Persistent Low-level Viremia Research Articles

High frequency of genotypic resistance in HIV‐1‐infected patients on highly active antiretroviral therapy with persistent low level viremia

BackgroundResistance is a major cause of virologic failure in HIV‐1‐infected patients; genotypic analyses optimize salvage therapy but technical constraints limit testing in plasma viral load (pVL) below 1000 copies/ml. Nevertheless a great amount of patients are failing therapy with a persistent low viral load, it is possible to obtain genotypic information at lower viremias although slight modifications are required during genotype standard procedures.ObjectiveTo assess genotypic resistance in HIV‐1‐infected patients with persistent low level viremia and virologic response after switching to genotype‐guided salvage therapy. To evaluate viral selection of mutation when previous genotypic information were available.Study designCohort prospective study in which eligible patients were at least 18 years old, provided informed consent, were on HAART for at least 12 months with two consecutive pVL between 200–999 copies/ml after achieving and maintaining viral suppression (two pVL <50 copies/ml). Modifications in genotype standard procedures included a larger volume of starting plasma, concentrating the sample by centrifugation and higher viral RNA input. Resistance was defined as the detection of any NRTI, NNRTI or PR major resistance mutations. Virologic response was assessed 12 weeks after salvage therapy.ResultsEighteen patients, 50% male, median age 52, median CD4 405 cells/mm3, median pVL 596 copies/ml, median of number of previous regimens 5, 17 (94%) with successful genotype. Resistance mutations were detected in 14 patients (77%). All patients had NRTI mutations, four patients had NNRTI mutations and ten patients had PR mutations, most common mutations were M41L, D67N, M184V, K103N, M46I, I47V, I54V and L90M. Of these fourteen patients, nine started a genotype‐guided salvage regimen and presented a pVL < 50 copies/ml after 12 weeks of follow up. For two patients there was previous genotypic information highlighting the selection and accumulation of resistance mutation during persistent low level viremia.ConclusionIn this group of heavily pretreated patients with persistent low viremia, a high frequency of genotypic resistance was observed; obtaining genotypic information may prevent further accumulation of resistance mutation and preserve future therapeutic options.

Is it justifiable to transplant infected livers into haemophilia recipients?

Is it justifiable to transplant infected livers into haemophilia recipients?

Persistent low-level HIV-1 RNA between 20 and 50 copies/mL in antiretroviral-treated patients: associated factors and virological outcome

The aim of our study was to identify factors associated with persistent low-level viraemia (LLV) in HIV-infected patients under suppressive antiretroviral therapy and to assess the virological outcome of these patients. LLV was defined as at least two HIV-1 RNA values between 20 and 50 copies/mL during 1 year of follow-up. We compared patients with all values <20 copies/mL (LLV-) and patients with LLV (LLV+). The 'blip ratio' was defined as (number of HIV-1 RNA values >50 copies/mL)/(number of HIV-1 RNA determinations) before study inclusion. Among the 656 patients included, 5.8% were in group LLV+. CDC stage B/C at study inclusion and a higher blip ratio before the study period were the only factors independently associated with LLV. During the 1 year follow-up, the proportion of patients experiencing virological failure was not different between the LLV- and LLV+ groups, and 40% of patients shifted from LLV+ to LLV- status. LLV was infrequent in our series and the follow-up did not evidence a higher rate of virological failure than in fully suppressed patients. LLV seems to be a transient phenomenon that might be driven by residual ongoing viral replication and/or viral release and/or accuracy of viral load assay at lower values.

Clinical consequences of persistent low level viremia

Work done by this group nearly 7 years ago, evaluated a cohort of patients who, for a variety of reasons, elected to remain on a virologically failing ARV regimen. We re-evaluated these patients to determine whether their earlier years living with low level viremia impacted their future treatment options. In the absence of a cure and with the goal of maintaining HIV infection as a chronic, yet manageable disease, it is important to understand the consequences of persistent immune system activation.

Improved Viral Suppression After Treatment Optimization in HIV-Infected Patients With Persistent Low-Level Viremia

Optimizing treatment for patients with persistent low-level viremia is complicated because most genotyping tests are validated for viral loads >1000 copies per milliliter. In this study, genotypes of 92 treatment-experienced patients with persistent low-level viremia were determined using an in-house assay. Based on the resistance profiles obtained from genotyping and patient pharmacologic history, patients were either maintained on their antiviral regimen (n = 51) or received an optimized regimen (n = 41). In the group receiving optimized treatment, undetectable viral loads were achieved in 73.2% at 6 months and at 90.2% at 1 year, indicating that treatment guided by genotyping of patients with low-level viremia is effective in achieving viral suppression.

