TAG HIV Basic Science, Vaccines, and Cure Project Blog

Thai Vaccine Trial Update: AIDS Vaccine Research Subcommittee Squints at the Path Forward

The National Institute for Allergy & Infectious Diseases (NIAID) has an advisory committee that provides input on HIV vaccine research called the AIDS Vaccine Research Subcommittee (AVRS). The AVRS met back in February to discuss the results of the RV144 trial in Thailand and consider their implications for the future of of the field, and specifically for NIAID-supported research efforts. A report summarizing some of the presentations and discussion at the meeting has been posted to the TAG website.

The Makings of Memory CD4 T Cells

Two free full-text reviews addressing the development and functions of memory CD4 T cells are available online from the journal Immunology.

Immunology. 2010 Mar 16. [Epub ahead of print]

The potential of CD4(+) T-cell memory.

McKinstry KK, Strutt TM, Swain SL.

Trudeau Institute, Saranac Lake, NY, USA.

While many aspects of memory T-cell immunobiology have been characterized, we suggest that we know only a fraction of the effector functions that CD4 T cells can bring to bear during secondary challenges. Exploring the full impact of memory CD4 T-cell responses is key to the development of improved vaccines against many prominent pathogens, including influenza viruses, and also to a better understanding of the mechanisms of autoimmunity. Here we discuss factors regulating the generation of memory CD4 T cells during the activation of naïve cells and how the nature of the transition from highly activated effector to resting memory upon the resolution of primary responses might impact memory CD4 T-cell heterogeneity in vivo. We stress that memory CD4 T cells have unique functional attributes beyond the secretion of T helper (Th) subset-associated cytokines that can shape highly effective secondary responses through novel mechanisms. These include the recruitment of innate inflammatory responses at early phases of secondary responses as well as the action of enhanced direct effector functions at later phases, in addition to well-established helper roles for CD8 T-cell and B-cell responses.

Immunology. 2010 Mar 16. [Epub ahead of print]

Memory CD4 T cells: generation, reactivation and re-assignment.

Macleod MK, Kappler JW, Marrack P.

Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Health, Denver, CO.

Immunological memory is one of the features that define the adaptive immune response: by generating specific memory cells after infection or vaccination, the host provides itself with a set of cells and molecules that can prevent future infections and disease. Despite the obvious importance of memory cells, memory CD4 T cells are incompletely understood. Here we discuss recent progress in understanding which activated T cells surmount the barrier to enter into the memory pool and, once generated, what signals are important for memory cell survival. There is still, however, little understanding of how (or even whether) memory CD4 T cells are useful once they have been created; a surprising thought considering the critical role CD4 T cells play in all adaptive primary immune responses. In light of this, we will discuss how CD4 T memory T cells respond to reactivation in vivo and whether they are malleable to a re-assignment of their effector response.

Have Rumors of Poor Gut CD4 T Cell Reconstitution Been Greatly Exaggerated?

In recent years, loss of CD4 T cells from the gut of HIV-positive people has become a major research focus. Gut CD4 T cell depletion happens rapidly after infection, and many studies have suggested that recovery of these cells is typically limited even after prolonged antiretroviral therapy (ART). However, the bleakest data has been obtained by measuring the percentage of CD4 T cells in the gut relative to other lymphocytes, and this can produce misleading results because CD8 T cell numbers are increased in the setting of HIV infection.

A new paper from Irini Sereti’s laboratory at NIAID reports that the picture is far more encouraging when absolute numbers of CD4 T cells are measured. Taking samples from both the colon and terminal ileum, the researchers show that absolute CD4 T cell numbers among people on long-term (>5 years) ART with viral loads less than 50 copies are comparable to uninfected controls. The numbers are expressed as CD4 T cells per gram of tissue and the results for the ART-treated vs. control group were as follows: 3.9x10⁶ vs. 3.6x10⁶ (colon) and 1.0x10⁶ vs. 1.6x10⁶ (terminal ileum). The researchers note that in some prior papers, “the persistence of a high proportion of CD8 T cells in HIV-infected patients appeared to result in an underestimation of CD4 T cell reconstitution…our findings are in agreement with recent studies using both immunohistochemistry and flow cytometric analyses; some of these have suggested that gut CD4 T-cell reconstitution may even exceed what occurs in peripheral blood.”

