CD30 as a therapeutic target in adult haematological malignancies: Where are we now?

CD30 is a transmembrane protein from the tumour necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms. CD30 is a particularly interesting treatment target because its levels are high in tumours but low in healthy tissues. Several therapeutic strategies targeting CD30 have been developed, including monoclonal antibodies, conjugated antibodies (combination of brentuximab vedotin with chemotherapy or immunotherapy), bispecific antibodies and cell and gene therapies, such as anti-CD30 CAR-T cells in particular. We briefly review the biology of CD30 which makes it a good therapeutic target, and we describe all of the anti-CD30 therapies that have emerged to date.

Comparison of HIV-Infected and Noninfected Patients Undergoing Bariatric Surgery: The ObeVIH Study.

OBJECTIVE: The aim of this study was to compare clinical characteristics and adipose/liver tissue histology analysis in HIV-infected and HIV-uninfected subjects undergoing bariatric surgery. DESIGN: This was a cross-sectional study of HIV-infected subjects undergoing single-port sleeve gastrectomy with prospective enrolment and frequency age (±5 years), sex, and body mass index (BMI, ± 5 kg/m2) matched on HIV-uninfected subjects. METHODS: This study was conducted at a single clinical site at Pitié-Salpêtrière hospital-Paris-France comprising 19 HIV-uninfected and 21 HIV-infected subjects with plasma VL < 20 copies/mL, all with a BMI > 40 kg/m2 or >35 kg/m2 with comorbidities. Histology of subcutaneous and visceral abdominal adipose tissue (SCAT/VAT) and liver biopsies was collected during single-port sleeve gastrectomy. Outcomes included anthropometric characteristics, comorbidities, cardiovascular parameters, adipose tissue, and liver histology. RESULTS: The age of HIV-infected participants was (median, interquartile range IQR) 48 y (42-51), with 76.2% females, a BMI of 41.4 kg/m2 (37.3-44.4), an antiretroviral duration of 16 y (8-21), current integrase strand transfer inhibitor (INSTI)-based regimen in 15 participants and non-INSTI regimen in 6 participants, and a CD4 count of 864/mm3 (560-1066). The age of controls was 43 y (37-51), with 78.9% females and a BMI of 39.2 kg/m2 (36.3-42.6). Anthropometric characteristics, comorbidities, and cardiovascular parameters did not differ according to HIV status and INSTI treatment. The number of macrophage crown-like structures in SCAT was lower in INSTI-treated participants than in HIV-uninfected participants (P = 0.02) and non-INSTI-treated HIV-infected subjects (P = 0.07). Hepatic steatosis and liver disease severity global score were lower in INSTI-treated participants than in non-INSTI-treated HIV-infected participants (P = 0.05 and P = 0.04, respectively). CONCLUSIONS: HIV-infected and HIV-uninfected subjects undergoing bariatric surgery presented a similar profile regarding anthropometric measures, cardiovascular parameters, and comorbidities. However, INSTI-treated participants presented milder SCAT and liver alterations than non-INSTI-treated participants.

Routine screening for HIV, hepatitis B virus and hepatitis C virus in individuals undergoing oral and maxillofacial surgery.

OBJECTIVES: Given the effectiveness of treatment of HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, there are considerable benefits associated with determining HIV/HBV/HCV status. We evaluated the feasibility and acceptability of systematic screening and subsequent care in an oral and maxillofacial surgery department. METHODS: The anaesthesiologists proposed screening for HIV, HBV and HCV to all individuals of unknown infection status undergoing surgery between 19 April 2016 and 19 April 2017. The endpoints were the rates of test offer, acceptance/refusal and new diagnoses. Seropositive individuals were referred to infectious disease specialists. Associations between age, sex or surgery type and test offer (eligible individuals) or acceptance/refusal (those offered testing) were investigated. RESULTS: Of the 1407 individuals attending the department, 1322 were eligible for inclusion in the study. Testing was proposed to 899 individuals [68%; 95% confidence interval (CI) 65-71%], 831 of whom accepted the offer (92.4%; 95% CI 90.5-94.1%). Results were obtained for 787 individuals (41 samples were uncollected and three were invalid). Age was the only factor associated with test offer in multivariable analysis [odds ratio (OR) 0.90; 95% CI 0.84-0.97, per additional 10 years], and no factor was associated with acceptance. Of the five, three and eight individuals testing positive for HIV, HBV and HCV, four, two and one patient, respectively, reported prior knowledge of seropositivity. The new diagnosis rate was 0.13% (95% CI 0-0.7%) for HIV and HBV, and 0.89% (95% CI 0.36-1.82%) for HCV [three positive polymerase chain reaction (PCR) tests]. All individuals newly diagnosed with HIV or HCV infection received specific antiviral treatment. CONCLUSIONS: Rates of screening offer and acceptance were high. Substantial screening resources are required to decrease the impact of the hidden epidemics of HIV, HBV and HCV infections.

