TAG HIV Basic Science, Vaccines, and Cure Project Blog

SIV Pathogenesis: An Immune Response, Unresolved

SIV infection of two natural host species, sooty mangabeys and African green monkeys (AGMs), is rarely pathogenic. A trio of newly published studies evaluate the changes in gene expression that result from SIV infection in these animals compared to rhesus macaques, in which SIV typically causes T cell loss and simian AIDS. A novel feature of the research is that gene expression is analyzed from very early time points (~3 days onwards) in order to capture any transient changes during acute infection. All three studies report the same key finding: sooty mangabeys and AGMs initially mount an immune response to SIV that is accompanied by massive changes in gene expression, but these changes largely resolve after acute infection. In contrast, altered gene expression – particularly involving genes related to immune activation - persists in pathogenic SIV infection of rhesus macaques. These new papers refute a prior theory that SIV is generally non-pathogenic in sooty mangabeys and AGMs because their immune systems essentially ignore the virus.

The studies place a particular focus on genes related to the production of type 1 interferons and interferon-stimulated genes (ISGs) due to a previous report suggesting that sooty mangabey dendritic cells fail to produce interferon after exposure to SIV. The gene expression data clearly show that interferons and ISGs are massively but transiently upregulated during acute SIV infection in both sooty mangabeys and AGMs. In rhesus macaques, there is also a massive increase in expression of interferon genes and ISGs during acute SIV infection and these genes remain persistently upregulated into the chronic phase.

The research team led by Steven Bosinger also analyzes differences between sooty mangabeys and rhesus macaques by grouping genes together into seven broad categories: cell-mediated immune response, humoral immune response, inflammatory response, immune cell trafficking, cell death, cell cycle and hematopoiesis (click on the image to the left to see detail). The striking contrast that emerges from this analysis is that genes involved in cell mediated, humoral and inflammatory immune responses are more strongly upregulated at day 10 after infection in sooty mangabeys compared to rhesus macaques, but by day 180 this difference is reversed. Cell cycle gene upregulation also disappears by day 180 in sooty mangabeys but remains significantly upregulated in rhesus macques, consistent with pathogenic SIV infection causing increased T cell turnover. In both sooty mangabeys and AGMs, the rapid curtailment of immune activation after acute infection is associated with the upregulation of genes known to be involved in downmodulating immune responses.

The overall picture conveyed by the data is that sooty mangabeys and AGMs make a potent innate and adaptive immune response against SIV immediately after infection, but this immune response resolves (despite the fact that relatively high levels of SIV replication persist in the chronic phase). In contrast, rhesus macaques make a weaker initial response and continue to mount responses throughout the course of infection. A systems biology analysis by Bosinger and colleagues identifies the T cell exhaustion marker LAG3 as being a strong correlate of persistent immune activation in macaques, perhaps suggesting that T cell dysfunction plays an important role in the unresolved immune response against SIV in these animals.

J. Clin. Invest.  doi:10.1172/JCI40115.

Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys (free access to full text)

Steven E. Bosinger1,2, Qingsheng Li3, Shari N. Gordon1, Nichole R. Klatt1, Lijie Duan3, Luoling Xu2, Nicholas Francella1, Abubaker Sidahmed2, Anthony J. Smith3, Elizabeth M. Cramer1, Ming Zeng3, David Masopust3, John V. Carlis4, Longsi Ran2, Thomas H. Vanderford1, Mirko Paiardini1, R. Benjamin Isett5, Don A. Baldwin1,5, James G. Else6, Silvija I. Staprans7, Guido Silvestri1,6, Ashley T. Haase3 and David J. Kelvin2,8

1 Department of Pathology and Laboratory Medicine, and Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2 Division of Experimental Therapeutics, University Health Network, Toronto, Ontario, Canada. 3 Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA. 4 Department of Computer Science and Engineering, Institute of Technology, University of Minnesota, Minneapolis, Minnesota, USA. 5 Penn Microarray Facility, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 6 Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA. 7 Merck Vaccines and Infectious Diseases, Merck and Co., West Point, Pennsylvania, USA. 8 Division of Immunology, International Institute of Infection and Immunity, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China.

