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1.  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.
doi:10.1126/science.1195271
PMCID: PMC3235490  PMID: 21051598
2.  A Pilot Study Assessing the Safety and Latency-Reversing Activity of Disulfiram in HIV-1–Infected Adults on Antiretroviral Therapy 
In this pilot clinical trial, disulfiram was administered to HIV-infected patients on antiretroviral therapy to determine the drug's effect on the latent reservoir. Reservoir size did not change; however, some participants experienced transient increases in viremia. Disulfiram deserves further study as an antilatency agent.
Background. Transcriptionally silent human immunodeficiency virus type 1 (HIV-1) DNA persists in resting memory CD4+ T cells despite antiretroviral therapy. In a primary cell model, the antialcoholism drug disulfiram has been shown to induce HIV-1 transcription in latently infected resting memory CD4+ T cells at concentrations achieved in vivo.
Methods. We conducted a single-arm pilot study to evaluate whether 500 mg of disulfiram administered daily for 14 days to HIV-1–infected individuals on stable suppressive antiretroviral therapy would result in reversal of HIV-1 latency with a concomitant transient increase in residual viremia or depletion of the latent reservoir in resting memory CD4+ T cells.
Results. Disulfiram was safe and well tolerated. There was a high level of subject-to-subject variability in plasma disulfiram levels. The latent reservoir did not change significantly (1.16-fold change; 95% confidence interval [CI], .70- to 1.92-fold; P = .56). During disulfiram administration, residual viremia did not change significantly compared to baseline (1.53-fold; 95% CI, .88- to 2.69-fold; P = .13), although residual viremia was estimated to increase by 1.88-fold compared to baseline during the postdosing period (95% CI, 1.03- to 3.43-fold; P = .04). In a post hoc analysis, a rapid and transient increase in viremia was noted in a subset of individuals (n = 6) with immediate postdose sampling (HIV-1 RNA increase, 2.96-fold; 95% CI, 1.29- to 6.81-fold; P = .01).
Conclusions. Administration of disulfiram to patients on antiretroviral therapy does not reduce the size of the latent reservoir. A possible dose-related effect on residual viremia supports future studies assessing the impact of higher doses on HIV-1 production. Disulfiram affects relevant signaling pathways and can be safely administered, supporting future studies of this drug.
doi:10.1093/cid/cit813
PMCID: PMC3935499  PMID: 24336828
HIV-1 latent reservoir; disulfiram; latency-reversing agents
3.  Systemic Effects of Inflammation on Health during Chronic HIV Infection 
Immunity  2013;39(4):633-645.
Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications, but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affect health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging.
doi:10.1016/j.immuni.2013.10.001
PMCID: PMC4012895  PMID: 24138880
4.  Biomarker reveals HIV's hidden reservoir 
eLife  2014;3:e04742.
Determining the total amount of HIV DNA in people undergoing antiretroviral therapy could accelerate the development of novel therapies and potential cures for HIV infection.
doi:10.7554/eLife.04742
PMCID: PMC4199414  PMID: 25321627
HIV-1; reservoir; antiretroviral therapy; cure; primary infection; Human
5.  The CD8+ Memory Stem T Cell (TSCM) Subset Is Associated with Improved Prognosis in Chronic HIV-1 Infection 
Journal of Virology  2014;88(23):13836-13844.
ABSTRACT
Memory stem T cells (TSCM) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. The hallmarks of HIV-1 pathogenesis are CD4+ T cell depletion and abnormal cellular activation. We investigated the impact of HIV-1 infection on the TSCM compartment, as well as any protective role these cells may have in disease progression, by characterizing this subset in a cohort of 113 subjects with various degrees of viral control on and off highly active antiretroviral therapy (HAART). We observed that the frequency of CD8+ TSCM was decreased in all individuals with chronic, untreated HIV-1 infection and that HAART had a restorative effect on this subset. In contrast, natural controllers of HIV-1 had the highest absolute number of CD4+ TSCM cells among all of the infected groups. The frequency of CD4+ TSCM predicted higher CD8+ TSCM frequencies, consistent with a role for the CD4+ subset in helping to maintain CD8+ memory T cells. In addition, TSCM appeared to be progenitors for effector T cells (TEM), as these two compartments were inversely correlated. Increased frequencies of CD8+ TSCM predicted lower viral loads, higher CD4+ counts, and less CD8+ T cell activation. Finally, we found that TSCM express the mucosal homing integrin α4β7 and can be identified in gut-associated lymphoid tissue (GALT). The frequency of mucosal CD4+ TSCM was inversely correlated with that in the blood, potentially reflecting the ability of these self-renewing cells to migrate to a crucial site of ongoing viral replication and CD4+ T cell depletion.