Antiretroviral Drug Resistance in HIV-1–Infected Patients Experiencing Persistent Low-Level Viremia During First-Line Therapy

Population sequencing was performed for persons identified with persistent low-level viremia in 2 clinical trials. Persistent low-level viremia (defined as plasma HIV-1 RNA level >50 and <1000 copies/mL in at least 2 determinations over a 24-week period, after at least 24 weeks of antiretroviral therapy) was observed in 65 (5.6%) of 1158 patients at risk. New resistance mutations were detected during persistent low-level viremia in 37% of the 54 evaluable cases. The most common mutations were M184I/V (14 cases), K103N (9), and M230L (3). Detection of new mutations was associated with higher HIV-1 RNA levels during persistent low-level viremia.

The HIV Virologic Outcomes of Different Interventions Among Treatment-Experienced Patients With 2 Consecutive Detectable Low-Level Viremia

Approaches to treatment-experienced HIV-infected patients with persistent low-level viremia are limited by current commercial resistance genotyping assays when the viral load (VL) is <500 copies/mL. The best intervention to achieve virologic suppression in this population is unclear. This is a case control retrospective chart review study of 149 HIV-infected patients with a VL of 50 to 1000 copies/mL. Patients were in either regimen unchanged group or intervention group (intensification of regimen or switch without guidance from resistance testing). End point was VL < 100 copies/mL. At 6 months post change, 30.8% of patients with intervention versus 36.6% with no intervention achieved a complete virologic suppression. There were no statistically significant differences between these 2 groups (P = .254). The majority of patients without regimen change eventually progressed to complete virologic failure. Patients with persistent low levels of viremia are likely to progress to have virologic failure. This supports the adoption of a more proactive approach to treatment and more sensitive technique to identify drug resistance.

Antiretroviral Drug Resistance in HIV-1–Infected Patients Experiencing Persistent Low-Level Viremia During First-Line Therapy

Antiretroviral Drug Resistance in HIV-1–Infected Patients Experiencing Persistent Low-Level Viremia During First-Line Therapy

Evidence of persistent low-level viremia in long-term HAART-suppressed, HIV-infected individuals.

HAART can effectively reduce plasma HIV RNA levels to below the level of detection in most HIV-infected patients. The degree to which residual low-level viremia persists during HAART remains unclear. We identified 180 individuals (median duration of HIV infection 12 years) who had at least two consecutive plasma HIV-1 RNA levels below the level of detection (<50-75 copies/ml) while taking antiretroviral drugs; 36 of 180 had been virologically suppressed for more than 5 years. Longitudinal plasma samples that were taken from these individuals during periods of viral load suppression were selected and analyzed. The isothermal transcription-mediated amplification (TMA) (limit of detection <3.5 copies RNA/ml) assay was used to measure persistent viremia. A 'detuned' EIA assay was used to obtain quantitative HIV antibody levels. A total of 1606 TMA assays were performed on 438 specimens in 180 HAART-suppressed individuals (median 3 replicates per specimen). In the first year of viral suppression, plasma RNA levels declined significantly (P = 0.001), but after month 12 there was no evidence for a continued decline (P = 0.383). In the first year of viral suppression, HIV antibody levels also declined (P = 0.054), but after month 12 there was no evidence for a continued decline (P = 0.988). Viremia continued to decline during the first 12 months after viremia became undetectable using conventional methods, and then remained stable. HIV antibody levels also decreased in the first year of viral suppression and then remained stable. Viremia and the HIV-associated host response appear to achieve a steady-state 'set-point' during long-term combination therapy.

Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy.