The researchers also write: “It has also been proposed that initiating ART therapy during acute infection may result in more rapid and complete reconstitution of the CD4 T-cell population in the gut. Three of the four patients in this study who reconstituted their CD4 T-cell counts in the colon to values higher than the median of the HIV-uninfected group had peripheral nadir CD4+ T-cell counts of less than 250 cells per microliter. This suggests that CD4 T-cell restoration may occur despite substantial disease progression before ART initiation.”

Mucosal Immunology (2010) 3, 172–181; doi:10.1038/mi.2009.129; published online 2 December 2009

Cycling of gut mucosal CD4+ T cells decreases after prolonged anti-retroviral therapy and is associated with plasma LPS levels

E J Ciccone1, S W Read2, P J Mannon3, M D Yao4, J N Hodge1, R Dewar5, C L Chairez1, M A Proschan6, J A Kovacs7 and I Sereti1

1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA 2. The Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA 3. Division of Gastroenterology and Hepatology, University of Alabama-Birmingham, Birmingham, Alabama, USA 4. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA 5. SAIC-Frederick Inc., Frederick, Maryland, USA 6. The Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA 7. The Critical Care Medicine Department, NIH, Bethesda, Maryland, USA

The gut mucosa is an important site of HIV immunopathogenesis with severe depletion of CD4+ T cells occurring during acute infection. The effect of prolonged anti-retroviral therapy (ART) on cycling and restoration of T lymphocytes in the gut remains unclear. Colon and terminal ileal biopsies and peripheral blood samples were collected from viremic, untreated, HIV-infected participants, patients treated with prolonged ART (>5 years), and uninfected controls and analyzed by flow cytometry. In the gut, the proportion of cycling T cells decreased and the number of CD4+ T cells normalized in treated patients in parallel with β7 expression on CD4+ T cells in blood. Cycling of gut T cells in viremic patients was associated with increased plasma LPS levels, but not colonic HIV–RNA. These data suggest that gut T-cell activation and microbial translocation may be interconnected whereas prolonged ART may decrease activation and restore gut CD4+ T cells.

Bananas Over BanLec

A study just published in the Journal of Biochemistry has generated a great deal of press coverage because it reports that a compound derived from bananas can inhibit HIV in a lab dish. The substance, a banana lectin known as BanLec, was first discovered twenty years ago and shown to be a potent mitogen (a substance which non-specifically stimulates T cell proliferation). The mechanism of HIV inhibition appears related to its ability to bind to sugar molecules on the viral envelope, thereby blocking virus attachment and entry into target cells. This mechanism is similar to the broadly neutralizing monoclonal antibody 2G12, although the paper reports that, unlike 2G12, BanLec can inhibit HIV isolates from clade C as well as clade B. The researchers conclude that BanLec might be adapted for use in microbicides, but caution that its mitogenic potential would have to somehow be stymied. Unfortunately many of the press stories have missed this caveat, instead characterizing BanLec as “naturally occurring” as if this is synonymous with safe. But the caveat is crucial, because stimulation of T cell proliferation would carry the risk of increasing susceptibility to HIV infection and causing other untoward inflammation-related toxicities. A Google news search for “BanLec HIV” currently retrieves 156 results, a search for “BanLec mitogen” retrieves none.

J Biol Chem. 2010 Mar 19;285(12):8646-55. Epub 2010 Jan 15.

