Gladstone Institute of Virology and Immunology -

Recent Findings

Discovery that unsuccessful HIV infection of "bystander" CD4 T cells causes an accumulation of abortive HIV reverse transcripts, which further elicits innate antiviral and inflammatory responses – and results in death – for these non-permissive cells. (Greene Lab: Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML, Hebbler AM, Greene WC. Abortive HIV infection mediates CD4 T-cell depletion and inflammation in human lymphoid tissue. Cell 143:789–801, 2010. NIHMSID: NIHMS254640)

Key clinical study results from a multi-year, multi-city trial which prove that a single daily tablet of two HIV medications reduces risk of HIV infection in uninfected people. (Grant Lab: Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N. Engl. J. Med. 363:2587–2599, 2010.)

Studies identifying DGAT1 as a key factor in HCV infection, and showing that inhibiting DGAT1 impairs infectious virion production, suggesting a new target for antiviral therapy. (Ott Lab: Herker E, Harris C, Hernandez C, Carpentier A, Kaehlcke K, Rosenberg AR, Farese Jr. RV, Ott M. Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat. Med. 16:1295–1298, 2010.)

Idenfication of SIRT3 as a key protein in enery regulation, as it mediates the acetylation state regulating fatty acid oxidation (Verdin Lab: Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese Jr. RV, Alt FW, Kahn CR, Verdin E. SIRT3 regulates mitrochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–125, 2010. PMCID: PMC2841477)

Findings supporting the model that cyclin T1 acetylation acts as a switch liberating P-TEFb from inhibitors Hexim1 and 7SK snRNA, but is not required for cooperative action with HIV Tat. (Ott Lab: Cho S, Schroeder S, Kaelchke K, Kwon H-S, Pedal A, Herker E, Schnoelzer M, Ott M. Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells. EMBO J. 28:1407–1417, 2009. PMCID: PMC2688543)

Studies revealing methyl-CpG binding domain protein 2 (MBD2) as an epigenic regulator of HIV-1 latency. (Verdin Lab: Kauder S, Bosque A, Lindqvist A, Planelles V, Verdin E. Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Path. 5:e1000495, 2009. PMCID: PMC2695767)

Identification of peptides in human seman capable of forming amyloid fibrils (termed semen-derived enhancer of viral infection or SEVI) that greatly increase HIV infection. (Greene Lab: Roan NR, Muench J, Arhel N, Mothes W, Neidleman J, Kobayashi A, Smith-McCune K, Kirchhoff F, Greene WC. The cationic properties of SEVI underlie its ability to enhance HIV infection. J. Virol. 83:73–80, 2009. PMCID:PMC2612336)

Discovery that Apobec3 encodes Rfv3, a classical gene that influences the production of neutralizing antibody responses in pathogenic retrovirus infection. (Greene Lab: Santiago ML, Montano M, Benitez R, Messer RJ, Yonemoto W, Chesebro B, Hasenkrug KJ, Greene WC. APOBEC3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection. Science 321:1343–1346, 2008.)

Findings demonstrating that the HIV-1 Tat protein induces T cell hyperactivation through inhibition of the deacetylase activity of SIRT1 on NF-kB. (Ott Lab: Kwon H-S, Brent MM, Getachew R, Jayakumar P, Chen L-F, Schnolzer M, McBurney MW, Marmorstein R, Greene WC, Ott M. Human immunodeficiency virus type 1 Tat protein inhibits the SIRT1 deacetylase and induces T cell hyperactivation. Cell Host Microbe 3:158–167, 2008.)