Combination antiretroviral therapy suppresses but does not eradicate human immunodeficiency virus type 1 (HIV-1) in infected persons, and low-level viremia can be detected despite years of suppressive antiretroviral therapy. Short-course (28-day) intensification of standard antiretroviral combination therapy is a useful approach to determine whether complete rounds of HIV-1 replication in rapidly cycling cells contribute to persistent viremia. We investigated whether intensification with the integrase inhibitor raltegravir decreases plasma HIV-1 RNA levels in patients receiving suppressive antiretroviral therapy. Subjects (n = 10) with long-term HIV-1 suppression receiving combination antiretroviral regimens had their regimens intensified for 4 weeks with raltegravir. Plasma HIV-1 RNA level was determined before, during, and after the 4-week intensification period, using a sensitive assay (limit of detection, 0.2 copies of HIV-1 RNA/mL of plasma). A 4-week intensification course was chosen to investigate potential HIV-1 replication in cells with relatively short (approximately 1-14-day) half-lives. There was no evidence in any subject of a decline in HIV-1 RNA level during the period of raltegravir intensification or of rebound after discontinuation. Median levels of HIV-1 RNA before (0.17 log10 copies/mL), during (0.04 log10 copies/mL), and after (0.04 log10 copies/mL) raltegravir intensification were not significantly different (P > .1 for all comparisons in parametric analyses). High-performance liquid chromatography and mass spectroscopy experiments confirmed that therapeutic levels of raltegravir were achieved in plasma during intensification. Intensification of antiretroviral therapy with a potent HIV-1 integrase inhibitor did not decrease persistent viremia in subjects receiving suppressive regimens, indicating that rapidly cycling cells infected with HIV-1 were not present. Eradication of HIV-1 from infected persons will require new therapeutic approaches. ClinicalTrials.gov identifier: NCT00618371.

Defining the Risks for Cytomegalovirus Infection and Disease After Solid Organ Transplantation

Cytomegalovirus continues to be one of the most clinically significant infections after solid organ transplantation. Classic definitions of patients at high risk for infection and tissue-invasive disease are focused on recipient-donor serostatus, type of organ transplanted, and overall level of immunosuppression. However, recent trends in clinical practice call for a reevaluation of cytomegalovirus infection risks after solid organ transplantation. Indeed, whereas early-onset cytomegalovirus infection is usually controlled by antiviral prophylaxis with ganciclovir and derivatives, delayed- and late-onset cytomegalovirus infection can develop after the completion of a course of preventive therapy. In addition, indirect effects of cytomegalovirus infection may occur as a result of persistent low-level viremia. Suboptimal dosing of antiviral drugs due to specific drug toxicities may result in the development of ganciclovir-resistant cytomegalovirus disease. The relationship between organ allograft rejection and cytomegalovirus infection and disease has been recognized for some time. Transplantation of increasing numbers of extended-criteria donor organs increases the risk of delayed graft function and acute rejection, prompting the use of more intensive immunosuppression. In addition, the trend to spare long-term exposure to calcineurin inhibitors has contributed to a resurgence in the use of polyclonal T-cell induction immunosuppressive agents, which may reduce host anticytomegalovirus immunity. We discuss the current trends in solid organ transplantation that provide a foundation for defining risks for cytomegalovirus infection and disease, including identification of patients who would benefit from more aggressive cytomegalovirus monitoring and prevention strategies.

Identification of Ongoing Human Immunodeficiency Virus Type 1 (HIV-1) Replication in Residual Viremia during Recombinant HIV-1 Poxvirus Immunizations in Patients with Clinically Undetectable Viral Loads on Durable Suppressive Highly Active Antiretroviral Therapy

In most human immunodeficiency virus type 1 (HIV-1)-infected individuals who achieve viral loads of <50 copies/ml during highly active antiretroviral therapy (HAART), low levels of plasma virus remain detectable for years by ultrasensitive methods. The relative contributions of ongoing virus replication and virus production from HIV-1 reservoirs to persistent low-level viremia during HAART remain controversial. HIV-1 vaccination of HAART-treated individuals provides a model for examining low-level viremia, as immunizations may facilitate virus replication and sequence evolution. In a phase 1 trial of modified vaccinia virus Ankara/fowlpox virus-based HIV-1 vaccines in 20 HIV-infected young adults receiving HAART, we assessed the prevalence of low-level viremia and sequence evolution, using ultrasensitive viral load (<6.5 copies/ml) and genotyping (five-copy sensitivity) assays. Viral evolution, consisting of new drug resistance mutations and novel amino acid changes within a relevant HLA-restricted allele (e.g., methionine, isoleucine, glutamine, or arginine for leucine at position 205 of RT), was found in 1 and 3 of 20 subjects, respectively. Sequence evolution was significantly correlated with levels of viremia of between 6.5 and <50 copies/ml (P = 0.03) and was more likely to occur within epitopes presented by relevant HLA alleles (P < 0.001). These findings suggest that ongoing virus replication contributes to low-level viremia in patients on HAART and that this ongoing replication is subject to CD8(+) T-cell selective pressures.

