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1.  CD4+ T-Cell Help Enhances NK Cell Function following Therapeutic HIV-1 Vaccination 
Journal of Virology  2014;88(15):8349-8354.
Increasing data suggest that NK cells can mediate antiviral activity in HIV-1-infected humans, and as such, novel approaches harnessing the anti-HIV-1 function of both T cells and NK cells represent attractive options to improve future HIV-1 immunotherapies. Chronic progressive HIV-1 infection has been associated with a loss of CD4+ T helper cell function and with the accumulation of anergic NK cells. As several studies have suggested that cytokines produced by CD4+ T cells are required to enhance NK cell function in various infection models, we hypothesized that reconstitution of HIV-1-specific CD4+ T-cell responses by therapeutic immunization would restore NK cell activity in infected individuals. Using flow cytometry, we examined the function of CD4+ T cells and NK cells in response to HIV-1 in subjects with treated chronic HIV-1 infection before and after immunization with an adjuvanted HIV-1 Gp120/NefTat subunit protein vaccine candidate provided by GlaxoSmithKline. Vaccination induced an increased expression of interleukin-2 (IL-2) by Gp120-specific CD4+ T cells in response to HIV-1 peptides ex vivo, which was associated with enhanced production of gamma interferon (IFN-γ) by NK cells. Our data show that reconstitution of HIV-1-specific CD4+ T-cell function by therapeutic immunization can enhance NK cell activity in HIV-1-infected individuals.
IMPORTANCE NK cells are effector cells of the innate immune system and are important in the control of viral infection. Recent studies have demonstrated the crucial role played by NK cells in controlling and/or limiting acquisition of HIV-1 infection. However, NK cell function is impaired during progressive HIV-1 infection. We recently showed that therapeutic immunization of treated HIV-1-infected individuals reconstituted strong T-cell responses, measured notably by their production of IL-2, a cytokine that can activate NK cells. The current study suggests that reconstitution of T-cell function by therapeutic vaccination can enhance NK cell activity in individuals with chronic HIV-1 infection. Our findings provide new insights into the interplay between adaptive and innate immune mechanisms involved in HIV-1 immunity and unveil opportunities to harness NK cell function in future therapeutic vaccine strategies to target HIV-1.
PMCID: PMC4135926  PMID: 24829350
2.  Early Treatment and HIV-1 Reservoirs: A Stitch in Time? 
The Journal of Infectious Diseases  2013;208(8):1189-1193.
PMCID: PMC3778963  PMID: 23852126
HIV; antiretroviral therapy; HIV reservoirs; HIV persistence; gut-associated-lymphoid-tissue
3.  High frequency of hypothalamic-pituitary-adrenal axis dysfunction after local corticosteroid injection in HIV-infected patients on protease inhibitor therapy 
The frequency of hypothalamic-pituitary-adrenal (HPA) axis dysfunction among HIV-infected patients receiving steroid injections has not been reported, and risk factors for this adverse event are poorly characterized.
We conducted a retrospective analysis of data from HIV-infected patients in the Partners HealthCare system (Boston, MA) who received corticosteroid injection(s) between 2002 and 2011. Chart review focused on HIV status, antiretroviral therapy (e.g., protease inhibitors (PI)), steroid injection(s), and adrenal axis dysfunction (e.g., adrenal insufficiency (AI) and/or Cushing's syndrome). Because all cases occurred among patients on PIs, we performed additional detailed data extraction and conducted univariate and multivariate analyses to identify risk factors in this group.
171 HIV-infected patients received ≥1 corticosteroid injection(s) in the study period. Nine cases (event frequency, 5.3%; 95% CI, 2.4%-9.8%) of secondary AI were diagnosed; five (55%) of these nine patients also had clinical evidence of Cushing's syndrome. All cases occurred among the 81 patients on PIs (event frequency among those on PIs, 11.1%; 95% CI, 5.2%-20.0%). Among patients on PIs, the major risk factor for HPA-axis dysfunction was having ≥2 injections within 6 months.
In this retrospective cohort study, 11% of HIV-infected patients on PIs at the time of steroid injection were later diagnosed with HPA axis dysfunction. Corticosteroid injections in HIV-infected patients on PIs should only be used with great caution and close monitoring.
PMCID: PMC3805773  PMID: 23714741
HIV; adrenal insufficiency; Cushing's syndrome; corticosteroid; protease inhibitor; CYP34A
4.  Safety of midazolam for sedation of HIV-positive patients undergoing colonoscopy 
HIV medicine  2013;14(6):379-384.
Concerns regarding possible interactions between midazolam and antiretroviral medicines have caused clinicians to use second-line sedatives, such as diazepam, instead. We demonstrated that patients who received midazolam during colonoscopy had similar clinical outcomes as those who received diazepam.
Because of concerns regarding interactions between midazolam and antiretroviral therapy (ART), alternative sedatives are sometimes used during procedural sedation. Our objective was to compare outcomes in patients on ART who received intravenous (IV) midazolam versus IV diazepam, a second-line agent, during colonoscopy.
We conducted a retrospective analysis of adult HIV-infected patients who underwent colonoscopy over a 3.5-year period. Primary outcomes were sedation duration, nadir systolic blood pressure, nadir oxygen saturation, abnormal cardiac rhythm, and change in level of consciousness using a standardized scale. We calculated rates of adverse events according to benzodiazepine use and identified risk factors for complications using univariate and multivariate analyses.