Authorship note: Steven E. Bosinger and Qingsheng Li, as well as Guido Silvestri, Ashley T. Haase, and David J. Kelvin, contributed equally to this work.

Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs) in blood and lymph nodes. While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of the lymphocyte inhibitory receptor LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV.

J. Clin. Invest.  doi:10.1172/JCI40093.

Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response (free access to full text)

Béatrice Jacquelin1, Véronique Mayau1, Brice Targat2, Anne-Sophie Liovat1, Désirée Kunkel1, Gaël Petitjean1, Marie-Agnès Dillies3, Pierre Roques4, Cécile Butor5, Guido Silvestri6, Luis D. Giavedoni7, Pierre Lebon8, Françoise Barré-Sinoussi1, Arndt Benecke2,9 and Michaela C. Müller-Trutwin1

1 Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France. 2 Institut des Hautes ωtudes Scientifiques, Bures-sur-Yvette, France. 3 Institut Pasteur, Plateforme 2, Paris, France. 4 CEA, Division of Immuno-Virology, DSV/iMETI, Fontenay-aux-Roses, and Université Paris-Sud 11, UMR E01, Orsay, France. 5 Laboratoire d’Immunologie Humaine, INSERM U743, and Université Paris Diderot, Paris, France. 6 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 7 Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA. 8 Hôpital Saint-Vincent de Paul and Université Paris Descartes, Laboratoire de Virologie, Paris, France. 9 Institut de Recherche Interdisciplinaire, CNRS USR3078, Lille, France.

African green monkeys (AGMs) infected with the AGM type of SIV (SIVagm) do not develop chronic immune activation and AIDS, despite viral loads similar to those detected in humans infected with HIV-1 and rhesus macaques (RMs) infected with the RM type of SIV (SIVmac). Because chronic immune activation drives progressive CD4+ T cell depletion and immune cell dysfunctions, factors that characterize disease progression, we sought to understand the molecular basis of this AGM phenotype. To this end, we longitudinally assessed the gene expression profiles of blood- and lymph node–derived CD4+ cells from AGMs and RMs in response to SIVagm and SIVmac infection, respectively, using a genomic microarray platform. The molecular signature of acute infection was characterized, in both species, by strong upregulation of type I IFN–stimulated genes (ISGs). ISG expression returned to basal levels after postinfection day 28 in AGMs but was sustained in RMs, especially in the lymph node–derived cells. We also found that SIVagm induced IFN-α production by AGM cells in vitro and that low IFN-α levels were sufficient to induce strong ISG responses. In conclusion, SIV infection triggered a rapid and strong IFN-α response in vivo in both AGMs and RMs, with this response being efficiently controlled only in AGMs, possibly as a result of active regulatory mechanisms.

J. Clin. Invest.  doi:10.1172/JCI41509.

Commentary

Resolution of immune activation defines nonpathogenic SIV infection

Olivier Manches, Nina Bhardwaj

Natural nonhuman primate hosts of SIV do not succumb to AIDS despite significant viral replication, a phenomenon attributed to reduced levels of chronic and deleterious “immune activation.” Two studies in this issue of the JCI, by Bosinger et al. and Jacquelin et al., now show that SIV induces vigorous immune activation and upregulation of IFN-stimulated genes in both natural and susceptible hosts, but strikingly, the responses resolve only in the former (see the related articles, doi:10.1172/JCI40115 and 10.1172/JCI40093, respectively). Thus, natural hosts for SIV actively engage mechanisms to abort sustained immune activation and its associated harmful effects.

