Vanderbilt University School of Medicine

D'Aquila, Richard T. , M.D.

Lab Url: N/A

Phone Number: 615-322-8972

Email Address:richard.daquila@Vanderbilt.Edu

D'Aquila, Richard's picture

Office Address   Mailing Address

A-2200 Medical Center North

A-2200 MCN Division of Infectious Diseases, Department of Medicine 37232-2582

Research Keywords
Human immunodeficiency virus type 1 (HIV-1); Retroviruses; Human Apoplipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) proteins; APOBEC3G; APOBEC3F; HIV-1 virion infectivity factor (Vif);; HIV-1 functional cure; Antiretroviral drugs; Antiretroviral drug resistance,Immunology,Infectious disease,Microbiology,Molecular medicine,Virus

Research Specialty
Functional cure of HIV-1 infection and human APOBEC3 proteins

Research Description
The laboratory-based translational research program is focused on exploiting the apoplipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) family of host restriction factors to innovate a functional cure of HIV-1.

APOBEC3s evolved to block retrotransposition. APOBEC3G and APOBEC3F are also active against HIV-1. If APOBEC3s are present in virions, they can limit HIV-1 reverse transcription at multiple steps, and inhibit integration. Further, their cytidine deaminase enzymatic activity can introduce hypermutations into proviruses that do integrate into host chromosomes. HIV-1's virion infectivity factor (Vif) gene product is present in clinical isolates. Vif counters the anti-HIV effects of APOBEC3s by enhancing proteosomal degradation of these cellular proteins before virus is produced, preventing APOBEC3s from being incorporated into the progeny virions. Hypermutations are seen in a large proportion of integrated HIV-1 proviruses in patient primary cells, suggesting that some APOBEC3s escape degradation and are able to act against HIV-1 in vivo. However, it has been controversial whether APOBEC3G or F can block Vif-positive HIV-1 replication in vitro, or if they are only able to block retroviruses of non-human primates that differ in Vif (and thereby do not degrade human APOBEC3s).

The D'Aquila laboratory has pioneered documentation that APOBEC3G and F can have anti-HIV effects on early steps of Vif-positive, as well as Vif-negative, HIV-1 replication in human cells in vitro if their cellular expression is enhanced. An additional mechanism of anti-HIV activity of APOBEC3G at a late step in replication against Vif-negative HIV-1 in vitro was also characterized. Study of hypermutations in proviruses in patient cells has shown an inverse association with viral load, consistent with an anti-HIV effect in vivo.

The critical cells in which HIV-1 persists without replicating during antiretroviral therapy, and which serve as a "latent reservoir" from which HIV-1 can reactivate after antiretrovirals are stopped, are resting memory CD4+ T lymphocytes. The laboratory's hypothesis is that increasing expression of APOBEC3s in these cells can lead to production of only non-infectious virions, and that this may facilitate a "functional cure". A functional cure is defined as preventing viral rebound after antiretroviral drugs are stopped, without eradicating all proviruses. The signals in APOBEC3s, and in virion proteins, that mediate virion incorporation of APOBEC3s are also under study; increasing APOBEC3 in virions may also provide a strategy to facilitate functional cure.

The laboratory also undertakes clinical research projects in HIV immunopathogenesis and antiretroviral drug resistance. D'Aquila is PI for the Vanderbilt HIV Clinical Trials Unit (that includes sites for clinical research trials of the HVTN and ACTG networks of the NIH) and the Vanderbilt Meharry Center for AIDS Research.

Clinical Research Description
HIV pathogenesis and development of a functional cure. Antiretroviral therapy, including resistance to antiretroviral drugs, is also an interest.

Clinical Interests
Antiretroviral therapy, particularly resistance to antiretroviral drugs conferred by HIV mutations.

Cooper, J, Liu, L, Woodruff, EA, Taylor, HE, Goodwin, JS, D''Aquila, RT, Spearman, P, Hildreth, JE, Dong, X. Filamin a protein interacts with human immunodeficiency virus type 1 gag protein and contributes to productive particle assembly. J Biol Chem, 286(32), 28498-510, 2011.

D''Aquila, RT, Geretti, AM, Horton, JH, Rouse, E, Kheshti, A, Raffanti, S, Oie, K, Pappa, K, Ross, LL. Tenofovir (TDF)-selected or abacavir (ABC)-selected low-frequency HIV type 1 subpopulations during failure with persistent viremia as detected by ultradeep pyrosequencing. AIDS Res Hum Retroviruses, 27(2), 201-9, 2011.

Martin, KL, Johnson, M, D''Aquila, RT. APOBEC3G Complexes Decrease Human Immunodeficiency Virus Type 1 Production. J Virol, 85(18), 9314-26, 2011.