We identified 136 patients for this analysis: 70 received midazolam-based sedation and 66 received a diazepam-based regimen. There were no significant differences between the two groups with respect to sedation duration (48 versus 45.7 minutes, P = 0.68), nadir systolic blood pressure (97 versus 101.6 mmHg, P = 0.06), nadir oxygen saturation (94.6 versus 94.8%, P = 0.72), or rate of abnormal cardiac rhythm (11.4 versus 19.7%, P = 0.18). More patients in the midazolam group experienced a depressed level of consciousness (91 versus 74%, P = 0.0075), but no patient required reversal of sedation or became unresponsive.
Although IV midazolam interacts with ART, we did not find evidence that patients who received this agent for procedural sedation had clinical outcomes statistically different from those who received diazepam. These findings should be confirmed in prospective studies or in a randomized controlled trial.
PMCID: PMC4120820  PMID: 23332038
Midazolam; HIV; antiretrovirals; colonoscopy; sedation
5.  CD8+ T-cell Activation in HIV-1-Infected Patients Experiencing Transient Low-level Viremia During Antiretroviral Therapy 
Transient low-level viremia of 50–400 HIV RNA copies/mL (TLLV) is common during antiretroviral therapy, but its pathogenesis, consequences and optimal management are unclear. Heightened immune activation is associated with detrimental outcomes, including impaired CD4+ T-cell reconstitution. Using CD38/HLA-DR expression on CD8+ T-cells measured in two large studies, we determined associations between TLLV and immune activation levels before, during, and after TLLV. We found that TLLV does not significantly change CD8+ T-cell activation, and that higher CD8+ T-cell activation during viral suppression <50 copies/mL is associated with a modest increase in the risk of a subsequent TLLV.
PMCID: PMC3632289  PMID: 23392463
low-level; viremia; blip; immune; activation; CD8+
6.  Clinical Predictors for the Etiology of Peripheral Lymphadenopathy in HIV-Infected Adults 
HIV medicine  2012;14(3):182-186.
To determine the etiology and clinical predictors of peripheral lymphadenopathy in HIV-infected individuals during the antiretroviral (ARV) era in a non-Tuberculosis endemic setting.
Multi-centered, retrospective cohort study of peripheral lymph node biopsies in HIV-positive adults. 107 charts were identified and reviewed for clinical features, lymphadenopathy size, ARV use and duration. Biopsy results were categorized, and multivariate logistic regression determined independent predictors of lymphadenopathy etiology.
Evaluation of 107 peripheral lymph node biopsies revealed 42.9% due to malignancy, 49.5% reactive changes, and 7.5% infections, with only 2.8% of all cases secondary to tuberculosis. Fevers, weight loss, ARV use, and lower viral loads are significantly associated with non-reactive lymphadenopathy.
Lymphadenopathy is likely to be reactive or malignant in non-Tuberculosis endemic regions. Readily available clinical features can aid clinicians in predicting the underlying etiology, those at risk for malignancy, and who to biopsy.
PMCID: PMC3562378  PMID: 22805116
HIV; Lymphadenopathy; Tuberculosis; Opportunistic Infection; Biopsy
7.  Residual Plasma Viremia and Infectious HIV-1 Recovery from Resting Memory CD4 Cells in Patients on Antiretroviral Therapy: Results from ACTG A5173 
Antiviral therapy  2013;18(4):10.3851/IMP2543.
In HIV-1-infected patients receiving antiretroviral therapy (ART), the relationship between residual viremia and ex vivo recovery of infectious virus from latently-infected CD4 cells is uncertain.
We measured residual viremia (HIV-1 RNA copies/mL) by single-copy assay (SCA) and the latent reservoir by infectious virus recovery from resting memory CD4 cells (infectious units per million cells [IUPM]) in patients who initiated ART. We assessed immune activation by measuring CD38 expression on T cells.
Ten patients who initiated ART and maintained a plasma HIV-1 RNA level <200 copies/mL had residual viremia and IUPM measured every 24 weeks. Five of 10 patients had longitudinal IUPM measured at weeks 24–96; the remainder had IUPM measured 1–3 times over 24–72 weeks. Analyses of 29 paired measurements revealed a positive association between level of residual viremia and IUPM (0.56 higher log10 HIV-1 RNA copies/mL per 1 log10 higher IUPM, p=0.005). Residual viremia level was positively associated with CD38 density and percentage on CD8+ T-cells in concurrent samples and with pre-ART HIV-1 RNA levels.
In patients with HIV-1 RNA levels <200 copies/mL 24–96 weeks after initiating ART, the level of viremia is positively associated with infectious virus recovery from resting memory CD4 cells. Whether this association persists after longer-term suppressive ART needs to be determined. If additional studies show that residual viremia measured by SCA reflects the size of the latent reservoir in patients who have had virologic suppression for longer periods of time, this could facilitate testing of potentially curative strategies to reduce this important reservoir.
PMCID: PMC3887470  PMID: 23411421
HIV-1; reservoir; residual viremia; single-copy assay
8.  Predictors of Residual Viremia in Patients on Long-term Suppressive Antiretroviral Therapy 
Antiviral therapy  2012;18(1):39-43.
HIV-1-infected individuals with plasma RNA <50 copies/mL on antiretroviral therapy (ART) may have residual, low-level viremia detectable by PCR assays which can detect a single copy of viral RNA (single-copy assay, SCA). The clinical predictors of residual viremia in patients on long-term suppressive ART are incompletely understood.
We evaluated factors associated with residual viremia in patients on suppressive ART who underwent screening for a raltegravir intensification trial (ACTG A5244). The screened population was HIV-1-infected adults receiving ART for ≥12 months with pre-ART HIV-1 RNA >100,000 copies/mL and on-therapy RNA levels below detection limits of commercial assays for ≥6 months.