Randomized study providing evidence that growth hormone (GH) treatment of HIV-1-infected adults increases thymic mass and enhances thymic output. (Napolitano Lab: Napolitano LA, Schmidt D, Gotway M, Ameli N, Filbert EL, Ng MM, Clor JL, Epling L, Sinclair E, Baum PD, Li K, Killian ML, Bacchetti P, McCune JM. Growth hormone enhances thymic function in HIV-1–infected adults. J. Clin. Invest. 118:1085–1098, 2008. PMCID:PMC2248326)

Experiments proving that HDAC6-selective compounds have less cytotoxicity toward cancer cells than do pan-HDAC inhibitors. Illustrating synergistic antiproliferative activity with the proteasome inhibitor bortezomib, suggests the potential for combination anticancer therapy with less general toxicity. (Verdin Lab: Schafer S, Saunders L, Eliseeva E, Velena A, Jung M, Schwienhorst A, Strasser A, Diskmanns A, Ficner R, Schlimme S, Sippl W, Verdin E, Jung M. Phenylalanine-containing hydroxamic acids as selective inhibitors of class IIb histone deacetylases (HDACs). Bioorg. Med. Chem. 16:2011–2033, 2008.)

Studies challenging the "Trojen horse" model of HIV trans-infection by showing that the vast majority of virions transmitted in trans originate from the plasma membrane of dendritic cells rather than from intracellular vesicles. (Greene Lab: Cavrois M, Neidleman J, Greene WC. The achilles heel of the Trojan horse model of HIV trans-infection. PLoS Pathog. 4:e1000051, 2008. PMCID: PMC2430767)

Studies revealing the regulation of APOBEC3G expression and complex formation in various primary immune cells. (Greene Lab: Stopak KS, Chiu Y-L, Kropp J, Grant RM, Greene WC. Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells. J. Biol. Chem. 282:3539–3546, 2007.)

Discovery that HIV-1 virions transmitted in trans from dendritic cells to T cells principally originate from the surface of DCs, except during antigen recognition, when some internalized virions may also be transmitted to the antigen specific T cells. (Greene Lab: Cavrois M, Neidleman J, Kreisberg JF, Greene WC. In vitro-derived dendritic cells trans-infect CD4 T cells primarily with surface-bound HIV-1 virions. PLoS Path. 3:e4, 2007.)

Studies revealing that HIV-1 infection of primary, human CD4+ lymphocytes causes G2 arrest in a Vpr-dependant manner and that this response requires activation of the DNA damage sensor ATR kinase, as shown by RNA interference. (Grant and Greene Labs: Zimmerman ES, Sherman MP, Blackett JL, Neidleman JA, Kreis C, Mundt P, Williams SA, Warmerdam M, Kahn J, Hecht FM, Grant RM, de Noronha CMC, Weyrich AS, Greene WC, Planelles V. HIV-1 Vpr induces DNA replication stress in vitro and in vivo. J. Virol. 80:10407–10418, 2006.)

Key studies demonstrating that ABOBEC3G, in conjunction with RNA granules, functions to regulate endogenous mobile genetic elements (e.g., Alu RNAs), whose mobility contributes to a variety of human diseases including cancers and leukemias. (Greene Laboratory: Chiu Y-L, Witkowska HE, Hall SV, Santiago M, Soros V, Esnault C, Heidmann T and Greene WC. High-Molecular-Mass APOBEC3G Complexes Restrict Alu Retrotransposition. Proc. Natl. Acad. Sci. 103:15588–15593, 2006).

Novel finding that high levels of cellular polyamines sensitize tumor cells to histone deacetylase inhibitors, agents currently in clinical trials for cancer therapy. (Verdin Laboratory: Saunders LR, Verdin E. Ornithine decarboxylase activity in tumor cell lines correlates with sensitivity to cell death induced by histone deacetylase inhibitors. Mol. Cancer Ther. 5:2777–2785, 2006.)

Studies proving that laboratory-adapted CCR5-tropic 81A virions fuse rapidly and efficiently to immature MDDCs, whereas NL4-3, the isogenic CXCR4-tropic counterpart of 81A, fuse slowly and inefficiently to both immature and mature MDDCs. (Greene Lab: Cavrois M, Neidleman J, Kreisberg JF, Fenard D, Callebaut C, Greene WC. Human immunodeficiency virus fusion to dendritic cells declines as cells mature. J. Virol. 80:1992–1999, 2006.)