IMPORTANCE HIV-1 infection leads to profound impairment of the immune system. TSCM constitute a recently identified lymphocyte subset with stem cell-like qualities, including the ability to generate other memory T cell subtypes, and are therefore likely to play an important role in controlling viral infection. We investigated the relationship between the size of the CD8+ TSCM compartment and HIV-1 disease progression in a cohort of chronically infected individuals. Our results suggest that HAART restores a normal frequency of CD8+ TSCM and that the natural preservation of this subset in the setting of untreated HIV-1 infection is associated with improved viral control and immunity. Therefore, the CD8+ TSCM population may represent a correlate of protection in chronic HIV-1 infection that is directly relevant to the design of T cell-based vaccines, adoptive immunotherapy approaches, or the pharmacologic induction of TSCM.
doi:10.1128/JVI.01948-14
PMCID: PMC4248986  PMID: 25253339
6.  Immune activation and HIV persistence: Implications for curative approaches to HIV infection 
Immunological reviews  2013;254(1):326-342.
Summary
Despite complete or near-complete suppression of human immunodeficiency virus (HIV) replication with combination antiretroviral therapy, both HIV and chronic inflammation/immune dysfunction persist indefinitely. Untangling the association between the virus and the host immune environment during therapy might lead to novel interventions aimed at either curing the infection or preventing the development of inflammation-associated end-organ disease. Chronic inflammation and immune dysfunction might lead to HIV persistence by causing virus production, generating new target cells, enabling infecting of activated and resting target cells, altering the migration patterns of susceptible target cells, increasing the proliferation of infected cells, and preventing normal HIV-specific clearance mechanisms from function. Chronic HIV production or replication might contribute to persistent inflammation and immune dysfunction. The rapidly evolving data on these issues strongly suggest that a vicious cycle might exist in which HIV persistence causes inflammation that in turn contributes to HIV persistence.
doi:10.1111/imr.12065
PMCID: PMC3694608  PMID: 23772629
AIDS; immunodeficiency diseases; dell activation; cell differentiation; cell proliferation; inflammation
7.  The End of AIDS: HIV Infection as a Chronic Disease 
Lancet  2013;382(9903):1525-1533.
Antiretroviral therapy has been a spectacular success. People are now asking if the end of AIDS is possible. For those who are motivated to take therapy and who have access to lifelong treatment, AIDS-related illnesses are no longer the primary threat, but a new set of HIV-associated complications have emerged, resulting in a novel chronic disease that for many will span several decades of life. Treatment does not fully restore immune health; as a consequence, a number of inflammation-associated and/or immunodeficiency complications such as cardiovascular disease and cancer are increasing in importance. Cumulative toxicities from exposure to antiretroviral drugs for decades cause clinically-relevant metabolic disturbances and end-organ damage. There are growing concerns that the multi-morbidity associated with HIV disease may impact healthy aging and could overwhelm some health care systems, particularly those in resource-limited regions that have yet to fully develop a chronic care model. Given the problems inherent in treating and caring for a chronic disease that might persist for several decades, a global effort to identify a cure is now underway.
doi:10.1016/S0140-6736(13)61809-7
PMCID: PMC4058441  PMID: 24152939
8.  The Kynurenine Pathway of Tryptophan Catabolism, CD4+ T-Cell Recovery, and Mortality Among HIV-Infected Ugandans Initiating Antiretroviral Therapy 
The Journal of Infectious Diseases  2014;210(3):383-391.
Background. Human immunodeficiency virus (HIV) infection–induced indoleamine 2,3-dioxygenase-1 (IDO) expression in activated monocytes and dendritic cells catabolizes tryptophan to kynurenine and other downstream catabolites that inhibit T-cell proliferation and interleukin 17 (IL-17) production. The prognostic significance of this pathway in treated HIV disease is unknown.