Of 103 patients eligible for analysis, the median age was 46 years and the median duration of viral suppression was 4.8 years. Sixty-two percent had detectable viremia (>0.2 copies/mL) by SCA (median 0.2 copies/mL; quartile [Q] 1, Q3 [<0.2, 1.8]). Younger patients had lower HIV-1 RNA levels than older individuals (r=0.27, p=0.005). Patients with virologic suppression on ART for 2 years or less had higher residual viremia than those with suppression for more than 2 years (median 2.3 vs. 0.2 copies/mL, p=0.016).
Among HIV-1-infected patients with pre-ART HIV-1 RNA >100,000 copies/mL, residual viremia was detectable in the majority (62%) despite many years of suppressive ART. Higher level viremia was associated with older age and less than 2 years of virologic suppression on ART. These findings should help in selection of candidates for clinical trials of interventions designed to eliminate residual viremia.
PMCID: PMC3578982  PMID: 22914318
HIV-1; Single-copy assay; residual viremia
9.  A Pilot Trial of Adding Maraviroc to Suppressive Antiretroviral Therapy for Suboptimal CD4+ T-Cell Recovery Despite Sustained Virologic Suppression: ACTG A5256 
The Journal of Infectious Diseases  2012;206(4):534-542.
Background. Despite viral suppression, antiretroviral therapy (ART) does not restore CD4+ T-cell counts in many patients infected with human immunodeficiency virus type 1 (HIV-1).
Methods. In a single-arm pilot trial involving ART recipients with suppressed plasma levels of HIV-1 RNA for at least 48 weeks and stable suboptimal CD4+ T-cell recovery, subjects added maraviroc, a CCR5 antagonist, to their existing ART for 24 weeks. After stopping maraviroc, they were followed for an additional 24 weeks. A Wilcoxon signed-rank test was used to evaluate whether maraviroc was associated with an increase of at least 20 cells/µL in the CD4+ T-cell count.
Results. A total of 34 subjects were enrolled. The median age was 50 years, and the median baseline CD4+ T-cell count was 153 cells/µL. The median increase in CD4+ T-cell count from baseline to week 22/24 was 12 cells/µL (90% confidence interval, 1–22). A CD4+ T-cell count increase of at least 20 cells/µL was not detected (P = .97). Markers of immune activation and apoptosis decreased during maraviroc intensification; this decline partially reversed after discontinuing maraviroc.
Conclusions. Adding maraviroc to suppressive ART for 24 weeks was not associated with an increase in CD4+ T-cell counts of at least 20 cells/µL. Further studies of CCR5 antagonists in the dampening of immune activation associated with HIV infection are warranted.
Clinical Trials Registration. NCT 00709111.
PMCID: PMC3491731  PMID: 22740718
12.  No Effect of Raltegravir Intensification on Viral Replication Markers in the Blood of HIV-1-infected Patients Receiving Antiretroviral Therapy 
Controversy continues regarding the extent of ongoing viral replication in HIV-1-infected patients on effective antiretroviral therapy (ART). Adding an additional potent agent, such as raltegravir, to effective ART in patients with low-level residual viremia may reveal whether there is ongoing HIV-1 replication.
We previously reported the outcome of a randomized, placebo-controlled study of raltegravir intensification in patients on ART with HIV-1 RNA <50 copies/mL that showed no effect on residual viremia measured by single copy assay (SCA). We now report the effects of raltegravir intensification in that trial on other potential measures of ongoing HIV-1 replication: 2-LTR HIV-1 circles, total cellular HIV-1 DNA and T cell activation.
Of 50 patients tested, 12 (24%) had 2-LTR-circles detected at baseline. Patients who were 2-LTR-positive had higher plasma HIV-1 RNA and HIV-1 DNA levels than 2-LTR-negative individuals. At week 12 of raltegravir intensification, there was no change from baseline in 2-LTR circles, in total HIV-1 DNA or in the ratio of 2-LTR circles to total HIV-1 DNA. There was also no change in markers of T cell activation.
In HIV-1-infected individuals on effective antiretroviral therapy, we find no evidence of ongoing viral replication in the blood that is suppressible by raltegravir intensification. The results imply that raltegravir intensification alone will not eradicate HIV-1 infection.
PMCID: PMC3423091  PMID: 22083073
Raltegravir; HIV-1; viral replication; reservoirs; 2-LTR circles; HIV-1 DNA; T cell activation
13.  Induction of Strong HIV-1-specific CD4+ T Cell Responses using an HIV-1 gp120/NefTat Vaccine adjuvanted with AS02A in ARV Treated HIV-1-Infected Individuals 
Induction of HIV-1-specific CD4+ T cell responses by therapeutic vaccination represents an attractive intervention to potentially increase immune control of HIV-1.
We performed a double-blinded, randomized, placebo-controlled clinical trial to determine the safety and immunogenicity of GSK Biologicals' HIV-1 gp120/NefTat subunit protein vaccine formulated with the AS02A adjuvant in subjects with well controlled chronic HIV-1 infection on HAART. Ten individuals received the vaccine; while adjuvant alone or placebo was given to five subjects each. Immunogenicity was monitored by intracellular cytokine flow cytometry and CFSE-based proliferation assays.
The vaccine was well tolerated with no related SAEs. Vaccine recipients had significantly stronger gp120-specific CD4+ T cell responses which persisted until week 48 and greater gp120-specific CD4+ T cell proliferation activity as compared to controls. In the vaccine group, the number of participants that demonstrated positive responses for both gp120-specific CD4+ T cell IL-2 production and gp120-specific CD8+ T cell proliferation was significantly higher at week 6.
