontaneously cured hepatitis B: 59.2% vs. 44.9%; p=0.3. Thus, the interleukin-28B (IL-28B) genotype does not seem to have a role in the development of chronic hepatitis B among HIV-infected patients.

HCV-specific T-cell responses in HIV/hepatitis C virus-coinfected patients on highly active antiretroviral therapy are comparable to those observed in hepatitis C virus-monoinfected individuals.

BACKGROUND: Cellular responses against hepatitis C virus (HCV) are impaired in HIV/HCV-coinfected patients showing uncontrolled viral replication and immune suppression. Very few studies have explored to what extent HCV-specific response improves as a consequence of control of HIV replication by highly active antiretroviral therapy. We compared HCV-specific T-cell responses between HIV/HCV-coinfected patients, showing complete viral suppression, and HCV-monoinfected patients. METHODS: HCV-specific T-cell responses were examined in 50 interferon-naive patients with chronic hepatitis C: 27 HCV-mono-infected and 23 HIV/HCV-coinfected on highly active antiretroviral therapy and undetectable HIV load. Production of interferon-γ and tumor necrosis factor-α was simultaneously measured in response to genotype-matched overlapping peptides spanning the whole HCV proteome by flow cytometry. Differences between groups were tested using nonparametric tests. RESULTS: More than half of patients presented CD4+ (60%) or CD8+ (57%) response to at least one HCV protein with no significant differences between both groups. Intensity and breadth of response were also similar between groups. The functional profile of response was represented, in both groups, mainly by monofunctional subsets, although there were some differences between CD4+ and CD8+ T-cell response. CD8+ response was mediated almost exclusively by monofunctional interferon-γ+ cells, whereas bifunctional interferon-γ+ tumor necrosis factor-α+ cells showed a moderate contribution to CD4+ response. Most of the CD8+ response was mediated by interferon-γ, whereas tumor necrosis factor-α was the highest contributor to CD4+ response. CONCLUSIONS: Our study demonstrates that in HIV/HCV-coinfected patients with maximal HIV suppression under highly active antiretroviral therapy, several characteristics of anti-HCV T-cell response are similar to those found in HCV-monoinfected patients, suggesting that control of HIV replication might improve HCV-specific T-cell response in HIV/HCV-coinfected patients.

Short communication: severe immune suppression in patients infected with R5-tropic HIV-1 strains is associated with increased gp120 net charge at variable regions.

CXCR4-tropic viruses have been associated with advanced immune suppression. However, 50% of patients with AIDS exclusively harbor CCR5-tropic viruses. The net charge at HIV-1 envelope gp120 variable regions was examined in 66 HIV-1-infected individuals with CCR5-tropic viruses, of whom 30 had less than 200 cells/mm(3). A positive net charge at gp120 variable regions was significantly associated with lower CD4 counts. Thus, the net charge at gp120 variable regions could influence HIV-1 disease progression in subjects with CCR5-tropic viruses.

Short communication: use of serum bilirubin levels as surrogate marker of early virological response to atazanavir-based antiretroviral therapy.

Given that atazanavir (ATV) increases bilirubin in an exposure-dependent manner, we tested whether bilirubin levels could be used as a surrogate of virological response to ATV-based regimens in 182 patients. Bilirubin increases of ≥0.7 mg/dl were independently associated with early virological response with an odds ratio of 5.2 (95% confidence interval 2.2-11.9). Total bilirubin, a nonexpensive, simple, and widely available parameter, might be used as a surrogate of virological response to ATV-based regimens, especially in areas with limited resources where HIV-RNA testing is not available.

Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is common in HIV-positive individuals and increases liver-related mortality. Nucleos(t)ide analogues with activity against both HBV and HIV are widely used in coinfected patients, but its long-term effect on liver disease is unknown. METHODS: Clinical outcomes, HBsAg and/or HBeAg clearance, and changes in liver stiffness were longitudinally evaluated retrospectively in all HIV-HBV-coinfected individuals followed at our institution. RESULTS: A total of 92 patients with HIV-HBV coinfection were identified, 19 of them superinfected with hepatitis delta virus. Their median time of follow-up was 35 months. Overall, 94% received lamivudine/emtricitabine and 82% tenofovir. Serum HBV-DNA was undetectable in 89%. Seven patients cleared serum HBsAg (2.6/100 patient-years), in four of them accompanied with anti-HBs seroconversion. Of note, two of them had hepatitis delta. Another 11 out of 42 HBeAg-positive patients cleared HBeAg (9/100 patient-years) and five of them experienced anti-HBe seroconversion. Liver decompensation and death occurred in eight (2.9/100 patient-years) and six (2.2/100 patient-years), respectively.At baseline, liver fibrosis was defined as null-mild (48%), moderate-advanced (28%) or cirrhosis (24%). At last visit, after a median of 40 months in 71 patients, 75% showed no changes, whereas improvement was recognized in 17% and worsening in 8%. CONCLUSION: Most HIV-HBV-coinfected patients treated with anti-HBV active nucleos(t)ide analogues experience an amelioration of liver fibrosis progression, with low rates of hepatic decompensation and death. Serum HBeAg or HBsAg seroconversion occurs at yearly rates of 9 and 2.6%, respectively, even in patients with delta hepatitis.

Simplification from protease inhibitors to once- or twice-daily raltegravir: the ODIS trial.

BACKGROUND: Raltegravir has demonstrated good antiviral activity and safety profile in twice-daily (bid) dosing. However, its long terminal elimination half-life might allow once-daily (qd) administration. METHODS: Consecutive HIV-infected individuals at our clinic under protease inhibitor (PI)-based regimens with plasma HIV-RNA <50 copies/mL for > 24 weeks were invited to replace PIs with raltegravir. Patients were randomly assigned to raltegravir 800 mg qd, 400 mg bid, or twice daily for the first 3 months and then once daily. RESULTS: A total of 222 patients completed 24 weeks of follow-up on raltegravir (149 once-daily arm, 35 twice-daily arm, and 38 twice-daily to once-daily arm). At inclusion, mean CD4+ count was 574±308 cells/µL. Within 24 weeks, 13 (5.9%) patients experienced virological failure: 12 (6.4%) in the once-daily arms, and 1 (2.9%) in the twice-daily arm (P = .18). The rate of virological failure was 16.2% (12/74) in patients with prior nucleoside reverse transcriptase inhibitor (NRTI) resistance but only 0.7% (1/148) in the rest (P < .001). CONCLUSION: A switch from PIs to raltegravir in HIV-infected patients with undetectable plasma HIV-RNA effectively sustains viral suppression, as long as prior NRTI resistance had not been selected. No significant differences were seen when comparing raltegravir twice daily or once daily in this context, although once-daily dosing tended to perform less well.

High sensitivity of specific genotypic tools for detection of X4 variants in antiretroviral-experienced patients suitable to be treated with CCR5 antagonists.

OBJECTIVES: Evaluation of the reliability of several V3-based genotypic predictors to infer viral tropism in patients infected with B and non-B strains of HIV-1. METHODS: Several genotypic tropism predictors were evaluated in plasma (RNA) samples from 198 HIV-1-infected patients, taking as gold standard the results of the phenotypic recombinant virus assay Phenoscript((R)). In addition, for 37 B subtype HIV-1 patients the phenotypic results from plasma samples were also compared with tropism predictions based on V3 amplification from paired peripheral blood mononuclear cells (PBMCs). RESULTS: A total of 150 paired genotypic/phenotypic results were obtained from plasma specimens. Concordance values ranged from 63% to 85%, depending on the genotypic algorithm used. The best predictors in terms of sensitivity/specificity to detect X4 variants were WebPSSM(X4/R5) (77%/87%), Geno2pheno(FPR) (=) (5%) (80%/77%) and an algorithm combining the '11/25' and 'Net charge' rules, termed Garrido's rule (80%/79%). The performance of genotypic predictors was better testing B than non-B clades. The overall sensitivity ranged from 28% to 94%, reaching 100% in subtype B antiretroviral-experienced patients using WebPSSM(SI/NSI), Geno2pheno(FPR) (> or =) (5%) and Garrido's rule. Conversely, the sensitivity when testing non-B subtypes was poorer, ranging from 17% to 67%. Interestingly, the correlation between genotypic and phenotypic results was better when testing PBMCs than plasma using all genotypic predictors. CONCLUSIONS: Genotypic tools based on V3 sequences may provide reliable information on HIV-1 tropism when testing clade B viruses, especially in antiretroviral-experienced patients. The sensitivity to detect X4 variants using genotypic tools may improve by testing proviral DNA instead of plasma RNA.

The benefit of simplification from tipranavir/ritonavir 500/200 bid to 500/100 bid guided by therapeutic drug monitoring.