Cu-Uvin, S, DeLong, AK, Venkatesh, KK, Hogan, JW, Ingersoll, J, Kurpewski, J, De Pasquale, MP, D''Aquila, R, Caliendo, AM. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS, 24(16), 2489-97, 2010.

Gandhi, RT, Zheng, L, Bosch, RJ, Chan, ES, Margolis, DM, Read, S, Kallungal, B, Palmer, S, Medvik, K, Lederman, MM, Alatrakchi, N, Jacobson, JM, Wiegand, A, Kearney, M, Coffin, JM, Mellors, JW, Eron, JJ, , . The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med, 7(8), , 2010. PMCID:2919424

High, KP, D''Aquila, RT, Fuldner, RA, Gerding, DN, Halter, JB, Haynes, L, Hazzard, WR, Jackson, LA, Janoff, E, Levin, MJ, Nayfield, SG, Nichol, KL, Prabhudas, M, Talbot, HK, Clayton, CP, Henderson, R, Scott, CM, Tarver, ED, Woolard, NF, Schmader, KE. Workshop on immunizations in older adults: identifying future research agendas. J Am Geriatr Soc, 58(4), 765-76, 2010.

Paredes, R, Lalama, CM, Ribaudo, HJ, Schackman, BR, Shikuma, C, Giguel, F, Meyer, WA, Johnson, VA, Fiscus, SA, D''Aquila, RT, Gulick, RM, Kuritzkes, DR, , . Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure. J Infect Dis, 201(5), 662-71, 2010. PMCID:2825289

, . Grinding to a halt: the effects of the increasing regulatory burden on research and quality improvement efforts. Clin Infect Dis, 49(3), 328-35, 2009. PMCID:2825289

Vetter, ML, D''Aquila, RT. Cytoplasmic APOBEC3G restricts incoming Vif-positive human immunodeficiency virus type 1 and increases two-long terminal repeat circle formation in activated T-helper-subtype cells. J Virol, 83(17), 8646-54, 2009. PMCID:2738200

Vetter, ML, Johnson, ME, Antons, AK, Unutmaz, D, D''Aquila, RT. Differences in APOBEC3G expression in CD4+ T helper lymphocyte subtypes modulate HIV-1 infectivity. PLoS Pathog, 5(2), e1000292, 2009. PMCID:2631133

Charles, M, Noel, F, Leger, P, Severe, P, Riviere, C, Beauharnais, CA, Miller, E, Rutledge, J, Bang, H, Shealey, W, D''Aquila, RT, Gulick, RM, Johnson, WD, Wright, PF, Pape, JW, Fitzgerald, DW. Survival, plasma HIV-1 RNA concentrations and drug resistance in HIV-1-infected Haitian adolescents and young adults on antiretrovirals. Bull World Health Organ, 86(12), 970-7, 2008. PMCID:2649577

Donahue, JP, Vetter, ML, Mukhtar, NA, D''Aquila, RT. The HIV-1 Vif PPLP motif is necessary for human APOBEC3G binding and degradation. Virology, 377(1), 49-53, 2008. PMCID:2474554

Hulgan, T, Tebas, P, Canter, JA, Mulligan, K, Haas, DW, Dub??, M, Grinspoon, S, Robbins, GK, Motsinger, AA, Kallianpur, AR, , . Hemochromatosis gene polymorphisms, mitochondrial haplogroups, and peripheral lipoatrophy during antiretroviral therapy. J Infect Dis, 197(6), 858-66, 2008. PMCID:2474554

Koelsch, KK, Liu, L, Haubrich, R, May, S, Havlir, D, G??nthard, HF, Ignacio, CC, Campos-Soto, P, Little, SJ, Shafer, R, Robbins, GK, D''Aquila, RT, Kawano, Y, Young, K, Dao, P, Spina, CA, Richman, DD, Wong, JK. Dynamics of total, linear nonintegrated, and integrated HIV-1 DNA in vivo and in vitro. J Infect Dis, 197(3), 411-9, 2008. PMCID:2474554

Kuritzkes, DR, Lalama, CM, Ribaudo, HJ, Marcial, M, Meyer, WA, Shikuma, C, Johnson, VA, Fiscus, SA, D''Aquila, RT, Schackman, BR, Acosta, EP, Gulick, RM. Preexisting resistance to nonnucleoside reverse-transcriptase inhibitors predicts virologic failure of an efavirenz-based regimen in treatment-naive HIV-1-infected subjects. J Infect Dis, 197(6), 867-70, 2008. PMCID:2474554

Rebeiro, PF, Kheshti, A, Bebawy, SS, Stinnette, SE, Erdem, H, Tang, YW, Sterling, TR, Raffanti, SP, D''Aquila, RT. Increased detectability of plasma HIV-1 RNA after introduction of a new assay and altered specimen-processing procedures. Clin Infect Dis, 47(10), 1354-7, 2008. PMCID:2605467

