JAIDS Journal of Acquired Immune Deficiency Syndromes:
Critical Review: Clinical Science
Disease-Modifying Therapeutic Concepts for HIV in the Era of Highly Active Antiretroviral Therapy
Butler, Scott L. PhD*; Valdez, Hernan MD†; Westby, Michael PhD*; Perros, Manos PhD‡; June, Carl H. MD§; Jacobson, Jeffrey M. MD‖; Levy, Yves MD¶; Cooper, David A. MD, DSc#; Douek, Daniel MD, PhD**; Lederman, Michael M. MD††; Tebas, Pablo MD‡‡
*Pfizer Global Research and Development, Sandwich, United Kingdom
†Pfizer Inc, New York, NY
‡AstraZeneca Pharmaceuticals, Waltham, MA
§Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
‖Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA
¶INSERM, Unité U955, Université Paris-Est, Faculté de Médicine, Créteil AP-HP, Groupe Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique, Créteil, France
#National Centre in HIV Epidemiology and Clinical Research, University of New South Wales and Centre for Applied Medical Research, St Vincent's Hospital, Darlinghurst, NSW, Australia
**Vaccine Research Center, National Institutes of Health, Bethesda, MD
††Case Western Reserve University, University Hospitals/Case Medical Center, Cleveland, OH
‡‡Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA
SB, HV, and MW are employees of Pfizer and/or ViiV Healthcare. MP is a former Pfizer employee. All other authors have no conflicts of interest to disclose.
The study was sponsored by Pfizer Global Research and Development and was funded by Pfizer, Inc. Editorial assistance was provided by Jennifer Tobin of Health Interactions Ltd, with funding by Pfizer, Inc. C.J., Y.L., D.C., M.L., and P.T. were paid for their participation in the round-table discussions.
Correspondence to: Scott L. Butler, PhD, Infectious Diseases Group, Pfizer Global Research and Development, Sandwich, United Kingdom CT13 9NJ (e-mail: firstname.lastname@example.org).
Received March 8, 2011
Accepted July 7, 2011
Abstract: Chronic HIV infection is associated with persistent immune activation and inflammation even among patients virologically suppressed on antiretroviral therapy for years. Chronic immune activation has been associated with poor outcomes—both AIDS-defining and non-AIDS–defining clinical events—and persistent CD4 T-cell depletion. The cause of chronic immune activation in well-controlled HIV infection is unknown. Proposed drivers include residual viral replication, microbial translocation, and coinfecting pathogens. Therapeutic interventions targeting immune activation are emerging, from approaches that interfere directly with activation and inflammatory pathways to those that prevent microbial translocation or decrease the availability of host target cells for the virus. In the context of the disappointing results of the interleukin-2 trials, the main challenges to developing these disease-modifying therapies include identifying an adequate target population and choosing surrogate endpoints that will provide positive proof-of-concept that the interventions will translate into long-term clinical benefit before embarking on large clinical endpoint trials.
In the era of highly active antiretroviral therapy (HAART), the majority of HIV-infected patients can control HIV replication appropriately. Most treated patients suppress viral load to undetectable levels and increase to variable degrees CD4 T-cell counts.1–5 Survival has improved dramatically, and HAART has made HIV infection a chronic manageable illness. However, despite years of viral suppression, a substantial proportion of patients demonstrate persistent immune activation, which is associated with disease progression and mortality.6–10 In addition, many patients do not achieve complete CD4 reconstitution (≥500 cells/mm3),4,5,11,12 and this has been linked to a high rate of clinical events (Fig. 1).13–19 This may account for the shortened life expectancy in HIV infection, which remains reduced by an estimated 10 years compared with the general population.15,20,21 Although initiating therapy earlier may result in more complete immune restoration and better outcomes,22,23 many patients still present late, and this is associated with diminished immune restoration and shorter survival.4,24,25 These patients will need additional interventions to address the immune activation and incomplete immune restoration that persist during HAART.