Despite being among the most potent protease inhibitors, the use of tipranavir (TPV) is hampered by a high pill burden and frequent side effects compared with other boosted protease inhibitors. A total of 10 patients receiving TPV/ritonavir (TPV/RTV) 500/200 for longer than 6 months were randomized to stay on the same dosing schedule or switch to TPV/RTV 500/100. Although all patients on TVP/RTV 500/200 remained stable for the next 12 weeks, 3 out of 5 patients who switched doses experienced benefits in terms of reducing aminotransferases and total cholesterol. Fasting triglycerides were also reduced in 2 of them. Plasma HIV-RNA remained undetectable in all patients, despite the observed decline in TPV trough concentrations.

Plasma ribavirin trough concentrations at week 4 predict hepatitis C virus (HCV) relapse in HIV-HCV-coinfected patients treated for chronic hepatitis C.

The influence of ribavirin trough concentrations (RBV C(trough)) on the risk of hepatitis C virus (HCV) relapse was retrospectively analyzed in 99 HIV-HCV-coinfected patients who achieved end-of-treatment response with pegylated alpha interferon plus weight-based RBV. The independent predictors (odds ratio [OR] [95% confidence interval (CI)]) of HCV relapse were RBV plasma C(trough) of <2.5 microg/ml (4.5 [1.3 to 15.5]), baseline serum HCV RNA (2.5 [1.2 to 5.1]), and HCV genotype 1 or 4 (13.3 [2.6 to 66.7]). Monitoring of RBV C(trough) may permit early adjustment of RBV dosage to avoid HCV relapse.

[Malignancies in HIV infected patients: study of 139 cases]. / Tumores en pacientes con infección por el virus de la inmunodeficiencia humana: estudio de 139 casos.

BACKGROUND AND OBJECTIVE: Since the introduction of highly active antiretroviral therapy (HAART), the natural history of HIV infection has been altered by an increasing survival. Following this, neoplastic diseases have become more common in HIV positive patients. The purpose of this study was to describe the types of tumor, clinical features and prognosis of HIV infected patients with malignant diseases. PATIENTES AND METHODS: A descriptive study of epidemiological and clinical features was undertaken at Hospital Carlos III, in Madrid. Information was collected on age, sex, risk factors for HIV, HBV/HCV coinfection, malignancies, diagnosis of AIDS, viral load and CD4 cell counts at diagnosis, antiretroviral therapy and mortality. A total of 139 HIV-infected patients were identified who had at least one malignancy. Statistical analysis was performed using SPSS 15.0 package. RESULTS: Types of malignancy were Kaposi's Sarcoma (n=43, 30.9%); non-Hodgkin lymphoma (n=42, 30.2%); gynecologic malignancy (n=16, 11.5%); Hodgkin's disease (n=15, 10.8%); hepatocellular carcinoma (n=7, 5%) and others (n=16, 11.5%). Mean age at diagnosis was 40 years (IC 95% 38.51-1.50). Male/female ratio was 3.63. Patients with HBV or HCV coinfection were 1.4% and 35.3% respectively. Risk factor for HIV was MSM (n=64;46%), IDUs (n=48; 34.5%) and heterosexual (n=26; 18.7%). Viral load was undetectable in 27 cases (19.4%); CD4 cell count was<200 cell/mcl in 58 cases (41.7%). There were 77 (55.4%) patients on HAART when cancer was diagnosed. Mean time on HAART was 23.31 months. Ten patients (7.2%) developed a secondary tumor. Twelve years survival was 20%. CONCLUSIONS: Increased survival of HIV-infected patients receiving HAART makes it possible the development of secondary tumors and AIDS- unrelated malignancies, sometimes related to another virus.

El desafío de la nueva gripe A/H1N1 / The challenge of the new H1N1 influenza A

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Tumores en pacientes con infección por el virus de la inmunodeficiencia humana: estudio de 139 casos / Malignancies in HIV infected patients: Study of 139 cases