Haas, DW, Geraghty, DE, Andersen, J, Mar, J, Motsinger, AA, D''Aquila, RT, Unutmaz, D, Benson, CA, Ritchie, MD, Landay, A, , . Immunogenetics of CD4 lymphocyte count recovery during antiretroviral therapy: An AIDS Clinical Trials Group study. J Infect Dis, 194(8), 1098-107, 2006. PMCID:2474554

Motsinger, AA, Ritchie, MD, Shafer, RW, Robbins, GK, Morse, GD, Labbe, L, Wilkinson, GR, Clifford, DB, D''Aquila, RT, Johnson, VA, Pollard, RB, Merigan, TC, Hirsch, MS, Donahue, JP, Kim, RB, Haas, DW. Multilocus genetic interactions and response to efavirenz-containing regimens: an adult AIDS clinical trials group study. Pharmacogenet Genomics, 16(11), 837-45, 2006. PMCID:2474554

Haas, DW, Smeaton, LM, Shafer, RW, Robbins, GK, Morse, GD, Labbe, L, Wilkinson, GR, Clifford, DB, D''Aquila, RT, De Gruttola, V, Pollard, RB, Merigan, TC, Hirsch, MS, George, AL, Donahue, JP, Kim, RB. Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study. J Infect Dis, 192(11), 1931-42, 2005.

Chan, SY, Hulgan, T, D'Aquila, RT. The Role of Baseline HIV-1 Resistance Testing in Patients with Established Infection. Curr Infect Dis Rep, 6(3), 243-249, 2004.

Johnson, VA, Brun-V??zinet, F, Clotet, B, Conway, B, D''Aquila, RT, Demeter, LM, Kuritzkes, DR, Pillay, D, Schapiro, JM, Telenti, A, Richman, DD. Update of the drug resistance mutations in HIV-1: 2004. Top HIV Med, 12(4), 119-24, 2004. PMCID:2474554

Johnson, VA, Brun-V??zinet, F, Clotet, B, Conway, B, D''Aquila, RT, Demeter, LM, Kuritzkes, DR, Pillay, D, Schapiro, JM, Telenti, A, Richman, DD, , . Drug resistance mutations in HIV-1. Top HIV Med, 11(6), 215-21, 2004. PMCID:2474554

D'Aquila, RT, Schapiro, JM, Brun-V??zinet, F, Clotet, B, Conway, B, Demeter, LM, Grant, RM, Johnson, VA, Kuritzkes, DR, Loveday, C, Shafer, RW, Richman, DD. Drug resistance mutations in HIV-1. Top HIV Med, 11(3), 92-6, 2003.

De Pasquale, MP, Leigh Brown, AJ, Uvin, SC, Allega-Ingersoll, J, Caliendo, AM, Sutton, L, Donahue, S, D'Aquila, RT. Differences in HIV-1 pol sequences from female genital tract and blood during antiretroviral therapy. J Acquir Immune Defic Syndr, 34(1), 37-44, 2003.

Hulgan, T, Donahue, JP, Hawkins, C, Unutmaz, D, D'Aquila, RT, Raffanti, S, Nicotera, F, Rebeiro, P, Erdem, H, Rueff, M, Haas, DW. Implications of T-cell P-glycoprotein activity during HIV-1 infection and its therapy. J Acquir Immune Defic Syndr, 34(2), 119-26, 2003.

Hulgan, T, Morrow, J, D'Aquila, RT, Raffanti, S, Morgan, M, Rebeiro, P, Haas, DW. Oxidant stress is increased during treatment of human immunodeficiency virus infection. Clin Infect Dis, 37(12), 1711-7, 2003.

Shafer, RW, Smeaton, LM, Robbins, GK, De Gruttola, V, Snyder, SW, D''Aquila, RT, Johnson, VA, Morse, GD, Nokta, MA, Martinez, AI, Gripshover, BM, Kaul, P, Haubrich, R, Swingle, M, McCarty, SD, Vella, S, Hirsch, MS, Merigan, TC, , . Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med, 349(24), 2304-15, 2003. PMCID:2474554

D'Aquila, RT, , , Schapiro, JM, Brun-V??zinet, F, Clotet, B, Conway, B, Demeter, LM, Grant, RM, Johnson, VA, Kuritzkes, DR, Loveday, C, Shafer, RW, Richman, DD. Drug Resistance Mutations in HIV-1. Top HIV Med, 10(5), 21-25, 2002.

Youree, BE, D'Aquila, RT. Antiretroviral resistance testing for clinical management. AIDS Rev, 4(1), 3-12, 2002.

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