A Lectin Isolated from Bananas Is a Potent Inhibitor of HIV Replication

Michael D. Swanson‡, Harry C. Winter§, Irwin J. Goldstein§ and David M. Markovitz‡¶‖,1

From the ¶Department of Internal Medicine, Division of Infectious Diseases, ‡Program in Immunology, ‖Cellular and Molecular Biology Program, and

§Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Abstract

BanLec is a jacalin-related lectin isolated from the fruit of bananas, Musa acuminata. This lectin binds to high mannose carbohydrate structures, including those found on viruses containing glycosylated envelope proteins such as human immunodeficiency virus type-1 (HIV-1). Therefore, we hypothesized that BanLec might inhibit HIV-1 through binding of the glycosylated HIV-1 envelope protein, gp120. We determined that BanLec inhibits primary and laboratory-adapted HIV-1 isolates of different tropisms and subtypes. BanLec possesses potent anti-HIV activity, with IC50 values in the low nanomolar to picomolar range. The mechanism for BanLec-mediated antiviral activity was investigated by determining if this lectin can directly bind the HIV-1 envelope protein and block entry of the virus into the cell. An enzyme-linked immunosorbent assay confirmed direct binding of BanLec to gp120 and indicated that BanLec can recognize the high mannose structures that are recognized by the monoclonal antibody 2G12. Furthermore, BanLec is able to block HIV-1 cellular entry as indicated by temperature-sensitive viral entry studies and by the decreased levels of the strong-stop product of early reverse transcription seen in the presence of BanLec. Thus, our data indicate that BanLec inhibits HIV-1 infection by binding to the glycosylated viral envelope and blocking cellular entry. The relative anti-HIV activity of BanLec compared favorably to other anti-HIV lectins, such as snowdrop lectin and Griffithsin, and to T-20 and maraviroc, two anti-HIV drugs currently in clinical use. Based on these results, BanLec is a potential component for an anti-viral microbicide that could be used to prevent the sexual transmission of HIV-1.

Peripheral T Cell Depletion Linked to TB Reactivation in Macaque Model of Coinfection

A new paper in PLoS One by Collin Diedrich and colleagues reports progress in developing an animal model of HIV/TB coinfection. Cynomolgus macaques with latent TB were infected with the pathogenic SIVmac251 and studied to assess the factors associated with reactivation of TB. The authors report that there was a significant correlation between the depletion of peripheral blood CD4 T cells (measured 2–8 weeks after SIV infection) and time to TB reactivation (p=0.011, R² = 0.755). An association with CD4 T cell depletion from the airways was also observed. The data are consistent with a paper from 2008 by Christof Geldmacher that reported an early loss of TB-specific CD4 T cell responses after acute HIV infection. Taken together, these studies offer insight into why TB is frequently the earliest opportunistic disease in people co-infected with both pathogens. Dierdrich et al plan to use their model to explore the pathogenesis of HIV/TB coinfection in greater detail.

PLoS ONE 5(3): e9611. doi:10.1371/journal.pone.0009611

Reactivation of Latent Tuberculosis in Cynomolgus Macaques Infected with SIV Is Associated with Early Peripheral T Cell Depletion and Not Virus Load

Collin R. Diedrich1#, Joshua T. Mattila1#, Edwin Klein2, Chris Janssen2, Jiayao Phuah1, Timothy J. Sturgeon3, Ronald C. Montelaro3, Philana Ling Lin4, JoAnne L. Flynn1*

1 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America, 2 Division of Laboratory Animal Resources, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America, 3 Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America, 4 Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America

HIV-infected individuals with latent Mycobacterium tuberculosis (Mtb) infection are at significantly greater risk of reactivation tuberculosis (TB) than HIV-negative individuals with latent TB, even while CD4 T cell numbers are well preserved. Factors underlying high rates of reactivation are poorly understood and investigative tools are limited. We used cynomolgus macaques with latent TB co-infected with SIVmac251 to develop the first animal model of reactivated TB in HIV-infected humans to better explore these factors. All latent animals developed reactivated TB following SIV infection, with a variable time to reactivation (up to 11 months post-SIV). Reactivation was independent of virus load but correlated with depletion of peripheral T cells during acute SIV infection. Animals experiencing reactivation early after SIV infection (<17 weeks) had fewer CD4 T cells in the periphery and airways than animals reactivating in later phases of SIV infection. Co-infected animals had fewer T cells in involved lungs than SIV-negative animals with active TB despite similar T cell numbers in draining lymph nodes. Granulomas from these animals demonstrated histopathologic characteristics consistent with a chronically active disease process. These results suggest initial T cell depletion may strongly influence outcomes of HIV-Mtb co-infection.