Anaplastic Kaposi's sarcoma: 5 cases of a rare and aggressive type of Kaposi's sarcoma.

BACKGROUND: Anaplastic Kaposi's sarcoma (KS) is a rare form of KS characterized clinically by the development of a tumour mass with unusual local aggressiveness and histologically by a specific architecture and cytological morphology. A very small number of limited series in endemic countries have established characteristics common to these anaplastic forms of KS. We present five patients with an anaplastic form in a context of KS ongoing for several years in a non-endemic country. MATERIALS AND METHODS: We collected 5 cases of anaplastic KS followed in our department over a period of 20years. We describe the main developmental, clinical, virological and histological features. RESULTS: The cases involved 4 men and 1 woman whose mean age at diagnosis of anaplastic KD was 70years, with an average time of 25years between initial diagnosis of KD and anaplastic transformation. Our patients were all treated with chemotherapy and/or radiotherapy (RT) prior to diagnosis of anaplastic transformation. All patients had a tumour mass of the lower limbs developing in classically indolent KS with associated chronic lymphoedema. Progression was very aggressive locally with deep invasion of the soft tissues as well as osteoarticular involvement, without visceral dissemination. At present, three patients are dead, one patient is showing partial response, and one patient is in locoregional progression. Diagnosis of the disease was based on histopathological findings. The tumour cells were undifferentiated, pseudo-cohesive, and chiefly organized in sheets. The mitotic count was high (27 mitoses per 10 fields at high magnification). Necrosis was constant. DISCUSSION: To our knowledge, this is the first series describing anaplastic Kaposi's sarcoma in a non-endemic country. The severity of the prognosis, despite the absence of visceral dissemination, is related to the local aggressiveness of anaplastic KS and to its resistance to radiotherapy and chemotherapy, with amputation being required in certain cases.

Expression pattern of the CXCL12/CXCR4-CXCR7 trio in Kaposi sarcoma skin lesions.

BACKGROUND: Recent studies have independently implicated the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, in the pathophysiology of Kaposi sarcoma (KS). OBJECTIVES: We investigated whether the CXCL12/CXCR4-CXCR7 protein trio could constitute KS biomarkers. METHODS: Endothelial and spindle cells positive for CXCL12/CXCR4-CXCR7, human herpesvirus-8 latency-associated nuclear antigen (LANA), Ki67 antigen (proliferation) and vascular endothelial growth factor (VEGF) were quantitated in skin lesions from patients with AIDS-associated KS, patients with classic KS and patients with angiomas, using immunohistochemistry and quantitative image analysis (16, 21 and 20 skin lesions, respectively). Plasma CXCL12 concentrations were measured by enzyme-linked immunosorbent assay from 20 patients with AIDS-KS, 12 HIV-infected patients without KS and 13 healthy donors' samples. RESULTS: Cells positive for CXCL12, CXCR4, CXCR7, LANA, Ki67 and VEGF were significantly enriched in patients with AIDS-associated KS and classic KS vs. angiomas (P < 0·001), and in nodular vs. macular/papular KS lesions (P < 0·05). CXCL12, CXCR4 and CXCR7 detection correlated with LANA, Ki67 and VEGF detection (r > 0·4; P < 0·05). However, plasma CXCL12 concentrations did not differ between patients with AIDS-associated KS, HIV-infected patients without KS, and healthy donors. CONCLUSIONS: The CXCL12/CXCR4-CXCR7 trio is upregulated in KS and correlates with KS pathophysiological markers and the severity of skin lesions. Histological assessment of the CXCL12 axis could serve as a valuable biomarker for KS diagnosis and progression.

Soluble biomarkers of immune activation and inflammation in HIV infection: impact of 2 years of effective first-line combination antiretroviral therapy.