THE IMPACT OF CHRONIC IMMUNE ACTIVATION
Immune Activation and CD4 Cell Depletion
Immune activation begins during the acute phase of infection when there is a profound depletion of CD4 cells, mainly from the gastrointestinal tract, and levels of cytokines and chemokines rise with HIV load. During the chronic stage, viral load is reduced, but immune activation persists. This stage is characterized by increased turnover and altered phenotypes of T cells and B cells26–31; raised levels of proinflammatory cytokines including tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6; elevations in C-reactive protein (CRP) and the coagulation marker D-dimer;32,33 and fibrosis of lymphatic tissue, including extensive collagen deposition in the gut-associated lymphoid tissue (GALT).34–36
Although HAART reduces immune activation, virologically suppressed patients on HAART maintain levels of activated CD4 and CD8 T cells that are significantly higher than those in HIV-negative subjects (Fig. 2), both in peripheral blood and lymph nodes.5,37,38 Similarly, elite controllers—patients who maintain viral load <50 copies per milliliter without antiretroviral therapy—have higher levels of activated T cells than uninfected controls.39 Studies show an inverse correlation between T-cell activation and CD4 restoration,37,39–41 both among HAART-treated patients37 and elite controllers.39 Moreover, both high levels of T-cell activation and low CD4 counts have been correlated with clinical events.6,7,14,17,18 Thus, modulating immune activation may affect CD4 count and vice versa, and it is unclear whether modulating either variable will result in clinical benefit. To date, connections among immune activation, immunodeficiency, and adverse outcomes are based on correlation studies.
Immune Activation and Cardiovascular and Other Clinical Events
Markers of inflammation and coagulation are also elevated in HIV-positive persons compared with uninfected controls.33 A comparison of HIV-infected patients from the Strategies for Management of Antiretroviral Therapy (SMART) study with participants from 2 population-based studies showed that SMART participants had higher levels of IL-6, hsCRP, D-dimer, and cystatin-C, although the majority of SMART participants were virologically suppressed on HAART.33 The increased levels of IL-6 and hsCRP were predictors of clinical events, including all-cause mortality and AIDS-related opportunistic infections.9,10,33,42 Other studies have corroborated the association between elevated hsCRP and cardiovascular events43 or progression of atherosclerosis.44,45 More broadly, indices of activation and inflammation in HAART-treated patients have been associated with clinical events and mortality.9,10,46 Together with associations between low on-treatment CD4 counts and clinical events (Fig. 1),14–19 these findings suggest that persistent immune activation and incomplete CD4 restoration may contribute to the excess risk of morbidity and mortality in HIV-infected individuals, despite suppressive HAART.
POTENTIAL MECHANISMS OF IMMUNE ACTIVATION AND TARGETS FOR INTERVENTION
Drivers of Immune Activation
What drives immune activation? Several hypotheses, not mutually exclusive, have been proposed. Potential drivers include residual HIV replication, microbial translocation, and coinfections. Fibrosis of lymphatic tissue may drive immune activation indirectly by preventing CD4 T-cell restoration. Each of these proposed drivers has implications for intervention.
Residual Viral Replication
If ongoing HIV replication in tissue compartments drives chronic immune activation, suppressing residual replication with intensification of HAART should be beneficial. However, intensification has been attempted with generally disappointing results.47–51 Intensification with abacavir,48 raltegravir,47,49–51 or maraviroc52,53 yielded no consistent evidence of additional viral suppression (as measured by plasma viral load) beyond that achieved by the existing HAART regimen. However, some intensification studies showed reduced T-cell activation47,49,52,53 without effect on residual viremia,52 suggesting that agents such as maraviroc or raltegravir may have direct immunomodulatory effects.
In the small, uncontrolled study of maraviroc intensification by Wilkin et al,52 the decrease in immune activation markers did not correlate with CD4 increases. However, other studies suggest that blocking CCR5 is associated with an enhanced immunologic response.54 Maraviroc has been associated with enhanced CD4 responses compared with other regimens in both treatment-naive and treatment-experienced patients,55,56 independent of viral load suppression.57 The mechanism may be linked to decreased immune activation: in one subanalysis, maraviroc-induced CD4 cell increases correlated with decreases in CD4 and CD8 cell activation.58
In individuals with virologic suppression who intensified their maraviroc therapy for different reasons, the effects on immune activation are controversial. In 2 different single-arm studies,52,59 CD38 expression was diminished with maraviroc, whereas in another recently reported placebo-controlled study, maraviroc was associated with modest increases in CD38 and HLA-DR on circulating and gut mucosal cells.60 The reason for the disparity in results is unclear; however, in the former studies, samples were examined fresh after overnight shipping or in real time, whereas in the latter study, cells were cryopreserved on site and examined in batch at the end of the study.