Modeling HIV Transmission: New SHIV Recapitulates Differences in Risk by Mucosal Route

An important goal of animal model studies is to recapitulate HIV infection in humans as closely as possible. For researchers working on strategies to prevent transmission, the priority is to mimic the efficiency of virus transfer across different mucosal surfaces. A study just published in the Journal of Infectious Diseases reports that in macaques, an HIV-SIV hybrid called SHIV‐1157ipd3N4 (comprising a backbone of SIVmac239 with the envelope of an R5-using primary clade C HIV isolate) shows differing transmission efficiencies via oral, vaginal and rectal routes that are within the same range reported for HIV in humans. The researchers also show that the induction of inflammation increased the efficiency of transmission, as is also the case in humans, although this was demonstrated only via the oral route in this first study. The paper concludes with the suggestion that SHIV‐1157ipd3N4 “could be a biologically relevant tool to assess mechanisms of mucosal transmission, including the role played by local inflammation and coinfection with other pathogens, and it could also be used to assess the protective potential of microbicides or vaccines in macaques of either Indian or Chinese origin against mucosal challenge.”

The Journal of Infectious Diseases 2010;201:1155–1163

DOI: 10.1086/651274

MAJOR ARTICLE

Relative Transmissibility of an R5 Clade C Simian‐Human Immunodeficiency Virus Across Different Mucosae in Macaques Parallels the Relative Risks of Sexual HIV‐1 Transmission in Humans via Different Routes

Agnès L. Chenine,2,3,a Nagadenahalli B. Siddappa,2,3 Victor G. Kramer,2 Gaia Sciaranghella,2,3 Robert A. Rasmussen,2,3 Sandra J. Lee,1 Michael Santosuosso,3,4 Mark C. Poznansky,3,4 Vijayakumar Velu,6 Rama R. Amara,6 Chris Souder,6 Daniel C. Anderson,6 François Villinger,6 James G. Else,6 Francis J. Novembre,6 Elizabeth Strobert,6 Shawn P. O’Neil,3,5 W. Evan Secor,7 and Ruth M. Ruprecht2,3

1Department of Biostatistics and Computational Biology, 2Dana‐Farber Cancer Institute, 3Harvard Medical School, 4Partners AIDS Research Center and Infectious Diseases Medicine, Massachusetts General Hospital, Boston, 5New England Primate Research Center, Southborough, Massachusetts; 6Yerkes National Primate Research Center, Emory University, and 7Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

Background. Worldwide, 90% of all human immunodeficiency virus (HIV) transmissions occur mucosally; almost all involve R5 strains. Risks of sexual HIV acquisition are highest for rectal, then vaginal, and finally oral exposures.

Methods. Mucosal lacerations may affect the rank order of susceptibility to HIV but cannot be assessed in humans. We measured relative virus transmissibility across intact mucosae in macaques using a single stock of SHIV‐1157ipd3N4, a simian‐human immunodeficiency virus encoding a primary R5 HIV clade C env (SHIV‐C).

Results. The penetrability of rhesus macaque mucosae differed significantly, with rectal challenge requiring the least virus, followed by vaginal and then oral routes ( , oral vs vaginal;  rectal vs vaginal). These findings imply that intrinsic mucosal properties are responsible for the differential mucosal permeability. The latter paralleled the rank order reported for humans, with relative risk estimates within the range of epidemiological human studies. To test whether inflammation facilitates virus transmission—as predicted from human studies—we established a macaque model of localized buccal inflammation. Systemic infection occurred across inflamed but not normal buccal mucosa.