Methods. We measured systemic IDO activity (calculated as the ratio of plasma levels of kynurenine to tryptophan; hereafter, the “KT ratio”) in HIV-infected Ugandans before and during antiretroviral therapy (ART)–mediated viral suppression and its association with the rate of subsequent CD4+ T-cell count recovery and mortality.
Results. Among 435 participants, a higher pre-ART KT ratio was associated with a higher plasma virus load (P < .001) and lipopolysaccharide level (P = .018), a lower CD4+ T-cell count (P < .001), and female sex (P = .047). Through month 12 of ART-mediated viral suppression, the plasma KT ratio decreased by approximately 50% (P < .001). After adjustment for pre-ART CD4+ T-cell count, virus load, age, and sex, a higher month 12 KT ratio predicted a slower rate of subsequent CD4+ T-cell count recovery (P = .001). Thirty-nine participants died. After adjustment for pre-ART CD4+ T-cell count, virus load, body mass index, sex, and age, a higher pre-ART and month 6 KT ratio predicted increased mortality (P ≤ .016).
Conclusions. The kynurenine pathway of tryptophan catabolism independently predicts poor CD4+ T-cell count recovery and increased mortality among HIV-infected Ugandans initiating ART and may be an important target for interventions.
doi:10.1093/infdis/jiu115
PMCID: PMC4148610  PMID: 24585899
Tryptophan; kynurenine; indoleamine 2,3-dioxygenase-1; HIV; mortality; antiretroviral therapy; Uganda
9.  Low Proportions of CD28− CD8+ T cells Expressing CD57 Can Be Reversed by Early ART Initiation and Predict Mortality in Treated HIV Infection 
The Journal of Infectious Diseases  2014;210(3):374-382.
Background. Unlike cytomegalovirus (CMV) infection and aging, human immunodeficiency virus (HIV) decreases the proportion of CD28−CD8+ T cells expressing CD57. Whether this abnormality predicts mortality in treated HIV infection and can be reversed by early antiretroviral therapy (ART) remains unknown.
Methods. We sampled recently HIV-infected individuals (<6 months) and HIV-uninfected controls and compared longitudinal changes in the proportion of CD28−CD8+ T cells expressing CD57 between those who initiated ART early (<6 months) vs later (≥2 years). We also assessed the relationship between this phenotype and mortality in a nested case-control study of ART-suppressed chronically infected individuals.
Results. Compared to HIV-uninfected controls (n = 15), individuals who were recently infected with HIV had lower proportions of CD28−CD8+ T cells expressing CD57 (P < .001), and these proportions increased during ART. The early ART group (n = 33) achieved normal levels, whereas the later ART group (n = 30) continued to have lower levels than HIV-uninfected controls (P = .02). Among 141 ART-suppressed participants in the SOCA study, those in the lowest quartile of CD28−CD8+ T cells expressing CD57 had 5-fold higher odds of mortality than those in the highest quartile (95% CI, 1.6–15.9, P = .007).
Conclusions. Abnormally low proportions of CD28−CD8+ T cells expressing CD57 predict increased mortality during treated HIV infection and may be reversed with early ART initiation.
doi:10.1093/infdis/jiu109
PMCID: PMC4110459  PMID: 24585893
HIV; CD57; CD28; Immunosenescence; aging; mortality; antiretroviral therapy; immune activation
10.  Lymphoma Immune Reconstitution Inflammatory Syndrome in the Center for AIDS Research Network of Integrated Clinical Systems Cohort 
In a multicenter cohort, unmasking immune reconstitution inflammatory syndrome (IRIS) was observed in 12% of HIV-associated lymphomas. Presentation and survival for lymphoma IRIS were similar to non-IRIS, with possibly increased early mortality among IRIS cases.
Background. Lymphoma incidence is increased among human immunodeficiency virus (HIV)–infected individuals soon after antiretroviral therapy (ART), perhaps due to unmasking immune reconstitution inflammatory syndrome (IRIS). Clinical characteristics and survival for unmasking lymphoma IRIS have not been described.