OBJECTIVES: The aim of the study was to assess the impact of rapid and sustained viral control produced by combination antiretroviral therapy (cART) on HIV-associated immune activation and inflammation. METHODS: In this longitudinal observational study, we examined changes in interleukin-6 (IL-6), interferon-γ-inducible protein-10 (IP-10), monokine induced by interferon-γ (MIG) and soluble CD14 (sCD14) levels during 2 years of effective first-line cART. Biomarker levels before and after cART were compared with those observed in healthy subjects, using the Wilcoxon signed rank test. Elevated biomarker levels were defined with respect to values for healthy subject (mean + 2 standard deviations). Factors associated with persistently elevated biomarker levels after 2 years of cART were identified by logistic regression. RESULTS: We included in the study 139 patients with a median HIV-1 RNA level of 4.8 log10 HIV-1 RNA copies/mL and a median CD4 cell count of 294 cells/µL at cART initiation [day 0 (D0)]. At D0, all biomarker levels were higher than in healthy subjects (P < 0.05). After 2 years of cART, IL-6, IP-10 and MIG levels fell significantly, by a median of 0.54, 420 and 1107 pg/mL, respectively (all P < 0.001), and were no longer elevated in > 75% of patients. In contrast, sCD14 levels did not change significantly (0.18 × 10(6) pg/mL; P = 0.102) and remained elevated. Older age was associated with elevated levels of IP-10 [odds ratio (OR) 1.60 per 10 years older; P = 0.047] and MIG (OR 1.92 per 10 years older; P = 0.007) after 2 years of cART. CONCLUSIONS: The rapid and sustained viral suppression produced by first-line cART reduced IL-6, IP-10 and MIG to normal levels, while sCD14, a marker of monocyte activation, remained elevated. High levels of IP-10 and MIG tended to persist in older patients.

Efficacy of raltegravir switching strategies in HIV-infected patients with suppressed viraemia according to the genotypic sensitivity score.

BACKGROUND AND PURPOSE: The lack of antiretroviral (ARV) backbone activity associated with raltegravir has been proposed as the main explanation for virological relapse observed in patients with undetectable viraemia who are switched from a ritonavir-boosted protease inhibitor (PI) to raltegravir. However ARV activity remains difficult to assess in this context. The aim of our study was to precisely assess the ARV backbone activity in patients with undetectable viraemia who underwent raltegravir switching strategies and to evaluate the efficacy of such switching strategies based on the genotypic sensitivity score (GSS). METHODS: Patients with a plasma human immunodeficiency virus type 1 (HIV-1) RNA level of <50 copies/mL on a stable two ARV-class regimen were enrolled if they switched one of their ARV drugs to raltegravir 400 mg twice daily. The GSS was calculated using a genotyping test performed on the HIV-1 RNA of the last plasma measurement with a HIV-1 RNA level of >50 copies/mL before the switch and on the results of all previous genotyping tests. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24. RESULTS: Fifty-six patients were enrolled in this study. The proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24 was 92.9 % (range 83.0-97.2 %) in the intent-to-treat analysis and 98.1 % (90.0-99.7 %) in per-protocol analysis. When the backbone was fully active, the proportion was 100.0 % (86.7-100.0 %) at week 24 and week 48 in the per-protocol analysis. We observed a decrease in plasma total cholesterol and triglycerides of -12.7 % (p = 0.005) and -26.5 % (p = 0.001), respectively. CONCLUSIONS: Raltegravir switching strategies are effective when the associated backbone is fully active according to the GSS. In the context of undetectable viraemia, where ARV activity remains difficult to assess, the determination of the GSS requires the entire ARV history of the patient and all previous HIV-RNA genotyping test results.

Human herpesvirus 8 (HHV8) transmission and related morbidity in organ recipients.

The aims of the study were to assess the risk of HHV8 transmission resulting from organ transplantation, and related morbidity in liver, heart and kidney transplant recipients. Donor and recipient serologies were screened between January 1, 2004 and January 1, 2005 using HHV8 indirect immunofluorescence latent assay (latent IFA) and indirect immunofluorescent lytic assay (lytic IFA). Recipients negative for latent IFA with a donor positive for at least one test were sequentially monitored for HHV8 viremia and underwent serological tests over a period of 2 years. The results showed that among 2354 donors, HHV8 seroprevalence was 9.9% (lytic IFA) and 4.4% (latent IFA). A total of 454 organ recipients (281 renal, 116 liver and 57 heart) were monitored over a 2-year period. Seroconversion was observed in 12 patients (cumulative incidence 28%) whose donor had positive latent IFA and in 36 patients (cumulative incidence 29%) whose donors were positive only for lytic IFA, without differences across types of transplants. Positive HHV8 viremia was detected in only 4 out of 89 liver transplant recipients during follow-up and not in recipients of other types of transplant. Two liver transplant recipients and one kidney transplant recipient developed KS. In conclusion, although HHV8 transmission is a frequent event after organ transplantation, HHV8-related morbidity is rather rare but can be life threatening. Donor screening is advisable for monitoring HHV8 seronegative liver transplant recipients.