The gp120/NefTat/AS02A vaccine induced strong gp120-specific CD4+ T cell responses, and a higher number of vaccinees developed both HIV-1-specific CD4+ T cell responses and CD8+ T cell proliferation. The induction of these responses may be important in enhancing immune-mediated viral control.
PMCID: PMC3241906  PMID: 21963936
HIV-1; Vaccination; Therapeutic Vaccination; HIV-1-specific CD4+ cells
14.  Replication Capacity in Relation to Immunologic and Virologic Outcomes in HIV-1 infected, Treatment-Naïve Subjects 
To evaluate the association between baseline (BL) replication capacity (RC) [RCBL] and immunologic/virologic parameters (at BL and after 48 weeks on therapy) in HIV-1 infected subjects initiating antiretroviral therapy.
RCBL was determined using a modified Monogram PhenoSense HIV drug susceptibility assay on plasma HIV-1 from 321 treatment-naïve subjects from ACTG384. Univariate and multivariable analyses were performed to determine the association of RCBL with BL and on-therapy virologic and immunologic outcomes.
Higher RCBL was associated with lower baseline CD4 (CD4BL) (r=−0.23, p<0.0001), higher baseline HIV-1 (RNABL) (r=0.25, p<0.0001), higher CD4BL activation percent (r=0.23, p<0.0001) and lower CD4BL memory count (r=−0.21, p=0.0002).
In a multivariable model, week 48 CD4 increase (ΔCD448) was associated with lower CD4BL memory count and higher CD4BL naive percent (p=0.004, p=0.015, respectively). The interaction between CD4BL and RCBL was significant (p=0.018), with a positive association between RCBL and ΔCD448 in subjects with higher CD4BL, and a negative association at lower absCD4BL.
At baseline, higher RC was significantly associated with higher HIV-1 RNA, higher CD4 cell activation, lower CD4 cell count, and lower CD4 memory cell count. These factors may interact, directly or indirectly, to modify the extent to which CD4 recovery occurs in patients starting antiretroviral therapy at different baseline CD4 counts.
PMCID: PMC3482469  PMID: 19194319
HIV; replication capacity; viral fitness; pathogenesis; immune reconstitution; activation; memory
15.  Coadministration of Lopinavir/Ritonavir and Rifampicin in HIV and Tuberculosis Co-Infected Adults in South Africa 
PLoS ONE  2012;7(9):e44793.
In HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine – in routine practice – the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment.
Methodology/Principle Findings
We conducted a retrospective review of HIV-infected patients who receiving second-line ART with a LPV/r-containing regimen who required concomitant TB treatment. We identified 29 patients; the median age was 36 years (IQR 29–40), 22 (76%) were female, the median CD4 cell count and viral load at first-line ART failure was 86 cells/mm3 (IQR 21–159) and 39,457 copies/mL (IQR 6,025–157,500), respectively. According to physician preference, 15 (52%) of 29 patients received super-boosted LPV/r (400 mg/400 mg) every 12 hours during TB treatment and 14 (48%) of 29 patients received standard dose LPV/r (400 mg/100 mg) twice daily during TB treatment. Among patients who received super-boosted LPV/r there was a trend towards a higher rate of symptomatic transaminitis (27% vs. 7%; p = 0.3), gastrointestinal toxicity (20% vs. 0%; p = 0.2) and a significantly increased need for treatment discontinuation (47% vs. 7%; p = 0.035. The durability of coadministered treatment was significantly shorter in patients who received super-boosted lopinavir/ritonavir with TB treatment compared to patients who received standard lopinavir/ritonavir dosing (log rank, P = 0.036). The rate of virologic failure was not higher in patients with unadjusted LPV/r dosing.
We observed a high rate of toxicity and need for treatment discontinuation among patients on standard rifampicin-based TB treatment who received super-boosted LPV/r.
PMCID: PMC3460963  PMID: 23028623
16.  Update on Human Immunodeficiency Virus (HIV)-2 Infection 
Infection with human immunodeficiency virus type 2 (HIV-2) occurs mainly in West Africa, but an increasing number of cases have been recognized in Europe, India, and the United States. In this era of global integration, clinicians must be aware of when to consider the diagnosis of HIV-2 infection and how to test for this virus. Although there is debate regarding when therapy should be initiated and which regimen should be chosen, recent trials have provided important information on treatment options for HIV-2 infection. In this review, we present information on recent clinical advances in our understanding of HIV-2 infection and highlight remaining diagnostic and therapeutic challenges.
PMCID: PMC3106263  PMID: 21367732
17.  Role of CD4+ and CD8+ T-Cell Responses against JC Virus in the Outcome of Patients with Progressive Multifocal Leukoencephalopathy (PML) and PML with Immune Reconstitution Inflammatory Syndrome ▿  
Journal of Virology  2011;85(14):7256-7263.
Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the brain caused by JC virus (JCV). To assess the role of CD4+ and CD8+ T-cells against JCV in the clinical outcome of PML and PML in the setting of immune reconstitution inflammatory syndrome (IRIS), we tested gamma interferon (IFN-γ) response by enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) in 117 subjects, including 66 PML patients with different clinical outcomes. Both assays were concordant and demonstrated that the cellular immune response against JCV is associated with better clinical outcome. PML survivors had an early CD8+ T-cell response more frequently than PML progressors (100% versus 27.3%; P = 0.001), while only a trend was observed for the early CD4+ T-cell response between these two groups (80% versus 45.5%; P = 0.18). Although IRIS itself was more frequent in the PML survivor group, there was no difference in IFN-γ-producing CD4+ and CD8+ T-cells between IRIS and non-IRIS PML patients, suggesting that T-cells expressing other cytokines likely have a role in the immunopathogenesis of IRIS. ELISpot and ICS assays are useful prognostic markers of PML evolution and may help in the clinical management of these patients.