Methods. We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) from 1996 until 2011. Unmasking lymphoma IRIS was defined as lymphoma within 6 months after ART accompanied by a ≥0.5 log10 copies/mL HIV RNA reduction. Differences in presentation and survival were examined between IRIS and non-IRIS cases.
Results. Of 482 lymphoma patients, 56 (12%) met criteria for unmasking lymphoma IRIS. Of these, 12 (21%) had Hodgkin lymphoma, 22 (39%) diffuse large B-cell lymphoma, 5 (9%) Burkitt lymphoma, 10 (18%) primary central nervous system lymphoma, and 7 (13%) other non-Hodgkin lymphoma. Median CD4 cell count at lymphoma diagnosis among IRIS cases was 173 cells/µL (interquartile range, 73–302), and 48% had suppressed HIV RNA <400 copies/mL. IRIS cases were similar overall to non-IRIS cases in histologic distribution and clinical characteristics, excepting more frequent hepatitis B and C (30% vs 19%, P = .05), and lower HIV RNA at lymphoma diagnosis resulting from the IRIS case definition. Overall survival at 5 years was similar between IRIS (49%; 95% confidence interval [CI], 37%–64%) and non-IRIS (44%; 95% CI, 39%–50%), although increased early mortality was suggested among IRIS cases.
Conclusions. In a large HIV-associated lymphoma cohort, 12% of patients met a uniformly applied unmasking lymphoma IRIS case definition. Detailed studies of lymphoma IRIS might identify immunologic mechanisms of lymphoma control.
doi:10.1093/cid/ciu270
PMCID: PMC4102912  PMID: 24755860
HIV/AIDS; lymphoma; Hodgkin lymphoma; non-Hodgkin lymphoma; immune reconstitution inflammatory syndrome
11.  Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations 
Nature  2015;517(7534):381-385.
Despite antiretroviral therapy (ART), HIV-1 persists in a stable latent reservoir1, 2, primarily in resting memory CD4+ T cells3, 4. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed5 and tested both in vitro and in vivo6–8. A key remaining question is whether virus-specific immune mechanisms including cytolytic T lymphocytes (CTL) can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (>98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.
doi:10.1038/nature14053
PMCID: PMC4406054  PMID: 25561180
12.  Markers of inflammation and activation of coagulation are associated with anemia in antiretroviral-treated HIV disease 
AIDS (London, England)  2014;28(12):1791-1796.
Objective
to determine the relationship between inflammatory (IL-6 and hsCRP) and coagulation (D-dimer) biomarkers and the presence and type of anemia among HIV+ individuals.
Design
cross-sectional study
Methods
cART-treated adults participating in an international HIV trial with hemoglobin and mean corpuscular volume (MCV) measurements at entry were categorized by presence of anemia (hemoglobin ≤ 14 g/dL in men and ≤ 12 g/dl in women) and, for those with anemia, by type (microcytic [MCV< 80 fL], normocytic [80–100], macrocytic [>100]). We analyzed the association between inflammation (IL-6 and hsCRP) and coagulation (D-dimer) and hemoglobin, controlling for demographics (age, race, and gender), body mass index, HIV plasma RNA levels, CD4+ T cell counts (nadir and baseline), Karnofsky score, previous AIDS diagnosis, hepatitis B/C co-infection and use of zidovudine.
Results
Among 1,410 participants, 313 (22.2%) had anemia. Of these, 4.1%, 27.2% and 68.7% had microcytic, normocytic and macrocytic anemia, respectively. When compared with participants with normal hemoglobin values, those with anemia were more likely to be older, black, male and on zidovudine. They also had lower baseline CD4+ T cell counts and lower Karnofsky scores. Adjusted relative odds of anemia per two fold higher biomarker levels were 1.22 (P= 0.007) for IL-6, 0.99 for hsCRP (P= 0.86) and 1.35 (P< 0.001) for D-dimer. Similar associations were seen in those with normal and high MCV values.