Damage to the gastrointestinal tract during acute HIV infection is both immunologic (massive depletion of CD4 T cells) and structural. The latter includes damage to the gastrointestinal epithelium with loss of mucosal integrity,61 and may include massive apoptosis of intestinal epithelial cells.62 One cause of this enteropathy could be the loss of Th17 cells, a subset of CD4 T cells known to produce cytokines that help maintain gut enterocytes.63,64 The damaged gastrointestinal tract allows microbial translocation. Consistent with this hypothesis, levels of circulating plasma lipopolysaccharide (LPS),65 bacterial 16S rDNA,66 and peptidoglycan (D. Douek, unpublished data, December 2010) are elevated in HIV-infected patients, and plasma LPS and bacterial DNA levels correlate with the frequency of activated T cells.65
If microbial translocation contributes to immune activation, then repairing the gut epithelium, reducing gut bacterial load, or reducing circulating LPS might dampen it. This is an area of active research. Oral bovine colostrum was shown to promote GALT development and enhance CD4 counts.67 Aryl hydrocarbon receptor agonists promote Th17 cell differentiation in vitro.68 Ongoing trials are evaluating nonabsorbable antibiotics such as rifaximin to decrease gut bacterial load (clinicaltrirals.gov identifier NCT00603616), and the phosphate binder sevelamer has shown LPS-binding properties that could reduce circulating LPS.69
LPS may promote T-cell activation through stimulation of toll-like receptor (TLR) 4.70 TLRs are central to the innate immune system, and exposure of PBMCs to TLR ligands results in CD4 and CD8 T-cell activation.70 This suggests that systemic exposure to TLR agonists may drive T-cell activation and death during the chronic stage of HIV infection. Consistent with this hypothesis, a recent study showed that hydroxychloroquine, which modulates the TLR pathway, reduced immune activation and increased percentages of circulating CD4 cells in HIV-infected immunologic nonresponders.71
Occult or Apparent Coinfections
A large proportion of activated CD8 cells in HIV infection are specific for cytomegalovirus (CMV).72 One study of CMV-seropositive HAART-treated patients showed that valganciclovir suppressed CMV infection and reduced CD8 cell activation, although there was no effect on CD4 cells.73 If immune activation is driven by coinfecting pathogens including CMV, targeting those pathogens may reduce activation. Although valganciclovir failed due to poor tolerability, other agents may prove useful.
Fibrosis of lymphatic tissue is linked to persistent CD4 cell depletion.35,36,74,75 Collagen deposition may disrupt lymph node architecture, preventing maintenance and reestablishment of naive CD4 cell populations.36 Antifibrotic agents such as pirfenidone could prevent fibrosis in the GALT early in infection, limiting the initial massive CD4 cell depletion (for the few patients diagnosed in the acute phase of infection). Using such agents to reverse established fibrosis could help reconstitute CD4 cells. Although to our knowledge there is currently no clinical data on the use of antifibrotics for reversal or prevention GALT fibrosis, a recent study showed that patients with pulmonary fibrosis benefitted from treatment with pirfenidone.76
Mediators of Immune Activation
Proposed interventions may also target immune activation pathways directly. One study is evaluating chloroquine for blocking TLR signaling (clinicaltrials.gov: NCT00819390). Other possibilities include blocking IL-6, IL-1, and TNF, cytokines that contribute to early destruction in the gut.65,77 However, blocking cytokines may have unintended consequences in an already immunosuppressed population: IL-6 and IL-1 help respond to viral pathogens, while blocking TNF is associated with increased mycobacterial infections and lymphomas.78–80
Host Target Cells for the Virus
Because CD4 cell depletion likely contributes to immune activation, other interventions could interrupt the cycle of infection and depletion of host target cells. These interventions would also affect viral replication and could contribute to eradication strategies.
Target Cell Availability
The absence of CCR5 on CD4 T cells renders them uninfectable by R5 tropic HIV.81–83 Targeted gene therapy to downregulate or block CCR5 may confer resistance to HIV-1 acquisition.84,85 Ongoing studies are treating virologically suppressed patients with low CD4 cell counts by removing CD4 cells, genetically modifying them with zinc finger nuclease (ZFN) technology to inactivate CCR5, and reinfusing the cells.85,86 Perez et al86 reported in preclinical studies that adenovirus vector delivery of the CCR5-targeted ZFN pair led to disruption of ∼50% of CCR5 alleles in populations of primary human CD4 T cells and generated HIV-resistant primary CD4 T cells that expanded stably in HIV-infected cultures. When the cells were transplanted into an immunodeficient mouse followed by infection with CCR5-tropic HIV, the ZFN-modified T cells preferentially expanded. This approach is currently being tested in a phase 1 trial at the University of Pennsylvania (clinicaltirals.gov: NCT00842634).