JVI Accepts, published online ahead of print on 25 November 2009

J. Virol. doi:10.1128/JVI.01496-09

Non pathogenesis of SIV infection is associated with reduced inflammation and recruitment of plasmacytoid dendritic cells to lymph nodes, not to lack of an interferon type I response, during the acute phase.

Laure Campillo-Gimenez, Mireille Laforge, Michèle Fay, Audrey Brussel, Marie-Christine Cumont, Valérie Monceaux, Ousmane Diop, Yves Lévy, Bruno Hurtrel, John Zaunders, Jacques Corbeil, Carole Elbim, and Jérôme Estaquier

INSERM U955, Faculté Créteil Henri Mondor, Créteil, F-94000, France; Université Paris 7 Denis Diderot, Faculté de Médecine, site Bichat, Paris, F-75018, France; Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 28 rue du Docteur Roux, Paris, F-75015, France; Institut Pasteur, Dakar, Sénégal; Centre for Applied Medical Research, St Vincent's Hospital, Darlinghurst, NSW, Australia; Université Laval, Centre de Recherche en Infectiologie, G1V 4G2 Québec, Canada; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie – Paris 6, UMR S 872, Paris, F-75006 France; Université Paris Descartes, UMR S 872, Paris, F-75006 France; INSERM, U872, Paris, F-75006,France; Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil, France

Abstract

Divergent Toll-like receptor (TLR)-7 and TLR-9 signaling has been proposed to distinguish pathogenic from non pathogenic SIV infection in primate models. Herein, we demonstrate that increased expression of type I IFN in pathogenic rhesus macaques as compared to non pathogenic African green monkeys was associated with the recruitment of plasmacytoid dendritic cells (pDCs) in the lymph nodes and the presence of an inflammatory environment early after infection, instead of a difference in TLR-7/9 response.

Aging, HIV Infection & the Immune System

In the November 9^th issue of New York Magazine, David France reports on the emerging issue of accelerated aging in people with HIV infection. The article offers a series of disturbing vignettes about the complications some individuals are facing as they age, such as bone problems and impaired cognitive function, and raises important questions about how much attention is being paid to the issue by current research, particularly in terms of pursuing new therapeutic options. However, beyond mentioning inflammation, the piece does not really delve into the underlying immunological parallels between HIV infection and aging and consider how they might fit into the picture. This is a potentially important omission, as there is accumulating evidence that the accelerated aging of the immune system that has been documented in people with HIV is likely to be related to many of the clinical phenomena described in France’s article.

Although it’s not the sort of research that makes the front pages, the last decade or so has seen considerable progress in understanding the relationship between immune parameters and aging, and these studies provide a valuable frame of reference. Perhaps most importantly, an “immune risk phenotype” associated with mortality in the elderly has been described in some detail. The major features are an inverted CD4/CD8 T cell ratio, decreased proliferative responses and IL-2 production by T cells, increased levels of inflammatory cytokines (such as IL-6) and increased numbers of CD8 T cells lacking the CD28 co-stimulatory receptor (typically described as senescent cells). All of these immunological perturbations are also seen in HIV infection. Studies have also found that people with the chronic viral infections cytomegalovirus (CMV) and Epstein-Barr virus (EBV) face a greater likelihood of acquiring the immune risk phenotype in old age. The clinical manifestations associated with the phenotype include bone loss and increased fracture risk, cognitive impairment, increased susceptibility to infections and an increased incidence of cancers and cardiovascular, kidney and liver disease.

The overarching theme that is emerging from this research – although it is still in its infancy - is that a lifetime of antigenic challenges (in the form of all the pathogens an individual is exposed to) gradually erodes immune system resources, and this plays a major role in aging. This erosion of immune system resources has multiple facets:

• A steady decline in naive T cell production by the thymus from a torrent in childhood to a trickle in old age.
• Activation of antigen-specific naive T cells every time a new pathogen is encountered, which depletes the naive T cell pool and leads to a subset of these pathogen-specific cells maturing into memory cells (the impact of these episodes of naive T cell activation is minor when the thymus is vigorously producing new cells to replace those lost, but increases as thymic output declines).
• Repeated stimulation of memory T cells by pathogens, which can eventually lead to memory T cell senescence.