Resistencias genotípicas en pacientes con VIH-1 y grados de viremia persistentemente bajos

Highly active antiretroviral therapy (HAART) in HIV patients is considered successful when plasma viral load (VL) reaches < 50 copies/ml. However, many patients have a persistent VL of 50 to 1000 copies/ml, and treatment guidelines do not recommend genotypic resistance testing at these levels because of poor performance. The aim of this study was to evaluate the usefulness of a concentration technique for HIV-1 sequencing in samples with < 1000 copies/ml, and determine the virological consequences of HAART treatment changes guided by resistance testing in this scenario. Observational study performed in 51 patients with plasma VL between 50 and 1000 copies/m; 27 patients had these levels for at least 12 consecutive months. Prior to RNA extraction, virions were concentrated from 3-ml plasma samples and then genotyped following standard procedures. Forty-seven of the 51 samples were successfully sequenced, resulting in a sensitivity of 92%. Among these 47 patients, 27 showed a persistent viral load of 50-1000 copies/ml for 12 months, and 20 patients achieved undetectable viral load following the genotype-guided HAART change (intention-to-treat analysis: NC = F; 20 of 27 [74.1%]; on-treatment analysis: 20 of 23 [86.9%]). We report a simple method for genotype sequencing in patients with persistent low-level viremia that allowed a modification of the HAART regimen leading to undetectable plasma viremia.

Ultrasensitive assessment of residual HIV viraemia in HAART‐treated patients with persistently undetectable plasma HIV‐RNA: A cross‐sectional evaluation

Improvements in HIV-RNA assays have made accurate detection of as few as 2 copies/ml possible. This study objective was the evaluation of ultrasensitive HIV-RNA quantitation (beneath current threshold: 50 copies/ml) in patients receiving different antiretroviral regimens. A cross-sectional, ultrasensitive measurement of HIV-RNA levels (detection limit: 2.5 HIV-RNA copies/ml) was performed in 154 HIV-1-infected patients receiving ARV therapy, all classed as full responders according to the 50 copies/ml cut-off. Patients were undergoing treatment with two nucleoside/nucleotide reverse transcriptase inhibitors (N/NtRTIs) plus nevirapine (NVP, n = 48), efavirenz (EFV, n = 57) or lopinavir/ritonavir (LPV/r, n = 49). Undetectable HIV-RNA (<2.5 copies/ml) occurred in 29/48 (60.4%), 24/57 (42.1%) and 14/49 (28.6%) NVP, EFV and LPV/r recipients, respectively. Mean virological-suppression (<50 copies/ml) duration was 28.6 months (median = 22, SD = 17.8), and only in LPV/r recipients length of suppression was associated with significantly lower HIV-RNA levels (P = 0.015). Mean nadir CD4+ cell count of 270 cells/mm(3) (median = 240, SD = 194.5) was significantly lower in the LPV/r arm (P < 0.001). Nadir CD4+ level correlated with virological suppression but had opposite trends between NVP (positive) and LPV/r (negative; two tailed P = 0.01). Logistic regression analysis showed NVP was the only independent factor associated with virologic suppression. NVP has demonstrated a distinct virological advantage at sub-clinical viral loads, possibly due to its greater penetration in extra-vascular compartments, warranting further investigation in the context of persistent low-level viraemia in long-term HAART.

Low‐level plasma HIVs in patients on prolonged suppressive highly active antiretroviral therapy are produced mostly by cells other than CD4 T‐cells

The cellular source(s) and the clinical significance of persistent low-level viremia, below 50 HIV RNA copies per ml of plasma, achieved in many patients with high adherence to highly active antiretroviral therapy (HAART) remain unclear. Also, it is not clear if residual plasma HIVs during HAART can become predominant populations in the rebounding plasma viral loads after therapy interruption. Since, different HIV quasispecies tend to compartmentalize in various cell types and tissue locations in patients during chronic infection, the phylogenetic relationships between HIV sequences amplified from residual plasma viruses and CD4 T cells of five patients on long-term suppressive therapy were examined. Three of these patients stopped therapy voluntarily for 3 weeks, but only one of them demonstrated viral load rebound in plasma. In phylogenetic analyses, the residual plasma viruses were found to be distinct genetically from the majority of CD4 T cell-associated virus populations in four of five patients. The compartmental analyses revealed that in all patients, plasma- and CD4 T cell-derived viral sequences were compartmentalized separately. Interestingly, the plasma sequences obtained before and after HAART-off in two patients were produced apparently from the same compartment, which was different from the circulating CD4 T cell-compartment. These results suggest the possibility that residual plasma viruses in patients on long-term suppressive HAART may be produced persistently from a cellular source yet to be identified, and are capable of spreading quickly in vivo, accounting for the rapid rebound of viral loads in plasma after therapy interruption.