PMCID: PMC3126613  PMID: 21543472
18.  The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation 
Pereyra, Florencia | Jia, Xiaoming | McLaren, Paul J. | Telenti, Amalio | de Bakker, Paul I.W. | Walker, Bruce D. | Jia, Xiaoming | McLaren, Paul J. | Ripke, Stephan | Brumme, Chanson J. | Pulit, Sara L. | Telenti, Amalio | Carrington, Mary | Kadie, Carl M. | Carlson, Jonathan M. | Heckerman, David | de Bakker, Paul I.W. | Pereyra, Florencia | de Bakker, Paul I.W. | Graham, Robert R. | Plenge, Robert M. | Deeks, Steven G. | Walker, Bruce D. | Gianniny, Lauren | Crawford, Gabriel | Sullivan, Jordan | Gonzalez, Elena | Davies, Leela | Camargo, Amy | Moore, Jamie M. | Beattie, Nicole | Gupta, Supriya | Crenshaw, Andrew | Burtt, Noël P. | Guiducci, Candace | Gupta, Namrata | Carrington, Mary | Gao, Xiaojiang | Qi, Ying | Yuki, Yuko | Pereyra, Florencia | Piechocka-Trocha, Alicja | Cutrell, Emily | Rosenberg, Rachel | Moss, Kristin L. | Lemay, Paul | O’Leary, Jessica | Schaefer, Todd | Verma, Pranshu | Toth, Ildiko | Block, Brian | Baker, Brett | Rothchild, Alissa | Lian, Jeffrey | Proudfoot, Jacqueline | Alvino, Donna Marie L. | Vine, Seanna | Addo, Marylyn M. | Allen, Todd M. | Altfeld, Marcus | Henn, Matthew R. | Le Gall, Sylvie | Streeck, Hendrik | Walker, Bruce D. | Haas, David W. | Kuritzkes, Daniel R. | Robbins, Gregory K. | Shafer, Robert W. | Gulick, Roy M. | Shikuma, Cecilia M. | Haubrich, Richard | Riddler, Sharon | Sax, Paul E. | Daar, Eric S. | Ribaudo, Heather J. | Agan, Brian | Agarwal, Shanu | Ahern, Richard L. | Allen, Brady L. | Altidor, Sherly | Altschuler, Eric L. | Ambardar, Sujata | Anastos, Kathryn | Anderson, Ben | Anderson, Val | Andrady, Ushan | Antoniskis, Diana | Bangsberg, David | Barbaro, Daniel | Barrie, William | Bartczak, J. | Barton, Simon | Basden, Patricia | Basgoz, Nesli | Bazner, Suzane | Bellos, Nicholaos C. | Benson, Anne M. | Berger, Judith | Bernard, Nicole F. | Bernard, Annette M. | Birch, Christopher | Bodner, Stanley J. | Bolan, Robert K. | Boudreaux, Emilie T. | Bradley, Meg | Braun, James F. | Brndjar, Jon E. | Brown, Stephen J. | Brown, Katherine | Brown, Sheldon T. | Burack, Jedidiah | Bush, Larry M. | Cafaro, Virginia | Campbell, Omobolaji | Campbell, John | Carlson, Robert H. | Carmichael, J. Kevin | Casey, Kathleen K. | Cavacuiti, Chris | Celestin, Gregory | Chambers, Steven T. | Chez, Nancy | Chirch, Lisa M. | Cimoch, Paul J. | Cohen, Daniel | Cohn, Lillian E. | Conway, Brian | Cooper, David A. | Cornelson, Brian | Cox, David T. | Cristofano, Michael V. | Cuchural, George | Czartoski, Julie L. | Dahman, Joseph M. | Daly, Jennifer S. | Davis, Benjamin T. | Davis, Kristine | Davod, Sheila M. | Deeks, Steven G. | DeJesus, Edwin | Dietz, Craig A. | Dunham, Eleanor | Dunn, Michael E. | Ellerin, Todd B. | Eron, Joseph J. | Fangman, John J.W. | Farel, Claire E. | Ferlazzo, Helen | Fidler, Sarah | Fleenor-Ford, Anita | Frankel, Renee | Freedberg, Kenneth A. | French, Neel K. | Fuchs, Jonathan D. | Fuller, Jon D. | Gaberman, Jonna | Gallant, Joel E. | Gandhi, Rajesh T. | Garcia, Efrain | Garmon, Donald | Gathe, Joseph C. | Gaultier, Cyril R. | Gebre, Wondwoosen | Gilman, Frank D. | Gilson, Ian | Goepfert, Paul A. | Gottlieb, Michael S. | Goulston, Claudia | Groger, Richard K. | Gurley, T. Douglas | Haber, Stuart | Hardwicke, Robin | Hardy, W. David | Harrigan, P. Richard | Hawkins, Trevor N. | Heath, Sonya | Hecht, Frederick M. | Henry, W. Keith | Hladek, Melissa | Hoffman, Robert P. | Horton, James M. | Hsu, Ricky K. | Huhn, Gregory D. | Hunt, Peter | Hupert, Mark J. | Illeman, Mark L. | Jaeger, Hans | Jellinger, Robert M. | John, Mina | Johnson, Jennifer A. | Johnson, Kristin L. | Johnson, Heather | Johnson, Kay | Joly, Jennifer | Jordan, Wilbert C. | Kauffman, Carol A. | Khanlou, Homayoon | Killian, Robert