Resistance profiles of emtricitabine and lamivudine in tenofovir-containing regimens.

OBJECTIVES: To compare the frequency of the selection of the M184V/I resistance mutation in HIV-infected patients who experienced virological failure while receiving emtricitabine (FTC) or lamivudine (3TC), administered with tenofovir disoproxil fumarate (TDF) and either efavirenz (EFV) or a ritonavir-boosted protease inhibitor (PI; lopinavir or atazanavir). METHODS: Patient data held at two clinical centres in France were analysed retrospectively. Eligible patients had experienced virological suppression (plasma HIV RNA <200 copies/mL) for ≥ 6 months before experiencing their first virological failure (at least two measurements of plasma HIV RNA ≥ 200 copies/mL). RESULTS: Of the 880 patients eligible for the study, 278 patients had experienced virological failure while receiving FTC + TDF + ritonavir-boosted PI, 257 while receiving FTC + TDF + EFV, 178 while receiving 3TC + TDF + EFV and 167 while receiving 3TC + TDF + ritonavir-boosted PI. Proportions of patients harbouring the M184V/I mutation were 24% (n = 62) for those who received FTC + TDF + EFV versus 51% (n = 91) for 3TC + TDF + EFV (P < 0.0001; Fisher's exact test); proportions were 11% (n = 30) for FTC + TDF + ritonavir-boosted PI versus 22% (n = 37) for 3TC + TDF + ritonavir-boosted PI (P = 0.002; Fisher's exact test). The use of lamivudine versus emtricitabine (P = 0.001), non-nucleoside reverse transcriptase inhibitors versus ritonavir-boosted PIs (P = 0.01) and the level of viral load at the time of virological failure (P = 0.01) were associated with selection of the M184V/I mutation (logistic regression analysis). CONCLUSIONS: Emtricitabine and lamivudine showed differing resistance profiles when administered in combination with tenofovir disproxil fumarate and either efavirenz or a ritonavir-boosted PI. The prevalence of the M184V/I resistance mutation was significantly lower in patients who received emtricitabine and tenofovir disoproxil fumarate than in those who received lamivudine and tenofovir disoproxil fumarate.

[Primary effusion lymphoma in two kidney transplant recipients]. / Lymphome des séreuses chez le transplanté rénal: deux cas.

BACKGROUND: Primary effusion lymphoma (PEL) is a highly malignant non-Hodgkin lymphoma associated with Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 infection (KSHV/HHV-8). It is chiefly seen in HIV patients and is rare in transplant recipients, possibly going unrecognized. OBSERVATION: We describe two male kidney transplant recipients, aged 47 and 51 years, followed for Kaposi's sarcoma in skin, lymph nodes, gastrointestinal (GI) tract and lung whose disease was poorly controlled by sirolimus and chemotherapy. Recurrent pleural effusion contrasted with reduction of cutaneous Kaposi lesions. KHSV viral loads were negative or very low in plasma, were negative or very low, whereas those in pleural effusion were high. Lymphoma cells were discovered only seven to nine months after the initial effusion despite repeated needle biopsies. In one patient, tumour cells were co-infected with Epstein-Barr virus. CONCLUSION: The contrast between a very low KHSV viral load in plasma and a very high viral load pleural effusion should alert physicians and prompt suspicion of PEL in Kaposi's sarcoma patients with recurrent serous effusion. The potential inhibitory role of sirolimus on PEL progression is discussed.

The impact of preexisting or acquired Kaposi sarcoma herpesvirus infection in kidney transplant recipients on morbidity and survival.