Conclusions
Persistent inflammation and hypercoagulation appear to be associated with anemia. Routine measurements of hemoglobin might provide insights into the inflammatory state of treated HIV infection.
doi:10.1097/QAD.0000000000000344
PMCID: PMC4499102  PMID: 25003720
HIV; coagulation; D-dimer; CRP; inflammation; IL-6; anemia
13.  Viremic HIV controllers exhibit high plasmacytoid dendritic cell\reactive opsonophagocytic IgG antibody responses against HIV-1 p24 associated with greater antibody isotype diversification 
Identifying the mechanisms of natural control of HIV-1 infection could lead to novel approaches to prevent or cure HIV infection. Several studies have associated natural control of HIV-1 infection with IgG antibodies against HIV-1 Gag proteins (e.g. p24) and/or production of IgG2 antibodies against HIV-1 proteins. These antibodies likely exert their effect by activating anti-viral effector cell responses rather than virus neutralization. We hypothesized that an opsonophagocytic IgG antibody response against HIV-1 p24 that activates plasmacytoid dendritic cells (pDCs) through FcγRIIa would be associated with control of HIV and that this would be enhanced by antibody isotype diversification. Using the Gen2.2 pDC cell line, we demonstrated that pDC-reactive opsonophagocytic IgG antibody responses against HIV-1 p24 were higher in HIV controllers (HIV RNA <2000 copies/mL) than non-controllers (HIV RNA >10,000 copies/mL) particularly in controllers with low but detectable viremia (HIV RNA 75–2000 copies/mL). Opsonophagocytic antibody responses correlated with plasma levels of IgG1 and IgG2 anti-HIV-1 p24 and notably, correlated inversely with plasma HIV RNA levels in viremic HIV patients. Phagocytosis of these antibodies was mediated via FcγRIIa. Isotype diversification (towards IgG2) was greatest in HIV controllers and depletion of IgG2 from immunoglobulin preparations indicated that IgG2 antibodies to HIV-1 p24 do not enhance phagocytosis, suggesting that they enhance other aspects of antibody function, such as antigen opsonization. Our findings emulate those for pDC-reactive opsonophagocytic antibody responses against coxsackie, picorna and influenza viruses and demonstrate a previously undefined immune correlate of HIV-1 control that may be relevant to HIV vaccine development.
doi:10.4049/jimmunol.1402918
PMCID: PMC4492937  PMID: 25911748
14.  Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers 
Abstract
Galectin-9 (Gal-9) is a β-galactosidase-binding lectin that promotes apoptosis, tissue inflammation, and T cell immune exhaustion, and alters HIV infection in part through engagement with the T cell immunoglobulin mucin domain-3 (Tim-3) receptor and protein disulfide isomerases (PDI). Gal-9 was initially thought to be an eosinophil attractant, but is now known to mediate multiple complex signaling events that affect T cells in both an immunosuppressive and inflammatory manner. To understand the kinetics of circulating Gal-9 levels during HIV infection we measured Gal-9 in plasma during HIV acquisition, in subjects with chronic HIV infection with differing virus control, and in uninfected individuals. During acute HIV infection, circulating Gal-9 was detected as early as 5 days after quantifiable HIV RNA and tracked plasma levels of interleukin (IL)-10, tumor necrosis factor (TNF)-α, and IL-1β. In chronic HIV infection, Gal-9 levels positively correlated with plasma HIV RNA levels (r=0.29; p=0.023), and remained significantly elevated during suppressive antiretroviral therapy (median: 225.3 pg/ml) and in elite controllers (263.3 pg/ml) compared to age-matched HIV-uninfected controls (54 pg/ml). Our findings identify Gal-9 as a novel component of the first wave of the cytokine storm in acute HIV infection that is sustained at elevated levels in virally suppressed subjects and suggest that Gal-9:Tim-3 crosstalk remains active in elite controllers and antiretroviral (ARV)-suppressed subjects, potentially contributing to ongoing inflammation and persistent T cell dysfunction.
doi:10.1089/aid.2014.0004
PMCID: PMC4077009  PMID: 24786365
15.  Reply to Karch et al 
The Journal of Infectious Diseases  2014;210(1):159-160.
doi:10.1093/infdis/jiu027
PMCID: PMC4161999  PMID: 24421253
16.  Mitral Annular and Coronary Artery Calcification Are Associated with Mortality in HIV-Infected Individuals 
PLoS ONE  2015;10(7):e0130592.
Background
HIV infection increases cardiovascular risk. Coronary artery calcification (CAC) and mitral annular calcification (MAC) identify patients at risk for cardiovascular disease (CVD). The purpose of this study was to examine the association between MAC, CAC and mortality in HIV-infected individuals.