The feasibility of T cell–based and hematopoetic stem cell (HSC)–based gene therapy for HIV-1 has been shown in humans. Mitsuyasu et al87 showed that autologous HSCs transduced with the anti-HIV ribozyme OZ1 was safe and lowered HIV-1 load. Levine et al88 infused patients with autologous CD4 T cells modified by lentiviral vectors to express an antisense to HIV env. In a follow-up study, Tebas et al89 showed a decrease in viral load in the majority (88% [7/8]) of patients after stopping antiretroviral therapy, with one patient maintaining undetectable HIV RNA for 104 days. These novel therapeutic approaches will need to achieve a high bar of viral eradication or functional cure by replicating the outcome in the “Berlin” patient (discussed below)90,91 to proceed to advanced clinical development. Even if such approaches are successful, the challenges for widespread implementation will be considerable.
Target Cell Renewal
Increasing the CD4 count may interrupt disease progression, but will likely need to be coupled with viral suppression or with reducing the infectability of target (CD4) cells to be of lasting clinical value. The cytokines IL-2 and IL-7 are important drivers of proliferation and differentiation of T cells. Although recent results showed no benefit to expanding CD4 T cells using IL-2,92 studies are ongoing with IL-7. In 2 phase 1/2a studies, IL-7 for HAART-treated patients with undetectable HIV RNA and low CD4 counts (100–400 cells/mm3) reconstituted naive and central memory CD4 and CD8 T cells.93,94 Trials will be required to assess the clinical benefit conferred by this result, and it is still unclear what level of evidence must be demonstrated in proof-of-concept studies to justify embarking on large clinical endpoint trials.
PROPOSED INTERVENTIONS AND CLINICAL ENDPOINTS
The results of the IL-2 trials (Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy and Evaluation of Subcutaneous Proleukin in a Randomized International Trial) show the challenge of designing a study to demonstrate the clinical benefit of a proposed intervention in the current HAART era. Although IL-2 caused a substantial and sustained increase in CD4 T cells, the increases yielded no benefit in terms of reduced clinical events.92 Unexpectedly, a higher relative risk of clinical progression to AIDS was observed in patients with the greatest expansion of CD4 cells. On further analysis, the expanded CD4 T cells showed characteristics of regulatory T cells.95 A key challenge, then, in developing disease-modifying interventions is showing that a biomarker or combination of biomarkers is a surrogate for disease progression such that influencing that marker translates into clinical benefit before proceeding to large clinical endpoint trials. Current treatment guidelines recommending that nearly all HIV-infected individuals receive antiretroviral therapy make designing trials for new agents even more difficult because the number of events expected to occur in this population is relatively small.96,97
Proof-of-Concept Phase 2 Studies and Phase 3 Trial Design for Potential Therapies
In light of the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy and Evaluation of Subcutaneous Proleukin in a Randomized International Trial results, what level of evidence will give confidence that we can affect the disease state? What are the appropriate markers to use in phase 2 to better predict a positive effect on clinical endpoints in phase 3? In addition to total CD4 counts, markers could include T-cell immunophenotypic analyses (eg, activated and regulatory T cells), responses to immunization, parameters of innate immunity (eg, myeloid and plasmacytoid dendritic cells, NK cells), and changes in the viral reservoir (assessed by a validated assay). Other potential markers include CRP, IL-6, and D-dimer, and for interventions aimed at restoring the gut epithelium, LPS, bacterial 16sDNA, and peptidoglycan. Once we have established reliable markers and demonstrated positive phase 2 results, showing an effect on clinical outcomes will require careful consideration of which patient population might benefit from these interventions.
The target population must be defined in the current treatment context, in which nearly all HIV-infected individuals receive antiretroviral therapy, and the population harboring detectable virus has decreased dramatically. Viremic patients with multidrug resistance have the greatest need for new approaches, but elevated immune activation and declining CD4 counts also make them least likely to respond to immunologic therapies. Moreover, the needs of this population are best addressed by the continued development of new antiretroviral agents with different resistance profiles.
Among patients virologically suppressed on HAART, those who achieve a sustained CD4 count >500 cells per cubic millimeter have a very low incidence of clinical events (Fig. 1),14–18,98 such that demonstrating an effect in this population would require prohibitively large and lengthy studies. Even among HAART-suppressed patients with CD4 <500 cells per cubic millimeter, the low frequency of events would mandate a large study. Individuals initiating HAART with CD4 >200 cells per cubic millimeter also have a low likelihood of immunologic nonresponse4,11,12 and a low risk for future events. Thus, the success of HAART eliminates many patients from the potential population for testing new therapies. However, the substantial number of patients who initiate treatment late (with very low CD4 counts)24,25 may benefit from interventions in addition to HAART. Studies to evaluate such interventions should be designed similarly to those evaluating cancer therapies: if a favorable outcome is not obtained after treatment of a small and prespecified number of patients, the approach should be rejected.
