Pharmacodynamic and antiretroviral activities of combination nanoformulated antiretrovirals in HIV-1-infected human peripheral blood lymphocyte-reconstituted mice.
Lack of adherence, inaccessibility to viral reservoirs, long-term drug toxicities, and treatment failures are limitations of current antiretroviral therapy (ART). These limitations lead to increased viral loads, medicine resistance, immunocompromise, and comorbid conditions. To this end, we developed long-acting nanoformulated ART (nanoART) through modifications of existing atazanavir, ritonavir, and efavirenz suspensions in order to establish cell and tissue drug depots to achieve sustained antiretroviral responses. NanoART's abilities to affect immune and antiviral responses, before or following human immunodeficiency virus type 1 infection were tested in nonobese severe combined immune-deficient mice reconstituted with human peripheral blood lymphocytes. Weekly subcutaneous injections of drug nanoformulations at doses from 80 mg/kg to 250 mg/kg, 1 day before and/or 1 and 7 days after viral exposure, elicited drug levels that paralleled the human median effective concentration, and with limited toxicities. NanoART treatment attenuated viral replication and preserved CD4(+) Tcell numbers beyond that seen with orally administered native drugs. These investigations bring us one step closer toward using long-acting antiretrovirals in humans.
Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Upal
U
Roy
JoEllyn
J
McMillan
Yazen
Y
Alnouti
Nagsen
N
Gautum
Nathan
N
Smith
Shantanu
S
Balkundi
Prasanta
P
Dash
Santhi
S
Gorantla
Andrea
A
Martinez-Skinner
Jane
J
Meza
Georgette
G
Kanmogne
Susan
S
Swindells
Samuel M
SM
Cohen
R Lee
RL
Mosley
Larisa
L
Poluektova
Howard E
HE
Gendelman
D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology / Q000821:virology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D049329:Nanostructures / Q000737:chemistry*; D016176:T-Lymphocyte Subsets
D019380:Anti-HIV Agents; D004304:Dosage Forms; D053631:Interleukin Receptor Common gamma Subunit