Novel findings identifying NF-kB as a modulator of inhibitory tone in the brain by regulating expression of GAD65 in inhibitory GABAergic interneurons. (Greene Laboratory: O'Mahony A, Raber J, Foehr E, Montano M, Han V, Lu S, Kwon H, LeFevour A, Chakraborty-Sett S, Greene WC. NF-kB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity. Mol. Cell Biol. 26:7283–7298, 2006.)

Studies illustrating A3G postentry restriction of HIV infection in peripheral lymphocytes which is overcome by secreted factors in lymphoid tissues. (Greene Laboratory: Kreisberg JF, Yonemoto W, Greene WC. Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high-molecular-mass APOBEC3G complex formation. J. Exp. Med. 203:865–870, 2006.

Studies identifying NF-kB p50/HDAC1 as a transcriptionally repressive complex promoting HIV-1 latency (Greene Laboratory: Williams SA, Chen L-f, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC. NF-kB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 25:139–149, 2006).

Studies demonstrating the regulation of NF-kB RelA acetylation by phosphorylation of neighboring tyrosine residues (Greene Laboratory: Chen L-F, Williams SA, Mu Y, Nakano H, Duerr JM, Buckbinder LM, Greene WC. NF-kB RelA phosphorylation regulates RelA acetylation. Mol. Cell. Biol. 25:7966–7975, 2005).

Studies identifying HIV Nef association with cellular immunological synapses and modulation of T-cell signaling (Greene Laboratory: Fenard D, Yonemoto W, de Noronha C, Cavrois M, Williams SA, Greene WC. Nef is physically recruited into the immunological synapse and potentiates T-cell activation early after TCR engagement. J. Immunol. 175:6050–6057, 2005).

Commentary highlighting the need for close collaboration with local communities and national governments when conducting clinical trials of drugs for HIV prevention (Grant Laboratory: Grant RM, Buchbinder S, Cates W Jr., Clarke E, Coates T, Cohen MS, Delaney M, Flores G, Goicochea P, Gonsalves G, Harrington M, Lama JR, MacQueen KM, Moore JP, Peterson L, Sanchez J, Thompson M, Wainberg MA. AIDS. Promote HIV chemoprophylaxis research, don't prevent it. Science 309:2170–2171, 2005).

Recent findings that growth hormone both induces increased levels of hematopoietic stem cell proliferation and differentiation and promotes longer survival of progeny cells (McCune Laboratory: Hanley MB, Napolitano LA, McCune JM. Growth hormone-induced stimulation of multilineage human hematopoiesis. Stem Cells 23:1170–1179, 2005).

Studies revealing significant gender and ethnic differences in HIV-specific T cell immune responses (Nixon Laboratory: Sharp ER, Barbour JD, Karlsson RK, Jordan KA, Sandberg JK, Wiznia A, Rosenberg MG, Nixon DF. Higher frequency of HIV-1-specific T cell immune responses in African American children vertically infected with HIV-1. J. Infect. Dis. 192:1772–1780, 2005).

New insights confirming that latent HIV preferentially integrates in heterochomatin and gene deserts, domains not conducive to transcription (Verdin Laboratory: Lewinski MK, Bisgrove D, Shinn P, Chen H, Hoffmann C, Hannenhalli S, Verdin E, Berry CC, Ecker JR, Bushman FD. Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J. Virol. 79:6610–6619, 2005).

Studies identifying the role of SIRT1 as a regulator of Tat deacetylation (Ott laboratory: Pagans S, Pedal A, North BJ, Kaehlcke K, Marshall BL, Dorr A, Hetzer-Egger C, Henklein P, Frye R, McBurney MW, Hruby H, Jung M, Verdin E, Ott M. SIRT1 regulates HIV transcription via Tat deacetylation. PLoS Biol. 3(2):e41, 2005).

Studies of HIV virion fusion (Greene laboratory: Cavrois M, Neidleman J, Yonemoto W, Fenard D, Greene WC. HIV-1 virion fusion assay: uncoating not required and no effect of Nef on fusion. Virology 328:36–44, 2004).