Methods and Results
We studied 152 asymptomatic HIV-infected individuals with transthoracic echocardiography (TTE) and computed tomography (CT). MAC was identified on TTE using standardized criteria. Presence of CAC, CAC score and CAC percentiles were determined using the modified Agatston criteria. Mortality data was obtained from the Social Security and National Death Indices (SSDI/NDI). The median age was 49 years; 87% were male. The median duration of HIV was 16 years; 84% took antiretroviral therapy; 64% had an undetectable viral load. CVD risk factors included hypertension (35%), smoking (62%) and dyslipidemia (35%). Twenty-five percent of individuals had MAC, and 42% had CAC. Over a median follow-up of 8 years, 11 subjects died. Subjects with CAC had significantly higher mortality compared to those with MAC only or no MAC. The Harrell’s C-statistic of CAC was 0.66 and increased to 0.75 when MAC was added (p = 0.05). MAC, prior CVD, age and HIV viral load were independently associated with higher age- and gender-adjusted CAC percentiles in an adjusted model (p < 0.05 for all).
Conclusion
In HIV patients, the presence of MAC, traditional risk factors and HIV viral load were independently associated with CAC. Presence of CAC and MAC may be useful in identifying HIV-infected individuals at higher risk for death.
doi:10.1371/journal.pone.0130592
PMCID: PMC4488486  PMID: 26132465
17.  Targeting Host Nucleotide Biosynthesis with Resveratrol Inhibits Emtricitabine (FTC)-resistant HIV-1 
AIDS (London, England)  2014;28(3):317-323.
Objective
The M184V mutation in the HIV-1 reverse transcriptase (RT) gene is frequent (> 50 %) in patients, both in resource-rich and resource-limited countries, conferring high-level resistance (> 100-fold) to the cytosine analog RT inhibitors 3TC and FTC. The RT enzyme of M184V HIV-1 mutants has reduced processivity, resulting in reduced viral replication, particularly at low nucleotide (dNTP) levels. We hypothesized that lowering intracellular dNTPs with Resveratrol (RV), a dietary supplement, could interfere with replication of M184V HIV-1 mutants.
Design and Methods
Evaluation of the activity of RV on infection of primary peripheral blood lymphocytes (PBLs) by wild type and M184V mutant HIV-1. We assayed both molecular clones and primary isolates of HIV-1, containing M184V alone and in combination with other RT mutations. Viral infection was quantified by p24 ELISA and by quantitative real-time PCR analysis. Cell viability was measured by MTT assays.
Results
In virus infectivity assays, RV did not inhibit replication of wild-type NL43 (RV EC50 > 10 µM), but it inhibited NL43 184V mutant (RV EC50 = 5.8 µM). These results were confirmed by real-time PCR analysis of early and late products of reverse transcription. RV inhibited molecular clones and primary isolates carrying M184V, alone or in combination with other RT mutations (RV EC50 values ranging 2.5–7.7 µM).
Conclusions
RV inhibits HIV-1 strains carrying the M184V mutation in RT. We propose RV as a potential adjuvant in HIV-1 therapy, particularly in resource limited settings, to help control FTC-resistant M184V HIV-1 mutants.
doi:10.1097/QAD.0000000000000168
PMCID: PMC4469130  PMID: 24326355
HIV-1; drug resistance; cytosine analogs; NRTI; FTC; M184V mutation; antiretroviral therapy; resource-limited setting
18.  Immunologic Basis of Cardiovascular Disease in HIV-Infected Adults 
The Journal of Infectious Diseases  2012;205(Suppl 3):S375-S382.
Cardiovascular complications are more common in human immunodeficiency virus–infected individuals than in age-matched uninfected individuals. Antiretroviral therapy reduces the risk of cardiovascular complications, suggesting that viral replication directly or indirectly causes vascular disease. Long-term effective antiretroviral therapy does not fully restore vascular health, and treated adults continue to have higher-than-expected rates of disease progression. Although this excess risk during therapy is likely due to multiple factors, a growing body of evidence suggests that chronic inflammation, which persists during effective antiretroviral therapy, is directly and causally associated with vascular dysfunction and the accelerated development of atherosclerosis.
doi:10.1093/infdis/jis200
PMCID: PMC3349295  PMID: 22577211
19.  HIV Antibody Characterization as a Method to Quantify Reservoir Size During Curative Interventions 
The Journal of Infectious Diseases  2013;209(10):1613-1617.