Patients initiating HAART with CD4 counts <200 cells per cubic millimeter may fail to normalize CD4 levels even after years of virologic suppression.4,11,12 These patients also develop clinical events that are concentrated during the first year of HAART, when they are at higher risk of AIDS or death,97 and of non-AIDS events.14,99 This population may benefit from disease-modifying therapies and is targeted in ongoing and planned studies. A current study is investigating whether adding a CCR5 antagonist (maraviroc) to HAART decreases the incidence of immune reconstitution inflammatory syndrome in patients initiating treatment with CD4 counts ≤100 cells per cubic millimeter (clinicaltrials.gov: NCT00988780). A planned study will investigate whether adding a CCR5 antagonist to HAART in late-presenting patients (CD4 counts ≤200 per cubic millimeter or an AIDS-defining event) decreases the incidence of subsequent clinical events, including immune reconstitution inflammatory syndrome and new AIDS-defining and non-AIDS–defining events (clinicaltrials.gov: NCT01348308). Both studies target populations at high risk of events, such that dampening immune activation may show benefit.
IL-7 for patients with suboptimal CD4 responses is also under investigation. A previously mentioned phase 1/2a study showed an expanded nonregulatory CD4 T-cell population with IL-7.93 Planned studies will assess IL-7 in HAART-suppressed patients with CD4 cell counts below the limits of normal, with endpoints including T-cell immunophenotyping and clinical events. A sustained increase in CD4 T cells, associated with some evidence of improved function, could justify a phase 3 trial investigating long-term outcomes. Plasma viral load increases have been observed in some HIV-infected persons receiving IL-7, but the increases are transient and to date of unknown significance.93,94
Eradication and Cure
Preventing or slowing disease progression might be facilitated by eradication of HIV. Strategies aimed at clearing HIV from resting CD4 cells have included the use of histone deacetylase inhibitors in combination with HAART.100,101 Recent data, however, suggests that latent viral reservoirs are established in bone marrow hematopoietic progenitor cells as well, underscoring the need to further understand the scope of HIV reservoirs to effectively target them.102 A 40-year-old HIV-positive patient in Berlin who underwent HSC transplantation from a homozygous CCR5delta32 (CCR5-/CCR5-) donor subsequently demonstrated undetectable virus in the absence of antiretroviral therapy.90,91 Engraftment and division of the CCR5-/CCR5- HSCs may have deprived the virus of target cells, thus the case may be proof-of-concept for the disease-modifying strategy of rendering target cells uninfectable. However, chemotherapy, the lymphodepletion regimen, immunosuppression to prevent graft-versus-host disease, or the transplantation itself (via graft-versus-host disease) may have contributed. To test this hypothesis in HAART-treated patients with lymphoma, one could measure the latent viral reservoir both before and after chemotherapy, then before and after CCR5 inhibition (either pharmacologically or via ZFN technology); this would isolate the impact of blocking CCR5 on the viral reservoir. Finally, although the case of the Berlin patient demonstrates the possibility of rendering target cells uninfectable, it also illustrates the technical challenge inherent in developing a cure for HIV infection because the therapy administered in this case is clinically infeasible for the vast majority of patients.
Chronic HIV infection is associated with persistent immune activation and disease progression. Even patients virologically suppressed on HAART for years demonstrate elevated levels of immune activation and chronic inflammation and may eventually develop clinical events, often non-AIDS–defining events. The cause of chronic immune activation in well-controlled HIV infection is unknown. Although residual viral replication probably plays little or no role, there is increasing evidence that microbial translocation and coinfections may be significant contributors. Potential interventions targeting immune activation are emerging, from approaches aimed at directly interfering with inflammatory pathways to those aimed at preventing microbial translocation or decreasing the availability of infectable target cells. The main challenges to developing such therapies include identifying an adequate target population, choosing acceptable surrogate endpoints, and designing feasible studies that will provide positive proof-of-concept that these interventions will translate into long-term clinical benefit, conferring the confidence necessary to embark on large-scale clinical endpoint trials.