Conclusion. Our primate data recapitulate virus transmission risks observed in humans, thus establishing R5 SHIV‐1157ipd3N4 in macaques as a robust model system to study cofactors involved in human mucosal HIV transmission and its prevention.

HIV Vaccine Research – Opinion, Perspective & Review in Nature

The new issue of the journal Nature contains three articles offering summaries of the hurdles facing the HIV vaccine field, and recommendations for overcoming them. In what is perhaps not a surfeit of generosity, the opinion piece by Wayne Koff is being offered free of charge for one week.

Opinion

Nature 464, 161-162 (11 March 2010) | doi:10.1038/464161a; Published online 10 March 2010

Accelerating HIV vaccine development

Wayne C. Koff

Abstract

Translational-research programmes supported by flexible, long-term, large-scale grants are needed to turn advances in basic science into successful vaccines to halt the AIDS epidemic, says Wayne C. Koff.

Perspectives

Nature 464, 224-231 (11 March 2010) | doi:10.1038/nature08898

Immunology and the elusive AIDS vaccine

Herbert W. Virgin1 & Bruce D. Walker2

Developing a human immunodeficiency virus (HIV) vaccine is critical to end the global acquired immunodeficiency syndrome (AIDS) epidemic, but many question whether this goal is achievable. Natural immunity is not protective, and despite immunogenicity of HIV vaccine candidates, human trials have exclusively yielded disappointing results. Nevertheless, there is an indication that success may be possible, but this will be dependent on understanding the antiviral immune response in unprecedented depth to identify and engineer the types of immunity required. Here we outline fundamental immunological questions that need to be answered to develop a protective HIV vaccine, and the immediate need to harness a much broader scientific community to achieve this goal.

1. Washington University School of Medicine and Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Disease Research, Campus Box 8118, 660 South Euclid Avenue, Saint Louis, Missouri 63110, USA 2. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Howard Hughes Medical Institute, 149 13th Street, Charlestown, Massachusetts 02129, USA

Review

Nature 464, 217-223 (11 March 2010) | doi:10.1038/nature08757

Targeting early infection to prevent HIV-1 mucosal transmission

Ashley T. Haase1

Measures to prevent sexual mucosal transmission of human immunodeficiency virus (HIV)-1 are urgently needed to curb the growth of the acquired immunodeficiency syndrome (AIDS) pandemic and ultimately bring it to an end. Studies in animal models and acute HIV-1 infection reviewed here reveal potential viral vulnerabilities at the mucosal portal of entry in the earliest stages of infection that might be most effectively targeted by vaccines and microbicides, thereby preventing acquisition and averting systemic infection, CD4 T-cell depletion and pathologies that otherwise rapidly ensue.

1. Department of Microbiology, University of Minnesota, Minnesota 55455, USA

CD4 T Cells from HIV Controllers Have a Keen Sense of Antigen

Among the more consistent correlates of immunological control of HIV replication is the presence of polyfunctional HIV-specific CD4 T cells that can proliferate vigorously in response to viral antigens, particularly those from the Gag protein. Although there are examples of controllers who lack these responses, they are found in the majority of individuals studied (with a recent report indicating they are present in the rectal mucosa as well as the peripheral blood). In an attempt to shed light on how these responses are maintained in controllers, a group of scientists from the ANRS evaluated how efficiently their HIV-specific CD4 T cells recognized Gag antigens (in immunological terms, this is referred to the avidity of the response).

By using an assay in which the concentration of different Gag antigens (specifically, the epitopes Gag293, Gag263 and Gag161) could be serially reduced, it was found that CD4 T cell responses to Gag293 were significantly more sensitive and mounted robust responses even at minimal epitope concentrations. The researchers suggest that these responses may explain why many controllers are able to maintain HIV-specific CD4 T cell responses even though levels of viral load (and by inference, viral antigens) are typically extremely low. In addition, they recommend considering high avidity as a desirable property for vaccine-induced T cell responses. 