Quantitative humoral profiling of recent samples from a human immunodeficiency virus (HIV)–infected adult who was cured following a delta32/delta32 CCR5 stem cell transplant in 2007 revealed no antibodies against p24, matrix, nucleocapsid, integrase, protease, and gp120, but low levels of antibodies against reverse transcriptase, tat, and gp41. Antibody levels to these HIV proteins persisted at high and stable levels in most noncontrollers, elite controllers, and antiretroviral-treated subjects, but a rare subset of controllers had low levels of antibodies against matrix, reverse transcriptase, integrase, and/or protease. Comprehensive HIV antibody profiles may prove useful for monitoring curative interventions.
doi:10.1093/infdis/jit667
PMCID: PMC3997576  PMID: 24286982
antibodies; elite controllers; HIV-1; HIV-1 persistence; serology; viral reservoirs
21.  Disparities in the Quality of HIV Care When Using US Department of Health and Human Services Indicators 
Althoff, Keri N. | Rebeiro, Peter | Brooks, John T. | Buchacz, Kate | Gebo, Kelly | Martin, Jeffrey | Hogg, Robert | Thorne, Jennifer E. | Klein, Marina | Gill, M. John | Sterling, Timothy R. | Yehia, Baligh | Silverberg, Michael J. | Crane, Heidi | Justice, Amy C. | Gange, Stephen J. | Moore, Richard | Kitahata, Mari M. | Horberg, Michael A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Kenneth H. | Hogg, Robert S. | Richard Harrigan, P. | Montaner, Julio SG | Cescon, Angela | Samji, Hasina | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Moore, Richard D. | Carey, John T. | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann N. | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M.John | Deeks, Steven G. | Martin, Jeffrey N. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | Althoff, Keri N. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Morton, Liz | McReynolds, Justin | Lober, William B. | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
We estimated US Department of Health and Human Services (DHHS)–approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ≤200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.
doi:10.1093/cid/ciu044
PMCID: PMC3967825  PMID: 24463281
HIV; quality of care; retention in care; antiretroviral therapy; HIV RNA suppression
22.  Decade-Long Safety and Function of Retroviral-Modified Chimeric Antigen Receptor T-cells 
Science translational medicine  2012;4(132):132ra53.
The success of adoptive T cell gene transfer for treatment of cancer and HIV is predicated on generating a response that is both durable and safe. Here we report long term results from three clinical trials to evaluate gammaretroviral vector engineered T-cells for HIV. The vector encoded a chimeric antigen receptor (CAR) comprised of CD4 linked to the CD3-ζ signaling chain (CD4ζ). CAR T-cells were detected in 98% of samples tested for at least 11 years post-infusion at frequencies that exceed average T cell levels after most vaccine approaches. The CD4ζ transgene retained expression and function. There was no evidence of vector-induced immortalization of cells as integration site distributions showed no evidence of persistent clonal expansion or enrichment for integration sites near genes implicated in growth control or transformation. The CD4ζ T cells have stable levels of engraftment, with decay half-lives that exceed 16 years, in marked contrast to previous trials testing engineered T cells. These findings indicate that host immunosuppression prior to T cell transfer is not required in order to achieve long term persistence of gene-modified T cells. Further, our results emphasize the safety of T cells modified by retroviral gene transfer in clinical application, as measured in >500 patient years of follow up. Thus, previous safety issues with integrating viral vectors are hematopoietic stem cell or transgene intrinsic, and not a general feature of retroviral vectors. Engineered T cells are a promising form of synthetic biology for long term delivery of protein based therapeutics. These results provide a framework to guide the therapy of a wide spectrum of human diseases.
doi:10.1126/scitranslmed.3003761
PMCID: PMC4368443  PMID: 22553251
23.  Delayed switch of antiretroviral therapy after virologic failure associated with elevated mortality among HIV-infected adults in Africa 
AIDS (London, England)  2014;28(14):2097-2107.