1. Kaufmann GR, Zaunders JJ, Cunningham P, et al. Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection. AIDS. 2000;14:2643–2651
2. Mocroft A, Phillips AN, Gatell J, et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet. 2007;370:407–413
3. Moore RD, Keruly JC, Gebo KA, et al. An improvement in virologic response to highly active antiretroviral therapy in clinical practice from 1996 through 2002. J Acquir Immune Defic Syndr. 2005;39:195–198
4. Robbins GK, Spritzler JG, Chan ES, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384. Clin Infect Dis. 2009;48:350–361
5. Valdez H, Connick E, Smith KY, et al. Limited immune restoration after 3 years' suppression of HIV-1 replication in patients with moderately advanced disease. AIDS. 2002;16:1859–1866
6. Liu Z, Cumberland WG, Hultin LE, et al. CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:332–340
7. Giorgi JV, Hultin LE, McKeating JA, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999;179:859–870
8. Hazenberg MD, Otto SA, van Benthem BH, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS. 2003;17:1881–1888
9. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5:E203
10. Rodger AJ, Fox Z, Lundgren JD, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis. 2009;200:973–983
11. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44:441–446
12. Kelley CF, Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009;48:787–794
13. Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46:72–77
14. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22:841–848
15. Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS. 2008;22:2409–2418
16. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166:1632–1641
17. van Lelyveld S, Gras L, Kesselring A, et al. Incomplete immune recovery on HAART is associated with significantly more cardiovascular events and a trend towards more non-AIDS-related malignancies in Dutch ATHENA cohort Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections. February 16–19, 2010 San Francisco, CA
18. Silverberg M, Xu L, Chao C, et al. Immunodeficiency, HIV RNA levels, and risk of non-AIDS-defining cancers Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections. February 16–19, 2010 San Francisco, CA
19. Smith C, Sabin CA, Lundgren JD, et al.and The D:A:D Study Group. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D study. AIDS. 2010;24:1537–1548
20. Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med. 2007;146:87–95
21. Lewden C, Salmon D, Morlat P, et al. Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol. 2005;34:121–130
22. Robbins GK, Spritzler JG, Chan ES, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trial Group protocol 384. Clin Infect Dis. 2009;48:350–361
23. Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010;363:257–265
24. Althoff KN, Gange SJ, Klein MB, et al. Late presentation for human immunodeficiency virus care in the United States and Canada. Clin Infect Dis. 2010;50:1512–1520
25. Smit C, Hallett TB, Lange J, et al. Late entry to HIV care limits the impact of anti-retroviral therapy in the Netherlands. PLoS One. 2008;3:e1949
26. Giorgi JV, Liu Z, Hultin LE, et al. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: Results of 6 years of follow-up. J Acquir Immune Defic Syndr. 1993;6:904–912
27. Lin RY, Nygren EJ, Valinsky JE, et al. T cell immunophenotypes and DR antigen expression in intravenous drug users: relationship to human immunodeficiency virus serology. Arch Allergy Appl Immunol. 1988;87:263–268
28. Sachsenberg N, Perelson AS, Yerly S, et al. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by ki-67 antigen. J Exp Med. 1998;187:1295–1303
29. Lane HC, Masur H, Edgar LC, et al. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1983;309:453–458
30. Hellerstein M, Hanley MB, Cesar D, et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med. 1999;5:83–89
31. Hazenberg MD, Hamann D, Schuitemaker H, et al. T cell depletion in HIV-1 infection: How CD4+ T cells go out of stock. Nat Immunol. 2000;1:285–289
32. Valdez H, Lederman MM. Cytokines and cytokine therapies in HIV infection. AIDS Clin Rev. 1997:187–228
33. Neuhaus J, Jacobs DR Jr., Baker JV, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis. 2010;201:1788–1795
34. Brenchley JM, Schacker TW, Ruff LE, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004;200:749–759
35. Estes J, Baker JV, Brenchley JM, et al. Collagen deposition limits immune reconstitution in the gut. J Infect Dis. 2008;198:456–464
36. Schacker TW, Brenchley JM, Beilman GJ, et al. Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol. 2006;13:556–560
37. Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003;187:1534–1543
38. Fleury S, Rizzardi GP, Chapuis A, et al. Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 2000;97:5393–5398
39. Hunt PW, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008;197:126–133
40. Gandhi RT, Spritzler J, Chan E, et al. Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: Results from ACTG 384. J Acquir Immune Defic Syndr. 2006;42:426–434