Chronic pathogens (that are controlled rather than cleared) play a particularly important role because they place a persistent drain on immune system resources, as indicated by the way that memory T cell responses to CMV accumulate over time, such that 25-30% of CD8 T cells can be CMV-specific in an infected elderly person. Untreated HIV infection has an even greater effect; a young individual with AIDS typically will have lost almost all their naive T cells and 20% or more of their memory CD8 T cells can be HIV-specific. As shown recently in a study of the MACS cohort, a fast accumulation of senescent CD8 T cells lacking the CD28 molecule is associated with rapid progression from HIV infection to AIDS.

Additional insight into how immunological aging relates to health may come from people who have had their thymus removed (a thymectomy) at birth. This procedure is sometimes performed to enable better access to the heart to correct congenital heart defects. A recent study published in the Journal of Clinical Investigation (abstract and accompanying commentary appended below) reported that thymectomized individuals show evidence of accelerated aging of the immune system similar to the immune risk phenotype, but it is not yet known whether this will lead to the same clinical manifestations seen in the elderly. Continued follow-up will be crucial to gaining a better understanding of the relationship between the immunological and clinical consequences of aging.

In terms of HIV infection, the issue of accelerated aging raises many new questions and considerations for future research:

• Is immunology research in HIV adequately prioritized? The main clinical research network in the US, the AIDS Clinical Trials Group (ACTG), once had a specific immunology research committee but it was dissolved a few years ago and squished into a broader committee designated “Translational Research and Drug Development” (TRADD). There may be a case for re-establishing a specific immunology committee within the network.
• Do current research funding mechanisms offer adequate support for multidisciplinary and translational research? The spectrum of clinical manifestations associated with accelerated aging calls for collaborative research between groups specializing in many different disciplines (e.g. immunology, virology, pharmacology, toxicology, musculoskeletal system, cardiovascular, renal, liver, etc.), and support for this type of complex collaboration may call for the design of a specific funding mechanism (RFA). Exploration of novel therapies also requires support for conducting translational clinical research, which can be difficult and complicated to obtain under current grant procedures.
• Will earlier initiation of antiretroviral therapy prevent accelerated aging? Long term follow-up from studies such as ACTG 384 clearly shows that earlier suppression of HIV is associated with an almost complete normalization of many potentially important immune parameters including the CD4/CD8 T cell ratio, the ratio of naive T cells to memory T cells and levels of immune activation. In contrast, among individuals initiating therapy at lower CD4 T cell counts, these parameters improve but do not come close to mirroring those of uninfected individuals even after seven or more years of continuous HIV suppression. This may suggest that people who start treatment earlier will be at less risk for accelerated aging, but this has not yet been established.
• To what extent do drug toxicities contribute to accelerated aging? The fact that there are many close parallels between the immunology of HIV infection and aging argues strongly against drug toxicity being the primary cause, but there are clearly specific toxicities that can contribute to problems such as bone loss and cardiovascular disease. Research needs to parse out the role of drug toxicities so that safer treatments can be developed.
• Can novel therapies be developed to delay or reverse accelerated aging? The current data suggest a number of key targets for therapeutic research, including: enhancing thymic function to boost naive T cell production, reducing immune activation/inflammation and reducing numbers of senescent immune cells. Research is ongoing in these and other areas but greater resources, coordination and prioritization is needed.

TAG’s Hepatitis Coinfection Project and Michael Palm Project are currently collaborating with several other community activists to produce a comprehensive report and advocacy recommendations on HIV and aging. The report will be released next year prior to the International AIDS Conference. 