Evidence for Persistent Low-Level Viremia in Individuals Who Control Human Immunodeficiency Virus in the Absence of Antiretroviral Therapy

A subset of antiretroviral-untreated, human immunodeficiency virus (HIV)-infected individuals are able to maintain undetectable plasma HIV RNA levels in the absence of antiretroviral therapy. These "elite" controllers are of high interest as they may provide novel insights regarding host mechanisms of virus control. The degree to which these individuals have residual plasma viremia has not been well defined. We performed a longitudinal study of 46 elite controllers, defined as HIV-seropositive, antiretroviral-untreated individuals with plasma HIV RNA levels of <50 to 75 copies/ml. The median duration of HIV diagnosis was 13 years, the median baseline CD4(+) T-cell count was 753 cells/mm(3), and the median duration of follow-up was 16 months. Plasma and cellular HIV RNA levels were measured using the transcription-mediated amplification (TMA) assay (estimated limit of detection of <3.5 copies RNA/ml). A total of 1,117 TMA assays were performed (median of five time points/subject and four replicates/time point). All but one subject had detectable plasma HIV RNA on at least one time point, and 15 (33%) subjects had detectable RNA at all time points. The majority of controllers also had detectable cell-associated RNA and proviral DNA. A mixed-effect linear model showed no strong evidence of change in plasma RNA levels over time. In conclusion, the vast majority (98%) of elite controllers had measurable plasma HIV RNA, often at levels higher than that observed in antiretroviral-treated patients. This confirms the failure to eradicate the virus, even in these unique individuals who are able to reduce plasma viremia to very low levels without antiretroviral therapy.

Preemptive valganciclovir for cytomegalovirus infection in hematological patients

To the Editor We read with interest the ¢ndings by Busca et al. (1) published in the Journal, adding to similar recent ¢ndings supporting the e⁄cacy of preemptive valganciclovir in allogeneic hematopoietic stem cell transplant (HSCT) recipients (2, 3). We add here our single-center preliminary experience in hematological patients. Before November 2005 we usually treated cytomegalovirus (CMV) reactivation (higher than 1500 copies/mL) with intravenous ganciclovir. During a 24 -month period starting in November 2005, all our patients undergoing HSCTor aggressive chemotherapy were monitored with weekly real-time quantitative polymerase chain reaction (PCR) assay (Cobas Amplicor CMV Monitor test, Roche Diagnostics, Mannheim, Germany; sensitivity5 600 CMV DNAcopies/mL) on peripheral blood during treatment and in the ¢rst 3 months after discharge. Thirty-seven patients with CMV viremia higher than 1500 copies/mL (at a median of 45 from end of chemotherapy or HSCT) were identi¢ed and treated for 3 weeks with preemptive oral valganciclovir 450 mg b.i.d. (n5 5) or 900 mg b.i.d. (n5 32) according to renal function. No patient had concurrent infections or was receiving steroids at the time of reactivation. No reduction in immunosuppression was performed in allogeneic HSCT recipients at the time of CMVreactivation. All but 2 patientswho reactivated CMVafter aggressive chemotherapy (n513: 7 myeloablative and 6 nonmyelobalative), or autologous (n5 5: 4 high-dose melphalan and 1 BEAM) or allogeneic (n519) HSCTshowed weekly drops in CMV levels and ¢nally cleared viremia at the ¢nal control on day 21 day since beginning of treatment. Both patients who failed the endpoint were allogeneic HSCT recipients with initial loads lower than 5000 copies/mL who had been treated with valganciclovir 900mgb.i.d.; they had persistent low-level viremia (4000 copies/mL) for at least 2 months despite salvage treatment with intravenous foscarnet. Only 3 patients, all allogeneic HSCTrecipients, developed neutropenia (absolute neutrophil counto500/mL) while on valganciclovir, which could be explained by concurrent immunosuppressive drugs. The median initial viral load in our cohort was 3900 copies/mL, which is a relatively low level and could have contributed to the high e⁄cacy of valganciclovir.W|th the use of such a low threshold, we did not observe any case of symptomatic CMVdisease. Recent data support that the e⁄cacy of valganciclovir 450mg b.i.d. is identical to 900mg b.i.d. in allogeneic HSCT recipients (90% clearance of antigenemia on day 121) (4), and this is likely truewhenever initial CMV load remains quite low, allowing proper treatment of patients with renal failure. In reduced-intensity conditioning HSCT recipients without gastrointestinal graft-versus-host disease (GvHD), the r 2008 Wiley Periodicals, Inc.