41. Anthony KB, Yoder C, Metcalf JA, et al. Incomplete CD4 T cell recovery in HIV-1 infection after 12 months of highly active antiretroviral therapy is associated with ongoing increased CD4 T cell activation and turnover. J Acquir Immune Defic Syndr. 2003;33:125–133
42. Peters LINSIGHT SMART Study Group. . Biomarkers of inflammation and coagulation and risk of non-AIDS death in HIV/hepatitis co-infected patients in the SMART study Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections. February 16–19, 2010 San Francisco, CA
43. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr. 2009;51:268–273
44. Hsue PY, Hunt P, Schnell A, et al. Rapid progression of atherosclerosis at the carotid bifurcation is linked to inflammation in HIV-infected patients Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections. February 16–19, 2010 San Francisco, CA
45. Ross AC, Rizk N, O'Riordan MA, et al. Relationship between inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis. 2009;49:1119–1127
46. Lau B, Sharrett AR, Kingsley LA, et al. C-reactive protein is a marker for human immunodeficiency virus disease progression. Arch Intern Med. 2006;166:64–70
47. Buzón MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010;16:460–465
48. Kolber MA, Saenz MO, Tanner TJ, et al. Intensification of a suppressive HAART regimen increases CD4 counts and decreases CD8+ T-cell activation. Clin Immunol. 2008;126:315–321
49. Yukl SA, Shergill AK, McQuaid K, et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS. 2010;24:2451–2460
50. Hatano H, Hayes TL, Dahl V, et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis. 2011;203:960–968
51. Gandhi RT, Zheng L, Bosch RJ, et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: A randomized controlled trial. PLoS Med. 2010;7:e1000321
52. Wilkin T, Lalama C, Tenorio A, et al. Maraviroc intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG5256 Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections. February 16–19, 2010 San Francisco, CA
53. Gutierrez C, Diaz L, Hernandez-Nova B, et al. Effect of the intensification with CCR5 antagonist on the decay of the HIV-1 latent reservoir and residual viremia In: Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections. February 16–19, 2010 San Francisco, CA
54. Wilkin TJ, Ribaudo HR, Tenorio AR, et al. The relationship of CCR5 antagonists to CD4+ T-cell gain: A meta-regression of recent clinical trials in treatment-experienced HIV-infected patients. HIV Clin Trials. 2010;11:351–358
55. Asmuth DM, Goodrich J, Cooper DA, et al. CD4+
T-cell restoration after 48 weeks in the maraviroc treatment-experienced trials MOTIVATE 1 and 2. J Acquir Immune Defic Syndr. 2010;54:394–397
56. Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis. 2010;201:803–813
57. Saag M, Goodrich J, Fatkenheuer G, et al. A double-blind, placebo-controlled trial of maraviroc in treatment-experienced patients infected with non-R5 HIV-1. J Infect Dis. 2009;199:1638–1647
58. Funderburg N, Kalinowska M, Eason J, et al. Effects of maraviroc and efavirenz on markers of immune activation and inflammation and their association with CD4 cell rises in HIV-infected patients. PLoS One. 2010;5:e13188
59. Hernandez-Novoa B, Madrid N, Vallejo A, et al. Assessment of residual HIV-1 viremia and persistent viral replication in highly suppressed patients: comparison of direct and indirect methods Proceedings from the XVIII International AIDS Conference. July 18–23, 2010 Vienna, Austria
60. Hunt P, Shulman N, Hayes T, et al. Immunomodulatory effects of MVC intensification in HIV-infected individuals with incomplete CD4+
T cell recovery during suppressive ART Proceedings from the 18th Conference on Retroviruses and Opportunistic Infections. February 27–March 2, 2011 Boston, MA
61. Sankaran S, George MD, Reay E, et al. Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration. J Virol. 2008:538–545
62. Li Q, Estes JD, Duan L, et al. Simian immunodeficiency virus-induced intestinal cell apoptosis is the underlying mechanism of the regenerative enteropathy of early infection. J Infect Dis. 2008;197:420–429
63. El Hed A, Khaitan A, Kozhaya L, et al. Susceptibility of human Th17 cells to human immunodeficiency virus and their perturbation during infection. J Infect Dis. 2010;201:843–854
64. Cecchinato V, Trindade CJ, Laurence A, et al. Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol. 2008;1:279–288
65. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–1371
66. Jiang W, Lederman MM, Hunt P, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis. 2009;199:1177–1185
67. Floren CH, Chinenye S, Elfstrand L, et al. ColoPlus, a new product based on bovine colostrum, alleviates HIV-associated diarrhoea. Scand J Gastroenterol. 2006;41:682–686
68. Veldhoen M, Hirota K, Christensen J, et al. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med. 2009;206:43–49
69. Sun PP, Perianayagam MC, Jaber BL. Endotoxin-binding affinity of sevelamer: a potential novel anti-inflammatory mechanism. Kidney Int. 2009;76:S20–S25