Objective
Routine monitoring of plasma HIV RNA among HIV-infected patients on antiretroviral therapy (ART) is unavailable in many resource-limited settings. Alternative monitoring approaches correlate poorly with virologic failure and can substantially delay switch to second-line therapy. We evaluated the impact of delayed switch on mortality among patients with virologic failure in Africa.
Design
A cohort.
Methods
We examined patients with confirmed virologic failure on first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens from four cohorts with serial HIV RNA monitoring in Uganda and South Africa. Marginal structural models aimed to estimate the effect of delayed switch on mortality in a hypothetical trial in which switch time was randomly assigned. Inverse probability weights adjusted for measured confounders including time-updated CD4+ T-cell count and HIV RNA.
Results
Among 823 patients with confirmed virologic failure, the cumulative incidence of switch 180 days after failure was 30% [95% confidence interval (CI) 27–33]. The majority of patients (74%) had not failed immunologically as defined by WHO criteria by the time of virologic failure. Adjusted mortality was higher for individuals who remained on first-line therapy than for those who had switched [odds ratio (OR) 2.1, 95% CI 1.1 –4.2]. Among those without immunologic failure, the relative harm of failure to switch was similar (OR 2.4; 95% CI 0.99–5.8) to that of the entire cohort, although of borderline statistical significance.
Conclusion
Among HIV-infected patients with confirmed virologic failure on first-line ART, remaining on first-line therapy led to an increase in mortality relative to switching. Our results suggest that detection and response to confirmed virologic failure could decrease mortality.
doi:10.1097/QAD.0000000000000349
PMCID: PMC4317283  PMID: 24977440
antiretroviral; cohort studies; HIV; HIV RNA level; inverse probability weight; marginal structural model; time-dependent confounding; treatment failure; viral load
24.  CD8+ T-Cells Count in Acute Myocardial Infarction in HIV Disease in a Predominantly Male Cohort 
BioMed Research International  2015;2015:246870.
Human Immunodeficiency Virus- (HIV-) infected persons have a higher risk for acute myocardial infarction (AMI) than HIV-uninfected persons. Earlier studies suggest that HIV viral load, CD4+ T-cell count, and antiretroviral therapy are associated with cardiovascular disease (CVD) risk. Whether CD8+ T-cell count is associated with CVD risk is not clear. We investigated the association between CD8+ T-cell count and incident AMI in a cohort of 73,398 people (of which 97.3% were men) enrolled in the U.S. Veterans Aging Cohort Study-Virtual Cohort (VACS-VC). Compared to uninfected people, HIV-infected people with high baseline CD8+ T-cell counts (>1065 cells/mm3) had increased AMI risk (adjusted HR = 1.82, P < 0.001, 95% CI: 1.46 to 2.28). There was evidence that the effect of CD8+ T-cell tertiles on AMI risk differed by CD4+ T-cell level: compared to uninfected people, HIV-infected people with CD4+ T-cell counts ≥200 cells/mm3 had increased AMI risk with high CD8+ T-cell count, while those with CD4+ T-cell counts <200 cells/mm3 had increased AMI risk with low CD8+ T-cell count. CD8+ T-cell counts may add additional AMI risk stratification information beyond that provided by CD4+ T-cell counts alone.
doi:10.1155/2015/246870
PMCID: PMC4320893  PMID: 25688354
25.  Immunologic Strategies for HIV-1 Remission and Eradication 
Science (New York, N.Y.)  2014;345(6193):169-174.
Antiretroviral therapy (ART) is able to suppress HIV-1 replication indefinitely in individuals who have access to these medications, are able to tolerate these drugs, and are motivated to take them daily for life. However, ART is not curative. HIV-1 persists indefinitely during ART as quiescent integrated DNA within memory CD4+ T cells and perhaps other long-lived cellular reservoirs. In this review, we discuss the role of the immune system on the establishment and maintenance of this “latent” HIV-1 reservoir. A detailed understanding of how the host immune system shapes the size and distribution of the viral reservoir should lead to the development of a new generation of immune-based therapeutics, which might eventually contribute to a curative intervention.
doi:10.1126/science.1255512
PMCID: PMC4096716  PMID: 25013067

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