Replication-Dependent Pathogenicity of Attenuated nef-Deleted HIV-1 In Vivo

The Sydney Blood Bank Cohort (SBBC) of long-term survivors consists of 8 individuals infected with an attenuated nef-deleted strain of HIV-1 by means of contaminated blood products donated from a common blood donor between 1981 and 1984. We report the outcome of a 26-year prospective study documenting the clinical course of nef-deleted HIV-1 infection in 7 SBBC members. CD4 T-cell counts and plasma HIV-1 RNA levels were measured by flow cytometry and the COBAS AMPLICOR HIV-1 monitor version 1 or 1.5 (Roche Molecular Diagnostic Systems, Branchburg, NJ), respectively. Changes in these parameters with time were determined by least-squares analysis using STATA (StataCorp, College Station, TX) statistical software. Four subjects had persistent low-level viremia. Of these, progression to AIDS and/or evidence of CD4 T-cell loss occurred in 3; the fourth viremic individual died of non-HIV-1-related causes in 1995, only 12 years after infection. Three subjects have persistently undetectable plasma HIV-1 RNA levels and remain long-term nonprogressors. Our study shows that even weakened highly attenuated HIV-1 strains with nef deletions are ultimately pathogenic in humans unless replication is completely and persistently suppressed in vivo. This finding underscores the importance of aiming to achieve nothing less than complete and sustained suppression of HIV-1 replication by antiretroviral drugs and vaccines.

HIV-1 Viral Replication below 50 Copies/ml in Patients on Antiretroviral Therapy is not associated with CD8+ T-cell Activation

Objectives To determine if the expression of CD38 on CD8+ T-cells could be used as a marker of viral replication &lt;50 copies/ml in peripheral blood. Methods In a cross-sectional study of patients attending a single HIV clinic in London, an ultra-sensitive HIV RNA viral load assay, with a limit of detection of 3 copies/ml, was used to determine HIV-1 replication in plasma in 70 patients who had sustained viral suppression &lt;50 copies/ml by bDNA assays. Immune activation using the expression of CD38 on CD8+ T-cells was also assessed in patients on antiretroviral therapy (ART) with sustained viral suppression, individuals with persistent low-level viraemia &lt;400 copies/ml and subjects failing ART (viral load &gt;400 copies/ml). Results There was no significant difference in the percentage of CD8+CD38++ T-cells between patients with &lt;50 copies or &lt;3 copies/ml. Immune activation was significantly increased in patients with persistent low-level viraemia and in subjects failing ART. CD4+ T-cell counts in patients on long-term successful ART are inversely associated with CD8+ T-cell activation. Conclusions T-cell activation in patients on long-term successful ART is not due to residual low-level viral replication in the blood compartment of HIV-1. CD8+ T-cell activation in this patient group appears to be associated with poor CD4+ T-cell recovery.

Elite control of HIV infection: implications for vaccines

Although development of an effective AIDS vaccine to provide sterilizing immunity remains an elusive goal, vaccine protection from disease progression has been achieved in animal models, supporting this approach as a realistic goal for first generation vaccines for humans. The global epidemic would be expected to contract as long as viral load could be durably sustained at levels below 2000 RNA copies/ml, a level at which the probability of transmission and of disease progression are markedly reduced. Such control occurs in a subset of infected persons, but the immune responses in these persons have not been systematically defined. Here we examine HIV-specific cellular and humoral immune function in persons who have achieved such viral control without the need for medications, including those who maintain plasma virus below the level of detection (< 50–75 copies/ml, aviremic controllers, n = 64), persons with persistent low level viremia (75–2000 copies, viremic controllers, n = 60) and persons with chronic uncontrolled infection (n = 30). Results to be presented indicate substantial individual heterogeneity in adaptive immune responses among HIV controllers, and none of the parameters tested predicts the ability to contain virus. These results have important implications for current HIV vaccine development strategies aimed at durable maintenance of low level viremia.