Fundamento y objetivos: Desde la introducción del tratamiento antirretroviral de gran actividad (TARGA), la historia natural de la infección por el virus de la inmunodeficiencia humana (VIH) se ha modificado, por lo que ha aumentado la supervivencia. Por esto, el diagnóstico de una enfermedad neoplásica es cada vez más frecuente en estos pacientes. El objetivo de este estudio es describir las características clínicas y el pronóstico de un grupo de pacientes infectados por VIH que desarrollan enfermedades tumorales. Pacientes y método: Se realizó un estudio descriptivo sobre las características clínicas y epidemiológicas en el Hospital Carlos III de Madrid. La información recogida incluía edad, sexo, factores de riesgo para el VIH, coinfección con virus de la hepatitis B o C, tumores, diagnóstico de sida, carga viral y recuento de CD4 en el momento del diagnóstico, tratamiento antirretroviral y mortalidad. Se identificaron 139 pacientes infectados por VIH, diagnosticados de, al menos, un tumor. El análisis estadístico se realizó con el programa estadístico SPSS 15.0. Resultados: Los tumores encontrados fueron sarcoma de Kaposi (n=43 [30,9%]), linfoma no hodgkiniano (n=42 [30,2%]), ginecológicos (n=16 [11,5%]), enfermedad de Hodgkin (n=15 [10,8%]), carcinoma hepatocelular (n=7 [5%]) y otros (n=16 [11,5%]). La edad media al diagnóstico fue de 40 atildemos (intervalo de confianza del 95%: 38,51¨C1,50). La proporción varón/mujer fue de 3,63. El porcentaje de pacientes coinfectados por virus de la hepatitis B o C fue del 1,4 y del 35,3%, respectivamente. Las conductas de riesgo más frecuentes para la adquisición del VIH fueron las relaciones homosexuales (n=64 [46%]), la drogadicción parenteral (n=48 [34,5%]) y las relaciones heterosexuales (n=26 [18,7%]). La carga viral era indetectable en 27 casos (19,4%); el recuento de CD4 era menor de 200 células/mm3en 58 casos (41,7%) (…) (AU)

Background and objective: Since the introduction of highly active antiretroviral therapy (HAART), the natural history of HIV infection has been altered by an increasing survival. Following this, neoplastic diseases have become more common in HIV positive patients. The purpose of this study was to describe the types of tumor, clinical features and prognosis of HIV infected patients with malignant diseases. Patientes and methods: A descriptive study of epidemiological and clinical features was undertaken at Hospital Carlos III, in Madrid. Information was collected on age, sex, risk factors for HIV, HBV/HCV coinfection, malignancies, diagnosis of AIDS, viral load and CD4 cell counts at diagnosis, antiretroviral therapy and mortality. A total of 139 HIV-infected patients were identified who had at least one malignancy. Statistical analysis was performed using SPSS 15.0 package. Results: Types of malignancy were Kaposi¡äs Sarcoma (n=43, 30.9%); non-Hodgkin lymphoma (n=42, 30.2%); gynecologic malignancy (n=16, 11.5%); Hodgkin¡äs disease (n=15, 10.8%); hepatocellular carcinoma (n=7, 5%) and others (n=16, 11.5%). Mean age at diagnosis was 40 years (IC 95% 38.51¨C1.50). Male/female ratio was 3.63. Patients with HBV or HCV coinfection were 1.4% and 35.3% respectively. Risk factor for HIV was MSM (n=64;46%), IDUs (n=48; 34.5%) and heterosexual (n=26; 18.7%). Viral load was undetectable in 27 cases (19.4%); CD4 cell count was<200 cell/mcl in 58 cases (41.7%). There were 77 (55.4%) patients on HAART when cancer was diagnosed. Mean time on HAART was 23.31 months. Ten patients (7.2%) developed a secondary tumor. Twelve years survival was 20%. Conclusions: Increased survival of HIV-infected patients receiving HAART makes it possible the development of secondary tumors and AIDS- unrelated malignancies, sometimes related to another virus (AU)

Use of different inhibitory quotients to predict early virological response to tipranavir in antiretroviral-experienced human immunodeficiency virus-infected patients.