J. Clin. Invest. doi:10.1172/JCI40855.

Commentary

Reduced thymus activity and infection prematurely age the immune system

http://www.jci.org/articles/view/40855

Ronald E. Gress, Steven G. Deeks

Published September 21, 2009

The aging process affects all aspects of the immune system, particularly the T cells. The immune system in older individuals is often characterized by lower T cell numbers, lower naive/memory T cell ratios, and lower T cell diversity. Most measures of inflammation increase with age. Why this happens, and why there is so much person-to-person variability in these changes, is not known. In this issue of the JCI, Sauce and colleagues show that removal of the thymus during infancy results in premature onset of many of these age-associated changes to the immune system (see the related article, doi:10.1172/JCI39269). The effect of thymectomy was particularly notable in those individuals who acquired CMV infection. Data from this study, as well as data from other observational settings, suggest that reduced thymic function and persistent viral infections combine to accelerate a decline in immunologic function.

J. Clin. Invest. doi:10.1172/JCI39269.

Research Article

Evidence of premature immune aging in patients thymectomized during early childhood (free access to full text)

Delphine Sauce1, Martin Larsen1, Solène Fastenackels1, Anne Duperrier2, Michael Keller3, Beatrix Grubeck-Loebenstein3, Christophe Ferrand2, Patrice Debré1, Daniel Sidi4 and Victor Appay1

1 Infections and Immunity, INSERM UMRS 945, Avenir Group, Hôpital Pitié-Salpêtrière, UPMC University of Paris 06, Paris, France.

2 INSERM U645, Etablissement Français du Sang Bourgogne/Franche-Comté, Besançon, France.

3 Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.

4 Service de Cardiologie Pédiatrique, Hôpital Necker Enfants Malades, Paris, France.

Address correspondence to: Victor Appay, Cellular Immunology Laboratory, INSERM U945, Hôpital Pitié-Salpêtrière, Paris, France. Phone: 33-1-40-77-81-83; Fax: 33-1-42-17-74-90

Published September 21, 2009

Received for publication March 20, 2009, and accepted in revised form July 16, 2009.

While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4+ and CD8+ T cell counts were decreased, and these T cell populations showed substantial loss of naive cells and accumulation of oligoclonal memory cells. A subgroup of these young patients (22 years old) exhibited a particularly altered T cell profile that is usually seen in elderly individuals (more than 75 years old). This condition was directly related to CMV infection and the induction of strong CMV-specific T cell responses, which may exhaust the naive T cell pool in the absence of adequate T cell renewal from the thymus. Together, these marked immunological alterations are reminiscent of the immune risk phenotype, which is defined by a cluster of immune markers predictive of increased mortality in the elderly. Overall, our data highlight the importance of the thymus in maintaining the integrity of T cell immunity during adult life.

Pioneering CD4 T Cells Show CD8 T Cells The Way

Over the past decade it has become clear that CD8 T cells typically require help from CD4 T cells to become fully competent. CD8 T cells perform the viral task of recognizing and killing pathogen-infected cells, and hence are also known as cytotoxic T-lymphocytes (CTL). A study in the advance online section of Nature now reports that CD4 T cells are also needed to guide CD8 T cells to sites of infection in some circumstances. Yusuke Nakanishi and colleagues use a mouse model to show that in the absence of CD4 T cell help, CD8 T cell specific for herpes simplex type 2 (HSV-2) do not traffic to the site of infection in the vaginal mucosa. When CD4 T cells are present, HSV-2-specific CD4 T cells "pioneer" the way to the site of infection, drawing in HSV-2-specific CD8 T cells a day or two later via cytokine and chemokine signals. The researchers conclude:

“Many pathogens invade the host by establishing local infection before spreading to other organs. The recruitment of the effector lymphocytes to the initial site of microbial entry represents an important challenge in ensuring the protection of the host. Our findings indicate that vaccines that target CTL immunity must incorporate T helper epitopes to allow their migration to the site of infection once the pathogen invades the host.”