70. Funderburg N, Luciano AA, Jiang W, et al. Toll-like receptor ligands induce human T cell activation and death, a model for HIV pathogenesis. PLoS One. 2008;3:e1915
71. Piconi S, Parisotto S, Rizzardini G, et al. Hydroxychloroquine drastically reduces immune activation in HIV-infected, ART-treated, immunological non-responders. Blood. 2011 [published online ahead of print May 16, 2011] doi: 10.1182/blood-2011-01-329060
72. Naeger DM, Martin JN, Sinclair E, et al. Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. PLoS One. 2010;5:e8886
73. Hunt PW, Martin JN, Sinclair E, et al. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011;203:1474–1483
74. Mehandru S, Poles MA, Tenner-Racz K, et al. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med. 2006;3:e484
75. Schacker TW, Reilly C, Beilman GJ, et al. Amount of lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART-associated change in peripheral CD4 cell count. AIDS. 2005;19:2169–2171
76. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): Two randomised trials. Lancet. 2011;377:1760–1769
77. Brenchley JM, Douek DC. The mucosal barrier and immune activation in HIV pathogenesis. Curr Opin HIV AIDS. 2008;3:356–361
78. Siegel CA, Marden SM, Persing SM, et al. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of crohn's disease: a meta-analysis. Clin Gastroenterol Hepatol. 2009;7:874–881
79. Dinarello CA. Anti-cytokine therapeutics and infections. Vaccine. 2003;21(suppl 2):S24–S34
80. Centers for Disease Control and Prevention (CDC). . Tuberculosis associated with blocking agents against tumor necrosis factor-alpha–California, 2002–2003. MMWR Morb Mortal Wkly Rep. 2004;53:683–686
81. deRoda Husman AM, Blaak H, Brouwer M, et al. CC chemokine receptor 5 cell-surface expression in relation to CC chemokine receptor 5 genotype and the clinical course of HIV infection. J Immunol. 1999;163:4597–4603
82. Samson M, Libert F, Doranz BJ, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996;382:722–725
83. Novembre J, Galvani AP, Slatkin M. The geographic spread of the CCR5 Delta32 HIV-resistance allele. PLoS Biol. 2005;3:e399
84. Anderson JS, Walker J, Nolta JA, et al. Specific transduction of HIV-susceptible cells for CCR5 knockdown and resistance to HIV infection: A novel method for targeted gene therapy and intracellular immunization. J Acquir Immune Defic Syndr. 2009;52:152–161
85. Holt N, Wang J, Kim K, et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol. 2010;28:839–847
86. Perez EE, Wang J, Miller JC, et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008;26:808–816
87. Mitsuyasu RT, Merigan TC, Carr A, et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat Med. 2009;15:285–292
88. Levine BL, Humeau LM, Boyer J, et al. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci U S A. 2006;103:17372–17377
89. Tebas P, Stein D, Zifchak L, et al. Prolonged control of viremia after transfer of autologous CD4 T cells genetically modified with a lentiviral vector expressing long antisense to HIV env (VRX496) Proceedings from the 17th Conference on Retroviruses and Opportunistic Infections. February 16–19, 2010 San Francisco, CA
90. Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360:692–698
91. Allers K, Hutter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood. 2011;117:2791–2799
92. Abrams D, Lévy Y, Losso MH, et al.INSIGHT-ESPRIT Study Group, SILCAAT Scientific Committee. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361:1548–1559
93. Levy Y, Lacabaratz C, Weiss L, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest. 2009;119:997–1007
94. Sereti I, Dunham RM, Spritzler J, et al. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood. 2009;113:6304–6314
95. Weiss L, Letimier FA, Carriere M, et al. In vivo expansion of naive and activated CD4+CD25+FOXP3+ regulatory T cell populations in interleukin-2-treated HIV patients. Proc Natl Acad Sci U S A. 2010;107:10632–10637
96. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2011 Rockville, MD Department of Health and Human Services:1–166
97. Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373:1352–1363
98. Guiguet M, Porter K, Phillips A, et al. Clinical progression rates by CD4 cell category before and after the initiation of combination antiretroviral therapy (cART). Open AIDS J. 2008;2:3–9
99. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008;197:1133–1144
100. Lehrman G, Hogue IB, Palmer S, et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005;366:549–555
101. Margolis DM. Eradication therapies for HIV infection: time to begin again. AIDS Res Hum Retroviruses. 2011;27:347–353
102. Carter CC, Onafuwa-Nuga A, McNamara LA, et al. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010;16:446–451
clinical trials; disease-modifying therapy; genetic therapy; HIV infection; immune activation; microbial translocation; proof-of-concept
© 2011 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read