Information about the relationship between pharmacological parameters and an early virological response to tipranavir (TPV) is scarce. Human immunodeficiency virus (HIV)-infected patients who had received TPV as part of a salvage regimen were analyzed retrospectively. A virological response was defined as a decline in the HIV RNA level of > or = 1 log unit or to <50 copies/ml between weeks 4 and 12 of therapy. The virtual inhibitory quotient (vIQ) was calculated as the ratio of the TPV plasma trough concentration (C(trough))/virtual change in the 50% inhibitory concentration. Three genotypic inhibitory quotients (gIQs) were calculated by using different TPV resistance mutation scores (from the International AIDS Society-USA [IAS-USA], Randomized Evaluation of Strategic Intervention in Multidrug-Resistant Patients with Tipranavir [RESIST], and Agence Nationale de Recherches sur le Sida et les Hépatites Virales [ANRS] trials). The sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and likelihood ratios for a positive result (LHR+) and a negative result (LHR-) [LHR+ = sensitivity/(1-specificity); LHR- = (1-sensitivity)/specificity] were calculated. A total of 57 HIV-infected patients were analyzed. A virological response was achieved by 77% of the patients. TPV resistance mutations, TPV C(trough), vIQs, and gIQs were all significantly associated with a virological response. The vIQ had the best PPV and NPV (97% and 78%, respectively). The values of the LHR+ were 7.8 for vIQ, 3.4 for the RESIST gIQ, 3.3 for the IAS-USA gIQ, 3.1 for the ANRS gIQ, 2.2 for TPV C(trough), and 1.3 for the IAS-USA and RESIST scores. The values of LHR- were 0 for the RESIST score, 0.07 for vIQ, 0.09 for the IAS-USA score, 0.27 for the RESIST gIQ, 0.32 for the IAS-USA gIQ, 0.37 for the ANRS gIQ, and 0.48 for TPV C(trough). HIV-infected patients who initiate a salvage regimen based on TPV may benefit from baseline drug resistance testing and TPV plasma concentration determination, as vIQ is the best predictor of a virological response.

Liver complications have reached a plateau as cause of hospital admission and death in HIV patients in Madrid.

Hospital admissions and deaths due to liver-related complications as result of chronic viral hepatitis are globally on the rise in HIV patients. However, a steady decline in liver-related hospitalizations and deaths has occurred at our HIV clinic in Madrid since year 2003. Hepatic complications are currently still responsible for 8.7% of all hospital admissions and one-third of in-hospital deaths, with hepatitis C virus infection by far the leading etiologic agent.

Design and validation of new genotypic tools for easy and reliable estimation of HIV tropism before using CCR5 antagonists.

BACKGROUND: Genotypic tools may allow easier and less expensive estimation of HIV tropism before prescription of CCR5 antagonists compared with the Trofile assay (Monogram Biosciences, South San Francisco, CA, USA). METHODS: Paired genotypic and Trofile results were compared in plasma samples derived from the maraviroc expanded access programme (EAP) in Europe. A new genotypic approach was built to improve the sensitivity to detect X4 variants based on an optimization of the webPSSM algorithm. Then, the new tool was validated in specimens from patients included in the ALLEGRO trial, a multicentre study conducted in Spain to assess the prevalence of R5 variants in treatment-experienced HIV patients. RESULTS: A total of 266 specimens from the maraviroc EAP were tested. Overall geno/pheno concordance was above 72%. A high specificity was generally seen for the detection of X4 variants using genotypic tools (ranging from 58% to 95%), while sensitivity was low (ranging from 31% to 76%). The PSSM score was then optimized to enhance the sensitivity to detect X4 variants changing the original threshold for R5 categorization. The new PSSM algorithms, PSSM(X4R5-8) and PSSM(SINSI-6.4), considered as X4 all V3 scoring values above -8 or -6.4, respectively, increasing the sensitivity to detect X4 variants up to 80%. The new algorithms were then validated in 148 specimens derived from patients included in the ALLEGRO trial. The sensitivity/specificity to detect X4 variants was 93%/69% for PSSM(X4R5-8) and 93%/70% for PSSM(SINSI-6.4). CONCLUSIONS: PSSM(X4R5-8) and PSSM(SINSI-6.4) may confidently assist therapeutic decisions for using CCR5 antagonists in HIV patients, providing an easier and rapid estimation of tropism in clinical samples.

Increase in serum bilirubin in HIV/hepatitis-C virus-coinfected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin.

Atazanavir use is associated with increases in serum bilirubin. Ribavirin, used to treat hepatitis-C infection, cause hemolysis and may worsen hyperbilirubinemia. We studied HIV/hepatitis-C virus-coinfected patients who initiated hepatitis-C therapy. Hyperbilirubinemia grade 3-4 increased from 9% to 45% after the start of hepatitis-C treatment in patients who used atazanavir concomitantly. Atazanavir use and hemoglobin (Hb) drops were predictors of increases in bilirubin. A substantial proportion of patients under atazanavir-therapy experienced significant hyperbilirubinemia and jaundice following initiation of hepatitis-C therapy.