The impact of preexisting or acquired Kaposi sarcoma herpesvirus (KSHV) infection in kidney transplant recipients was evaluated in a prospective study. Serum collected from kidney donors and recipients before transplantation were tested for antibodies against KSHV latent nuclear antigen. Three groups of recipients were defined: group A (KSHV+), group B (KSHV-, KSHV+ donor) and group C (donor and recipient KSHV-). Blood was collected from recipients, every 3 months for 3 years, for KSHV viremia (groups A and B), quantitative (group A) and qualitative serology (group B). Data of group C recipients were extracted from a French database. The prevalence of KSHV antibodies was 1.1% in donors and 3.2% in recipients. There were respectively 161, 64 and 4744 recipients in groups A, B and C. In group A, 13% developed Kaposi's sarcoma (KS). Age >53.5 years (p = 0.025) and black skin (p = 0.0054) were associated with KS development. In group B, three recipients developed clinical manifestations related to KSHV infection. There was no difference in terms of survival and graft loss between the three groups. In conclusion, although kidney recipients should be aware of the additional risk of KSHV morbidity, KSHV+ recipients should not be systematically excluded from kidney transplantation.

Detection of human herpesviruses HHV-6, HHV-7 and HHV-8 in whole blood by real-time PCR using the new CMV, HHV-6, 7, 8 R-gene kit.

Human herpesviruses 6 (HHV-6), 7 (HHV-7) and 8 (HHV-8) are lymphotropic herpesviruses that may cause opportunistic diseases in immunosuppressed patients such as transplant or AIDS patients. The new commercial CMV HHV-6, 7, 8 R-gene kit (Argene, Varilhes, France) for the simultaneous quantitation of HHV-6 and qualitative detection of HHV-7 and HHV-8 was evaluated using whole blood samples (respectively, n=175, 100 and 161) and using different extraction and real-time PCR platforms in two Centers A and B. In comparison with HHV-6 in-house real-time PCR the commercial kit showed agreements of 96% (n=75) and 85% (n=100) in A and B, respectively, with significant Spearman's correlation between both techniques (in A: r=0.97 [p<0.001]; in B: r=0.70 [p<0.001]). The Bland-Altman test results and prospective monitoring of patients confirmed the accuracy of these HHV-6 real-time PCR techniques. The agreement between the in-house HHV-7 PCR and commercial kit was of 86% (n=100). In comparison with in-house HHV-8 real-time PCRs, the commercial kit showed agreements of 100% (n=61) and 93.7% (n=96) in A and B, respectively. These results demonstrate that the new commercial CMV HHV-6, 7, 8 R-gene kit was an efficient and reliable tool for the diagnosis of herpesvirus 6, 7, 8 infections.

KSHV after an organ transplant: should we screen?

The incidence of Kaposi sarcoma (KS) related to Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) after organ transplantation is 500-1000 times greater than in the general population, and its occurrence is associated with immunosuppressive therapy. The reported incidence of posttransplant KS ranges from 0.5% to 5%, depending on the patient's country of origin and the type of organ received, mainly after renal transplantation. Posttransplant KS is caused by two possible mechanisms: KSHV reactivation in patients who were infected before the graft and KSHV contamination from the infected organ's donor to the recipient. KSHV reactivation appears to play a greater role in the risk of KS than incident infections. However, some studies, with findings based not only on serological data but also on molecular tracing of the viral infection, have shown that organ-related transmission of KSHV could be more common than previously thought and associated in some cases with severe KSHV-related disease. Precise estimates of KSHV seroprevalence in the organ donor and recipient populations in different countries are lacking. However, studies have reported seroprevalences among donors and recipients that are similar to those among the general population of the country considered. Many studies have suggested the potential utility of screening of KSHV antibodies among organ donors and recipients. However, to date the results of these studies have argued in favor of KSHV screening, even in low-KSHV infection prevalence countries, not to exclude the graft but to have the KSHV status information in order to have the opportunity to monitor, clinically and biologically, patients at risk for KSHV-related disease development. The detection of KSHV antibodies could be done in the days after the transplantation and the results transmitted to the physicians retrospectively. In conclusion, the question of screening donors and recipients for KSHV, even in low-KSHV infection prevalence countries, is still debated, and prospective studies are needed to evaluate the benefit of pre- and posttransplantation strategies.

[HHV8, Kaposi's disease and organ transplantation: should we screen ?] / HHV8, maladie de Kaposi et transplantation d'organe : devrions-nous procéder à un dépistage ?