PLoS Pathog. 2010 Feb 26;6(2):e1000780.

HIV Controller CD4+ T Cells Respond to Minimal Amounts of Gag Antigen Due to High TCR Avidity.

Vingert B, Perez-Patrigeon S, Jeannin P, Lambotte O, Boufassa F, Lemaître F, Kwok WW, Theodorou I, Delfraissy JF, Thèze J, Chakrabarti LA; for the ANRS EP36 HIV Controllers Study Group.

Unité d'Immunogénétique Cellulaire, Institut Pasteur, Paris, France.

HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral treatment. Emerging evidence indicates that HIV control is mediated through very active cellular immune responses, though how such responses can persist over time without immune exhaustion is not yet understood. To investigate the nature of memory CD4+ T cells responsible for long-term anti-HIV responses, we characterized the growth kinetics, Vbeta repertoire, and avidity for antigen of patient-derived primary CD4+ T cell lines. Specific cell lines were obtained at a high rate for both HIV controllers (16/17) and efficiently treated patients (19/20) in response to the immunodominant Gag293 peptide. However, lines from controllers showed faster growth kinetics than those of treated patients. After normalizing for growth rates, IFN-gamma responses directed against the immunodominant Gag293 peptide showed higher functional avidity in HIV controllers, indicating differentiation into highly efficient effector cells. In contrast, responses to Gag161, Gag263, or CMV peptides did not differ between groups. Gag293-specific CD4+ T cells were characterized by a diverse Vbeta repertoire, suggesting that multiple clones contributed to the high avidity CD4+ T cell population in controllers. The high functional avidity of the Gag293-specific response could be explained by a high avidity interaction between the TCR and the peptide-MHC complex, as demonstrated by MHC class II tetramer binding. Thus, HIV controllers harbor a pool of memory CD4+ T cells with the intrinsic ability to recognize minimal amounts of Gag antigen, which may explain how they maintain an active antiviral response in the face of very low viremia.

Antiretroviral Therapy Initiation in HIV Controllers

Immunological control of HIV replication in the absence of treatment is associated with relative preservation of CD4 T cell counts. However recent studies have shown that, in most cases, levels of immune activation are still elevated compared to uninfected individuals, and the magnitude of immune activation is associated with the pace of attrition of peripheral blood CD4 T cells over time. A correlation with low-level HIV replication below the standard threshold of detection has also been reported. Eventually, CD4 T cell counts can fall to levels indicating that antiretroviral therapy (ART) should be initiated. As the response to treatment in this setting has not been well described, researchers from the US Military reviewed data from their cohort of HIV positive people in care and found sixty-two individuals who met the criteria for HIV controllers and had started combination ART. Six were defined as elite controllers (based on having three viral loads below the limit of detection for >12 months in the absence of treatment) and 56 were defined as viremic controllers (the same criteria but with a viral load threshold of 2000 copies/mL). CD4 T counts at the time of ART initiation were similar to those in a comparison group of non-controllers (376 vs 366 cells), but viral loads were significantly lower. Both the controllers and non-controllers experienced significant CD4 T cells gains after ART initiation with only a slight trend for smaller increases in the controllers  (151 vs 197 cells after 12 months and 200 vs 230 cells after 24 months). The authors conclude: “Our results support the current treatment guidelines, which emphasize initiating HAART on the basis of CD4 cell count rather than viral load.”