K. | Kim, Arthur Y. | Kim, David D. | Kinder, Clifford A. | Kirchner, Jeffrey T. | Kogelman, Laura | Kojic, Erna Milunka | Korthuis, P. Todd | Kurisu, Wayne | Kwon, Douglas S. | LaMar, Melissa | Lampiris, Harry | Lanzafame, Massimiliano | Lederman, Michael M. | Lee, David M. | Lee, Jean M.L. | Lee, Marah J. | Lee, Edward T.Y. | Lemoine, Janice | Levy, Jay A. | Llibre, Josep M. | Liguori, Michael A. | Little, Susan J. | Liu, Anne Y. | Lopez, Alvaro J. | Loutfy, Mono R. | Loy, Dawn | Mohammed, Debbie Y. | Man, Alan | Mansour, Michael K. | Marconi, Vincent C. | Markowitz, Martin | Marques, Rui | Martin, Jeffrey N. | Martin, Harold L. | Mayer, Kenneth Hugh | McElrath, M. Juliana | McGhee, Theresa A. | McGovern, Barbara H. | McGowan, Katherine | McIntyre, Dawn | Mcleod, Gavin X. | Menezes, Prema | Mesa, Greg | Metroka, Craig E. | Meyer-Olson, Dirk | Miller, Andy O. | Montgomery, Kate | Mounzer, Karam C. | Nagami, Ellen H. | Nagin, Iris | Nahass, Ronald G. | Nelson, Margret O. | Nielsen, Craig | Norene, David L. | O’Connor, David H. | Ojikutu, Bisola O. | Okulicz, Jason | Oladehin, Olakunle O. | Oldfield, Edward C. | Olender, Susan A. | Ostrowski, Mario | Owen, William F. | Pae, Eunice | Parsonnet, Jeffrey | Pavlatos, Andrew M. | Perlmutter, Aaron M. | Pierce, Michael N. | Pincus, Jonathan M. | Pisani, Leandro | Price, Lawrence Jay | Proia, Laurie | Prokesch, Richard C. | Pujet, Heather Calderon | Ramgopal, Moti | Rathod, Almas | Rausch, Michael | Ravishankar, J. | Rhame, Frank S. | Richards, Constance Shamuyarira | Richman, Douglas D. | Robbins, Gregory K. | Rodes, Berta | Rodriguez, Milagros | Rose, Richard C. | Rosenberg, Eric S. | Rosenthal, Daniel | Ross, Polly E. | Rubin, David S. | Rumbaugh, Elease | Saenz, Luis | Salvaggio, Michelle R. | Sanchez, William C. | Sanjana, Veeraf M. | Santiago, Steven | Schmidt, Wolfgang | Schuitemaker, Hanneke | Sestak, Philip M. | Shalit, Peter | Shay, William | Shirvani, Vivian N. | Silebi, Vanessa I. | Sizemore, James M. | Skolnik, Paul R. | Sokol-Anderson, Marcia | Sosman, James M. | Stabile, Paul | Stapleton, Jack T. | Starrett, Sheree | Stein, Francine | Stellbrink, Hans-Jurgen | Sterman, F. Lisa | Stone, Valerie E. | Stone, David R. | Tambussi, Giuseppe | Taplitz, Randy A. | Tedaldi, Ellen M. | Telenti, Amalio | Theisen, William | Torres, Richard | Tosiello, Lorraine | Tremblay, Cecile | Tribble, Marc A. | Trinh, Phuong D. | Tsao, Alice | Ueda, Peggy | Vaccaro, Anthony | Valadas, Emilia | Vanig, Thanes J. | Vecino, Isabel | Vega, Vilma M. | Veikley, Wenoah | Wade, Barbara H. | Walworth, Charles | Wanidworanun, Chingchai | Ward, Douglas J. | Warner, Daniel A. | Weber, Robert D. | Webster, Duncan | Weis, Steve | Wheeler, David A. | White, David J. | Wilkins, Ed | Winston, Alan | Wlodaver, Clifford G. | Wout, Angelique van’t | Wright, David P. | Yang, Otto O. | Yurdin, David L. | Zabukovic, Brandon W. | Zachary, Kimon C. | Zeeman, Beth | Zhao, Meng
Science (New York, N.Y.)  2010;330(6010):1551-1557.
Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.
PMCID: PMC3235490  PMID: 21051598
19.  Clinical outcome of long-term survivors of progressive multifocal leukoencephalopathy 
Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the polyomavirus JC (JCV) in immunosuppressed people. There is no cure for PML but one-year survival has increased from 10% to 50% in HIV-infected individuals treated with highly active antiretroviral therapy (HAART). We describe herein the clinical outcome of 24 PML patients whose survival exceeded 5 years, with a mean follow-up of 94.2 months (range 60–188 months). Of all patients, only 2 were females including one who had non-Hodgkin’s lymphoma and was HIV-negative. All 23 HIV-positive patients received HAART, and additional experimental therapies were not associated with a better clinical outcome.