The incidence of Kaposi's sarcoma (KS) related to Kaposi's sarcoma associated herpesvirus (KSHV/HHV-8) after organ transplantation is 500-1 000 times greater than in the general population and its occurrence is associated with immunosuppressive therapy. The reported incidence of post-transplant KS ranges from 0.5 % to 5 %, depending on the patient's country of origin and the type of organ received, mainly following renal transplantation. Post-transplant KS is caused by two possible mechanisms: KSHV reactivation in patients who were infected before the graft and KSHV contamination from infected organs donor to the recipient. KSHV reactivation appears to play a greater role on the risk of KS than incident infections. However, some studies, with findings based not only on serological data but also on molecular tracing of the viral infection, have shown that organ-related transmission of KSHV could be more common than previously thought and associated in some cases with severe KSHV related disease. Precise estimates of KSHV seroprevalence in the organ donor and recipient populations in different countries are lacking. However, studies have reported seroprevalences among donors and recipients that are similar to those among the general population of the country considered. Many studies have suggested the potential interest of screening of KSHV antibodies among organ donors and recipients. However, to date the results of these studies have argued in favor of KSHV screening, even in low KSHV infection prevalence countries, not to exclude the graft but to have the KSHV status information in order to have the opportunity to monitor, clinically and biologically, patients at risk to KSHVrelated disease development. The detection of KSHV antibodies could be done the days after the transplantation and the results transmitted to the physicians retrospectively. In conclusion, the question of screening donors and recipients for KSHV, even in low KSHV infection prevalence countries, is still debated and prospective studies are needed to evaluate the benefit of pre and posttransplantation strategies.

Reversibility of pulmonary arterial hypertension in HIV/HHV8-associated Castleman's disease.

The present study describes a case of pulmonary arterial hypertension (PAH) associated with multicentric Castleman's disease in a patient infected with HIV type 1 and human herpes virus 8. Therapy included highly active antiretroviral therapy, warfarin, diuretics, continuous i.v. epoprostenol and 12-monthly pulses of cyclophosphamide. The patient's condition improved dramatically with complete reversibility of PAH, allowing weaning of continuous i.v. epoprostenol therapy. After 5 yrs, both Castleman's disease and PAH have not relapsed. This supports the hypothesis that control of inflammation and retroviral replication may be of interest in the context of PAH, complicating the course of an inflammatory condition associated with viral infection. In conclusion, further studies should help in characterising the best candidates for anti-inflammatory treatment in the setting of pulmonary arterial hypertension.

Persistent low viral load on antiretroviral therapy is associated with T cell-mediated control of HIV replication.

BACKGROUND: It is unclear how stable low-level viral replication and CD4 cell numbers can be maintained under highly active antiretroviral therapy (HAART). This study was designed to analyse whether HIV-specific responses in stable partially controlled patients during antiretroviral therapy (ART) differ from those observed in complete HAART failure and whether they contribute to the control of viral load (VL). METHODS: Three groups of patients were selected according to plasma HIV RNA levels during 18 months of ART: persistently low VL (LoVL; HIV RNA <10,000 copies/ml; n = 28), undetectable VL (UnVL; HIV RNA <200 copies/ml; n = 29) and high VL (HiVL; HIV RNA >10,000 copies/ml; n = 14). T-cell responses were studied using lymphoproliferative and interferon (IFN)-gamma-ELISpot assays against HIV-p24, -gp160, recall antigens, and 15 pools of HIV-(Gag + RT) peptides. RESULTS: Frequencies of IFN-gamma-producing CD4 T cells against HIV-p24 were higher in LoVL than in UnVL or HiVL groups [median, 131, 47 and 23 spot-forming cells (SFC)/1 x 10 peripheral blood mononuclear cells (PBMC), respectively; P = 0.012 and P = 0.047]. Lymphoproliferative responses to HIV-p24 and recall antigens were similar in LoVL and UnVL groups but lower in HiVL (P = 0.004). Frequencies of HIV-specific CD8 T cells were higher in LoVL than in UnVL (1340 versus 410 SFC/1 x 10 PBMC; P = 0.001). They correlated negatively with VL in the LoVL and HiVL (r, -0.393, P = 0.039 and r, -0.643, P = 0.024, respectively) and positively correlated with anti-HIV CD4 cell frequencies in the LoVL group only (r, 0.420; P = 0.026). CONCLUSION: Persistently low viral replication (<10,000 copies/ml) during ART stimulates high frequencies of HIV-specific CD4 and CD8 T cells compared to full virus suppression or complete ART failure. The association of high anti-HIV activity with large numbers of HIV-specific CD8 T cells contribute to the control of viral replication.