Nature advance online publication 8 November 2009 | doi:10.1038/nature08511

Letter

CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help

Yusuke Nakanishi1, Bao Lu2, Craig Gerard2 & Akiko Iwasaki1

Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

Pulmonary Division, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

CD4+ T helper cells are well known for their role in providing critical signals during priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. T-cell help is required for the generation of primary CTL responses as well as in promoting protective CD8+ memory T-cell development1. However, the role of CD4 help in the control of CTL responses at the effector stage is unknown. Here we show that fully helped effector CTLs are themselves not self-sufficient for entry into the infected tissue, but rely on the CD4+ T cells to provide the necessary cue. CD4+ T helper cells control the migration of CTL indirectly through the secretion of IFN- and induction of local chemokine secretion in the infected tissue. Our results reveal a previously unappreciated role of CD4 help in mobilizing effector CTL to the peripheral sites of infection where they help to eliminate infected cells.

CD4 T Cells Can Wield a Chemokine Shield Against HIV

A new paper from Joseph Casazza and colleagues at the NIH’s Vaccine Research Center reports that some memory CD4 T cells can shield themselves against HIV infection by releasing beta chemokines. The researchers were following up on prior studies showing that CD4 T cells targeting HIV antigens are preferentially infected with the virus compared to CD4 T cells of other specificities (such as those targeting CMV). 

Looking at CMV-specific CD4 T cells in detail, they found that release of the chemokines MIP-1 alpha and MIP-1 beta is significantly correlated with resistance to HIV infection. These chemokines can inhibit HIV infection, both by blocking virus interactions with the CCR5 co-receptor and causing CCR5 downregulation from the cell surface. The researchers also report that the ability of CMV-specific CD4 T cells to make beta chemokines is linked to the maturational status of the cells; more mature CD4 T cells produce more chemokines. Maturation refers to the progressive acquisition of functions that occurs after a CD4 T cell is initially stimulated. This process is also referred to as differentiation and it typically progresses as CD4 T cells divide.

In contrast with CMV-specific cells, the study found that HIV-specific CD4 T cells rarely produce beta chemokines and are significantly less differentiated. This suggests that HIV infection inhibits the maturation of HIV-specific CD4 T cells, and is consistent with a study of acutely infected individuals which reported that the vast preponderance of HIV DNA is found in HIV-specific CD4 T cells that would normally be expected to mature into functional “memory” cells (these developing memory cells can be identified based on expression of the receptor for IL-7).

Casazza et al note that this research lays the groundwork for the development of strategies aiming to induce CD4 T cell responses against HIV that can self-protect against infection. The next step is to evaluate whether specific types of immunization can bias the virus-specific CD4 T cell response toward the production of the beta chemokines MIP-1 alpha and MIP-1 beta. If a successful approach can be discovered, it could conceivably be very useful for both preventive and therapeutic vaccine development.

PLoS Pathog 5(10): e1000646. doi:10.1371/journal.ppat.1000646

Autocrine Production of β-Chemokines Protects CMV-Specific CD4+ T Cells from HIV Infection

Joseph P. Casazza1*, Jason M. Brenchley2, Brenna J. Hill2, Ribka Ayana1, David Ambrozak1, Mario Roederer3, Daniel C. Douek4, Michael R. Betts5, Richard A. Koup1

1 Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America, 2 Immunopathogenesis Unit, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America, 3 ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America, 4 Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America, 5 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America

Abstract Top

Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1α and MIP-1β mRNA, resulting in a rapid increase in production of MIP-1α and MIP-1β after cognate antigen stimulation. Production of β-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of β-chemokines by CD4+ T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMV-specific CD4+ T cells which produced MIP-1β contained 10 times less Gag DNA than did those which failed to produce MIP-1β. These data suggest that CD4+ T cells which produce MIP-1α and MIP-1β bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.