Studies of NF-kB as an inducible antagonist of HIV latency (Greene Laboratory: Williams SA, Chen LF, Kwon H, Fenard D, Bisgrove D, Verdin E, Greene WC. Prostratin antagonizes HIV latency by activating NF-kB. J. Biol. Chem. 279:42008–42017, 2004).

Studies exploring the intriguing targeting and functional interplay of the core protein of the hepatitis C virus with mitochondrial membranes. This interplay may facilitate encapsidation of the HCV RNA genome and modify key intracellular processes, such as apoptosis and fat metabolism. (Ott Laboratory: Schwer B, Ren S, Kartenbeck J, Kaehlcke K, Pietschmann T, Bartenschlager R, Yen T, Ott M. Targeting of hepatitis C virus core protein to mitochondria through a novel C-terminal localization motif. J. Virol. 78:7958–7968, 2004).

Novel findings regarding the inhibitory function of the T-regulatory cell in HIV infection that counter the prevailing notion that HIV-specific CD4 T-cell responses in infected subjects are deleted. Instead these responses are specifically suppressed by T-regulatory cells (Nixon Laboratory: Aandahl EM, Michaelsson J, Moretto WJ, Hecht FM, Nixon DF. Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. J. Virol. 78:2454–2459, 2004).

New studies demonstrating that HIV superinfection is quite rare during chronic HIV infection, a finding with important positive implications for HIV vaccine development. (Grant Laboratory: Tsui R, Herring BL, Barbour JD, Grant RM, Bacchetti P, Kral A, Edlin BR, Delwart EL. Human immunodeficiency virus type 1 superinfection was not detected following 215 years of injection drug user exposure. J. Virol. 78:94–103, 2004).

Studies of the role of cell mediated immunity in the control of drug-resistant strains of HIV (McCune Laboratory: Deeks SG, Martin JN, Sinclair E, Harris J, Neilands TB, Maecker HT, Hagos E, Wrin T, Petropoulos CJ, Bredt B, McCune JM. Strong cell-mediated immune responses are associated with the maintenance of low-level viremia in antiretroviral-treated individuals with drug-resistant human immunodeficiency virus type 1. J. Infect. Dis. 189:312–321, 2004).

New studies on the use of growth hormone and interleukin-7 to enhance immune recovery after control of HIV infection (Napolitano Laboratory; Napolitano LA. Approaches to immune reconstitution in HIV infection. Top. HIV Med. 11:160–163, 2003).

New insights into immune abnormalities occurring during HIV infection, including defective production of long-lived memory T cells (McCune Laboratory: Hellerstein MK, Hoh RA, Hanley MB, Cesar D, Lee D, Neese RA, McCune JM. Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J. Clin. Invest. 112:956–966, 2003).

New studies of how the HIV Vif protein defeats the powerful antiviral action of the APOBEC3G enzyme present in CD4 T lymphocytes and macrophages; these findings may propel future identification of effective small molecule inhibitors of Vif (Greene Laboratory; Stopak K, de Noronha C, Yonemoto W, Greene WC. HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Mol. Cell 12:591–601, 2003).

Studies exploring the molecular basis of how HIV establishes latent forms of infection (Verdin Lab: Jordan A, Bisgrove D, Verdin E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J. 22:1868–1877, 2003.)

Studies of NKT cells in HIV infection (Nixon Laboratory: Sandberg JK, Bhardwaj N, Nixon DF. Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Valpha24 NKT cell compartment. Eur. J. Immunol. 33:588–596, 2003).

Studies revealing that the functional ability of Nef to downregulate CD4 most closely correlates with Nef-mediated enhancement of HIV pathogenicity in vivo (Stoddart and Greene Laboratories: Stoddart CA, Geleziunas R, Ferrell S, Linquist-Stepps V, Moreno ME, Bare C, Xu W, Yonemoto W, Bresnahan PA, McCune JM, Greene WC. Human immunodeficiency virus type 1 Nef-mediated downregulation of CD4 correlates with Nef enhancement of viral pathogenesis. J. Virol. 77:2124–2133, 2003).