Down-regulation of interleukin-7 receptor (CD127) in HIV infection is associated with T cell activation and is a main factor influencing restoration of CD4(+) cells after antiretroviral therapy.

BACKGROUND: Factors influencing the depletion of CD4(+) cells and the restoration of CD4(+) cells after antiretroviral therapy are not completely understood. Recently, attention has been paid to interleukin (IL)-7 and its receptor (CD127). We analyzed the influence of T cell activation and of suppression of viremia with antiretroviral therapy on this system, as well as its role in CD4(+) cell restoration after long-term antiretroviral therapy. METHODS: IL-7 levels and CD127 expression on several subsets of CD4(+) and CD8(+) T lymphocytes and the activation status (CD38) of these cells were examined at baseline and during 24 months of complete viral suppression under highly active antiretroviral therapy (HAART). RESULTS: A total of 42 individuals with human immunodeficiency virus (HIV) infection and 10 age-matched, uninfected control subjects were examined. Before HAART, IL-7 levels were increased and CD127 expression was decreased. Down-regulation of CD127 was mainly associated with T cell activation and reverted only partially after suppression of detectable plasma HIV RNA with HAART. In a multivariate analysis, CD127 expression on CD8(+) T cells was the main determinant of the extent of CD4(+) cell gains after successful HAART. CONCLUSIONS: The IL-7-CD127 system is impaired in HIV-infected patients. CD127 down-regulation is associated with T cell activation and with CD4(+) cell restoration after HAART.

HIV rebound after discontinuation of antiretroviral therapy increases and expands HIV-specific CD8+ responses but has no impact on its functionality.

A higher functionality of CD8(+) T cells might contribute to low-level HIV replication in long-term nonprogressors (LTNPs). However, the contrary could also be true, being the function of CD8(+) T cells modulated by HIV replication. We tested whether enhanced HIV replication following antiretroviral therapy interruption could modify the functional profile of HIV-specific CD8(+) responses. Production of MIP-1beta, IL-2, TNF-alpha, and CD107 expression by CD8(+) T cells in response to Gag and Nef optimal peptide pools was analyzed using polychromatic flow cytometry in nine HIV-infected individuals followed for 12 months after discontinuation of antiretroviral therapy. At baseline, CD8(+) T cell subsets with the greatest contribution to response were MIP-beta(+)TNF-alpha(-)IL-2(-)CD107(+) and MIP-beta(+)TNF-alpha(-)IL-2(-)CD107. Most responses were mediated by subsets expressing only one or two molecules. After 12 months of discontinuing antiretroviral therapy, no significant differences were observed in the functional profile of Gag- and Nef-specific CD8(+) responses. However, viral rebound induced a significant increase in the heterogeneity of Gag-specific CD8(+) responses. In summary, viral replication following discontinuation of antiretroviral therapy has no significant impact on qualitative aspects of HIV-specific CD8(+) responses. Thus, a higher functionality of CD8(+) responses does not seem to be the consequence of low-level virus replication.

No major differences in the functional profile of HIV Gag and Nef-specific CD8+ responses between long-term nonprogressors and typical progressors.

The mechanism explaining the failure of HIV-specific CD8(+) T cell responses to successfully control HIV replication remains elusive. A total of 83 drug-naive HIV-infected individuals, 27 of whom were long-term nonprogressors (LTNP), was examined. The ability of CD8(+) T lymphocytes to produce three different cytokines (MIP-1beta, TNF-alpha, IL-2) in response to HIV Gag and Nef peptides and to polyclonal stimuli and the ability of HIV-specific CD8(+) T cells to expand in vitro were evaluated by multiparameter flow cytometry. In response to polyclonal stimulation, LTNP presented significantly higher levels of several CD8(+) T cell subsets than progressors. While most patients presented detectable Gag and Nef-specific CD8(+) responses, no significant differences in any of the CD8(+) functional T cell subsets were recognized when comparing LTNP and progressors. HIV responses were dominated by cells producing only MIP-1beta or TNF-alpha, being similar in LTNP and progressors. However, expansion of HIV-specific CD8(+) T cells was more frequent in LTNP than progressors, especially for cells producing MIP-1beta. LTNP show higher levels of CD8(+) responses against polyclonal stimuli than progressors. However, HIV-specific CD8(+) responses do not differ between them except for a more preserved ability of cells from LTNP to expand in vitro.