Clinical Infectious Diseases 2010;50:000–000

DOI: 10.1086/651421

BRIEF REPORT

CD4 T Cell Count Reconstitution in HIV Controllers after Highly Active Antiretroviral Therapy

Jason F. Okulicz,1,3 Greg A. Grandits,1,4 Amy C. Weintrob,1,5 Michael L. Landrum,1,3 Anuradha Ganesan,1,2 Nancy F. Crum‐Cianflone,1,6 Brian K. Agan,1 and Vincent C. Marconi7

1Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, and 2Division of Infectious Diseases, National Naval Medical Center, Bethesda, Maryland; 3Infectious Disease Service, San Antonio Military Medical Center, San Antonio, Texas; 4Division of Biostatistics, University of Minnesota, Minneapolis; 5Infectious Disease Service, Walter Reed Army Medical Center, Washington, DC; 6Infectious Disease Clinic, Naval Medical Center San Diego, San Diego, California; and 7Emory University School of Medicine, Atlanta, Georgia

Sixty‐two human immunodeficiency virus (HIV) controllers (6 elite and 56 viremic controllers) in the US Military Department of Defense HIV Natural History Study cohort initiated highly active antiretroviral therapy (HAART) and achieved statistically significant mean CD4 cell count increases, although the gains were lower than those in treated noncontrollers. HIV controllers experienced CD4 cell count reconstitution with HAART regardless of pretherapy viral load, including patients with undetectable viral loads at HAART initiation.

T Cell to T Cell Spread of HIV is Sensitive to Entry Inhibition

One of the most efficient means by which HIV spreads between cells is by promoting cell to cell contacts. The virus is then transferred from infected to uninfected cell via what has been dubbed a “virological synapse.” Some prior studies have raised the concern that this process may be invulnerable to approaches designed to inhibit viral entry into cells, including neutralizing antibodies and entry inhibitor drugs. A new study published in the Journal of Virology offers some reassurance that this is not in fact the case. The researchers show that a variety of entry inhibitors both big (in the form of the monoclonal antibody b12) and small (the CCR5-blocking entry inhibitor compound TAK-779) remain capable of inhibiting infection in the setting of CD4 T cell to CD4 T cell transfer. They suggest prior results may have been misleading due to problems with the readout used to assess infection, and state: “these results are encouraging for use of prophylactic vaccines designed to elicit neutralizing antibodies and for entry inhibitors applied in a prophylactic or therapeutic setting.” There is, however, a caveat in that the results may not apply to other cell types such as macrophages, and the researchers note that some relatively recent data has indicated that transfer of HIV between dendritic cells and CD4 T cells may be resistant to inhibition by neutralizing antibodies. The paper is accompanied online by supplemental videos showing contacts between infected (red) and uninfected (green) cells (video S1) and visualizing the synapse in the context of both X4-using (video S2) and R5-using (video S3) HIV isolates.

Journal of Virology, April 2010, p. 3516-3527, Vol. 84, No. 7

doi:10.1128/JVI.02651-09

Virological Synapse-Mediated Spread of Human Immunodeficiency Virus Type 1 between T Cells Is Sensitive to Entry Inhibition

Nicola Martin,1 Sonja Welsch,2,4 Clare Jolly,3 John A. G. Briggs,4 David Vaux,1 and Quentin J. Sattentau1

The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom,1 Structural Biology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom,2 Wohl Virion Centre and MRC/UCL Centre for Medical Molecular Virology, University College London, London W1T 4JF, United Kingdom,3 Structural and Computational Biology Unit, European Molecular Biology Laboratory, D-69117 Heidelberg, Germany4

Human immunodeficiency virus type 1 (HIV-1) can disseminate between CD4+ T cells via diffusion-limited cell-free viral spread or by directed cell-cell transfer using virally induced structures termed virological synapses. Although T-cell virological synapses have been well characterized, it is unclear whether this mode of viral spread is susceptible to inhibition by neutralizing antibodies and entry inhibitors. We show here that both cell-cell and cell-free viral spread are equivalently sensitive to entry inhibition. Fluorescence imaging analysis measuring virological synapse lifetimes and inhibitor time-of-addition studies implied that inhibitors can access preformed virological synapses and interfere with HIV-1 cell-cell infection. This concept was supported by electron tomography that revealed the T-cell virological synapse to be a relatively permeable structure. Virological synapse-mediated HIV-1 spread is thus efficient but is not an immune or entry inhibitor evasion mechanism, a result that is encouraging for vaccine and drug design.