Marked neurological improvement occurred in 4/24(17%) of patients, while 11/24 (46%) had partial improvement and 9/24(37%) remained stable. By the end of the period of observation, 8/24(33%) of patients had no significant disability despite persistent symptoms (modified Rankin disability scale (MRDS) =1), 6/24(25%) had slight disability and were living independently (MRDS=2), 5/24(21%) were moderately disabled, requiring some help during activities of daily living (MRDS=3) and 5/24(21%) had moderately severe disability, requiring constant help or institutionalization (MRDS=4). Patients with cerebellar lesions tended to have a worse clinical outcome.
MRI showed leukomalacia with ventricular enlargement secondary to destruction of the white matter at the site of previous PML lesions, and focal areas of subcortical atrophy with preservation of the cortical ribbon.
Of 20 patients tested, 19(95%) had detectable CD8+ cytotoxic T-lymphocytes against JCV in their blood. In absence of a specific treatment, immunotherapies aiming at boosting the cellular immune response against JCV may improve the prognosis of PML.
PMCID: PMC3077967  PMID: 20710013
21.  Pre-treatment Levels of Soluble Cellular Receptors and Interleukin-6 are Associated with HIV Disease Progression in HAART-Treated Subjects 
The Journal of infectious diseases  2010;201(12):1796-1805.
To identify inflammatory pathways that may contribute to HIV disease pathogenesis, we explored associations between AIDS or death with different inflammatory markers, including selected soluble tumor necrosis factor superfamily receptors and ligands, interleukin (IL)-6, and CD8 T cell activation, in highly active antiretroviral therapy (HAART)-treated individuals.
Case-control study among subjects in AIDS Clinical Trials Group (ACTG) protocols 384 and 5015, matched by baseline CD4 cell counts and plasma viral load (pVL), using conditional logistic regression.
Higher pre-treatment soluble (s) TNFR-I, sCD27, sCD40L and plasma IL-6 concentrations were associated with a new AIDS-defining illness or death in separate models adjusted for age, sex, hemoglobin and latest CD4 cell counts. In additional models that excluded cases of opportunistic infections, sTNFR-I, sCD27, and sCD40L each was associated with a new AIDS-defining malignancy or death that developed a median of 51 weeks after HAART-initiation, by which time the majority of subjects had CD4 cell counts above 200/cm3 and achieved a pVL<50 copies/mL.
These data are compatible with a model where these soluble inflammatory markers identify pathways that may contribute to the pathogenesis HIV disease progression, pathways that might not be a direct consequence of ongoing HIV-1 replication.
PMCID: PMC2873127  PMID: 20446847
Immune activation; TNFR-I; CD27; CD40L; IL-6
22.  A Risk-Factor Guided Approach to Reducing Lactic Acidosis and Hyperlactatemia in Patients on Antiretroviral Therapy 
PLoS ONE  2011;6(4):e18736.
Stavudine continues to be used in antiretroviral treatment (ART) regimens in many resource-limited settings. The use of zidovudine instead of stavudine in higher-risk patients to reduce the likelihood of lactic acidosis and hyperlactatemia (LAHL) has not been examined.
Antiretroviral-naïve, HIV-infected adults initiating ART between 2004 and 2007 were divided into cohorts of those initiated on stavudine- or zidovudine-containing therapy. We evaluated stavudine or zidovudine use, age, sex, body mass index (BMI), baseline CD4 cell count, creatinine, hemoglobin, alanine aminotransferase, and albumin as predictors of time to LAHL with Cox Proportional Hazards (PH) regression models.
Among 2062 patients contributing 2747 patient years (PY), the combined incidence of LAHL was 3.2/100 PY in those initiating stavudine- and 0.34/100 PY in those initiating zidovudine-containing ART (RR 9.26, 95% CI: 1.28–66.93). In multivariable Cox PH analysis, stavudine exposure (HR 14.31, 95% CI: 5.79–35.30), female sex (HR 3.41, 95% CI: 1.89–6.19), higher BMI (HR 3.21, 95% CI: 2.16–4.77), higher creatinine (1.63, 95% CI: 1.12–2.36), higher albumin (HR 1.04, 95% CI: 1.01–1.07), and lower CD4 cell count (HR 0.96, 95% CI: 0.92–1.0) at baseline were associated with higher LAHL rates. Among participants who started on stavudine, switching to zidovudine was associated with lower LAHL rates (HR 0.15, 95% CI: 0.06–0.35). Subgroup analysis limited to women with higher BMI≥25 kg/m2 initiated on stavudine also showed that switch to zidovudine was protective when controlling for other risk factors (HR 0.21, 95% CI .07–0.64).
Stavudine exposure, female sex, and higher BMI are strong, independent predictors for developing LAHL. Patients with risk factors for lactic acidosis have less LAHL while on zidovudine- rather than stavudine-containing ART. Switching patients from stavudine to zidovudine is protective. Countries continuing to use stavudine should avoid this drug in women and patients with higher BMI.
PMCID: PMC3073990  PMID: 21494566
23.  The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial 
PLoS Medicine  2010;7(8):e1000321.
In a double-blind trial, Rajesh Gandhi and colleagues detect no significant reduction in viral load after people with low-level HIV viremia added an integrase inhibitor to their treatment regimen.
Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients.
Methods and Findings
Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median −0.2 and −0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus −44 cells/mm3, p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood.
In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection.
Trial Registration NCT00515827
Please see later in the article for the Editors' Summary
Editors' Summary
Acquired immunodeficiency syndrome (AIDS) has killed about 25 million people since 1981 and more than 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV is a retrovirus—its genetic blueprint is made of ribonucleic acid (RNA). HIV infects human immune system cells and destroys them, leaving infected individuals susceptible to other infections. Early during the AIDS epidemic, most HIV-positive people died within ten years of infection. Then, in 1996, effective antiretroviral therapy (ART) was developed. ART consists of combinations of drugs that prevent viral replication by inhibiting essential viral enzymes such as reverse transcriptase (the enzyme that makes a DNA copy of the viral RNA; a viral enzyme called integrase inserts this DNA copy into the host cell DNA where it remains dormant until the host cell is activated) and protease (an enzyme needed for the production of new viral particles, which are released into the blood stream). Now, in industrialized countries, the life expectancy of HIV-infected patients treated with ART is similar to that of people with diabetes and other chronic conditions.
Why Was This Study Done?
Although ART can reduce the number of viral RNA copies in the plasma (the liquid portion of blood) of HIV-positive patients to less than 50 copies/mL (the limit of detection of commercial assays), it is does not eradicate HIV. When very sensitive assays are used to detect viral RNA (for example, the “single copy assay” or SCA), most patients on ART have one copy or more of HIV RNA per mL of plasma. The origin of this low-level residual viremia (virus in the blood) is controversial. Residual viremia could arise from ongoing cycles of viral replication, in which case intensification of ART should reduce it. Alternatively, residual viremia could be due to HIV release from stable reservoirs such as latently infected resting immune system cells, in which case intensification of ART should have no effect on residual viremia. In this randomized, controlled trial (a study in which randomly selected groups of patients are given different treatments and the effects of these treatments compared), the researchers assess whether the addition of raltegravir (a drug that inhibits HIV integrase) to standard ART has any effect on residual viremia.
What Did the Researchers Do and Find?
The researchers enrolled 53 HIV-positive patients who had been receiving ART containing several reverse transcriptase inhibitors and, in some cases, a protease inhibitor for at least 12 months and who had a plasma HIV RNA level below 50 copies/mL but detectable viremia by SCA. The patients were randomly assigned to receive either raltegravir or a dummy drug (placebo) in addition to their normal ART for 12 weeks. They were then crossed-over (swapped) to the other therapy for a further 12 weeks. At baseline, the trial participants had an average plasma HIV RNA level of 1.7 copies/mL. The HIV RNA level at weeks 10/12 (the average of SCA results at 10 and 12 weeks) was similar in the raltegravir group and in the placebo group and did not differ significantly from this baseline level. There was also no significant change in plasma HIV RNA levels from weeks 10/12 to weeks 22/24 after the patients crossed-over between treatment groups.
What Do These Findings Mean?
In this randomized, cross-over study, raltegravir intensification of ART for 12 weeks did not demonstrably reduce low-level residual viremia in HIV-positive patients receiving standard ART. It is possible that 12 weeks is too short a time to see an effect of raltegravir on residual viremia. Furthermore, although this is one of the biggest trials of this type done to date, it might be that insufficient patients were included in the trial to detect a subtle effect of raltegravir on residual viremia. Nevertheless, these findings argue against the hypothesis that residual viremia arises from ongoing cycles of viral replication and the infection of new cells. Instead, they suggest that residual viremia might be due to the release of HIV from stable reservoirs. If so, new therapeutic strategies designed to eliminate these reservoirs of latently infected cells will be required to cure HIV infection.
Additional Information
Please access these Web sites via the online version of this summary at
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS, and on the treatment of HIV
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including information on antiretroviral therapies
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including the treatment of HIV and AIDS (in English and Spanish)
MedlinePlus has links to further resources on AIDS and on AIDS medicines (in English and Spanish)
PMCID: PMC2919424  PMID: 20711481
24.  Characterization of Human Immunodeficiency Virus Type 1 Populations Containing CXCR4-Using Variants from Recently Infected Individuals 
We screened 150 individuals from two recent seroconverter cohorts and found that six (4%) had CXCR4-using viruses. Clonal analysis of these six individuals, along with a seventh individual identified during clinical care as a recent seroconverter, revealed the presence of both X4- and dual-tropic variants in these recently infected adults. The ability of individual CXCR4-using variants to infect cells expressing CD4/CXCR4 or CD4/CCR5 varied dramatically. These data demonstrate that virus populations in some newly infected individuals can consist of either heterogeneous populations containing both CXCR4-using and CCR5-tropic viruses, or homogeneous populations containing only CXCR4-using viruses. The presence of CXCR4-using viruses at early stages of infection suggests that testing for viral tropism before using CCR5 antagonists may be important even in persons with known recent infection. The presence of CXCR4-using viruses in a subset of newly infected individuals could impact the efficacies of vaccine and microbicide strategies that target CCR5-tropic viruses.
PMCID: PMC2827835  PMID: 19678765
25.  No Evidence for Decay of the Latent Reservoir in HIV-1–Infected Patients Receiving Intensive Enfuvirtide-Containing Antiretroviral Therapy 
The Journal of infectious diseases  2010;201(2):293-296.
Human immunodeficiency virus type 1 (HIV-1) persists in a latent reservoir of infected resting memory CD4 cells in patients receiving antiretroviral therapy. We assessed whether multitarget therapy with enfuvirtide, 2 reverse-transcriptase inhibitors, and a ritonavir-boosted protease inhibitor leads to decay of this reservoir. Nineteen treatment-naive patients initiated this regimen; 9 experienced virologic suppression and continued enfuvirtide-containing therapy for at least 48 weeks. In enfuvirtide-treated patients with virological suppression, there was no decay of the latent reservoir (95% confidence interval for half-life, 11 months to infinity). The stability of the latent reservoir despite intensive therapy suggests that new strategies are needed to eradicate HIV-1 from this reservoir.
PMCID: PMC2887684  PMID: 20001856

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