title: HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads.
abstract: HIV infection treatment strategies have historically defined effectiveness through measuring patient plasma HIV RNA. While combined antiretroviral therapy (cART) can reduce plasma viral load (pVL) to undetectable levels, the degree that HIV is eliminated from other anatomical sites remains unclear. We investigated the HIV DNA levels in 229 varied autopsy tissues from 20 HIV-positive (HIV(+)) cART-treated study participants with low or undetectable plasma VL and cerebrospinal fluid (CSF) VL prior to death who were enrolled in the National Neurological AIDS Bank (NNAB) longitudinal study and autopsy cohort. Extensive medical histories were obtained for each participant. Autopsy specimens, including at least six brain and nonbrain tissues per participant, were reviewed by study pathologists. HIV DNA, measured in tissues by quantitative and droplet digital PCR, was identified in 48/87 brain tissues and 82/142 nonbrain tissues at levels >200 HIV copies/million cell equivalents. No participant was found to be completely free of tissue HIV. Parallel sequencing studies from some tissues recovered intact HIV DNA and RNA. Abnormal histological findings were identified in all participants, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. All brain tissues demonstrated some degree of pathology. Ninety-five percent of participants had some degree of atherosclerosis, and 75% of participants died with cancer. This study assists in characterizing the anatomical locations of HIV, in particular, macrophage-rich tissues, such as the central nervous system (CNS) and testis. Additional studies are needed to determine if the HIV recovered from tissues promotes the pathogenesis of inflammatory diseases, such as HIV-associated neurocognitive disorders, cancer, and atherosclerosis.
  
  
  
  It is well-known that combined antiretroviral therapy (cART) can reduce plasma HIV to undetectable levels; however, cART cannot completely clear HIV infection. An ongoing question is, "Where is HIV hiding?" A well-studied HIV reservoir is "resting" T cells, which can be isolated from blood products and succumb to cART once activated. Less-studied reservoirs are anatomical tissue samples, which have unknown cART penetration, contain a comparably diverse spectrum of potentially HIV-infected immune cells, and are important since <2% of body lymphocytes actually reside in blood. We examined 229 varied autopsy specimens from 20 HIV(+) participants who died while on cART and identified that >50% of tissues were HIV infected. Additionally, we identified considerable pathology in participants' tissues, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. This study substantiates that tissue-associated HIV is present despite cART and can inform future studies into HIV persistence.
authors.affiliation: Bioinfoexperts, LLC, Thibodaux, Louisiana, USA.
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Lamers
authors.affiliation: Bioinfoexperts, LLC, Thibodaux, Louisiana, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rose
authors.affiliation: Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Maidji
authors.affiliation: The University of Hawaii, Department of Tropical Medicine, Medical Microbiology & Pharmacology and Hawaii Center for AIDS, Honolulu, Hawaii, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Agsalda-Garcia
authors.affiliation: Bioinfoexperts, LLC, Thibodaux, Louisiana, USA The University of Florida Emerging Pathogens Institute, Department of Pathology and Laboratory Medicine, Gainesville, Florida, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nolan
authors.affiliation: Natural Selection, Inc., San Diego, California, USA.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Fogel
authors.affiliation: The University of Florida Emerging Pathogens Institute, Department of Pathology and Laboratory Medicine, Gainesville, Florida, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Salemi
authors.affiliation: The AIDS and Cancer Specimen Resource, San Francisco, California, USA University of California, San Francisco, Department of Medicine, San Francisco, California, USA.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Garcia
authors.affiliation: The AIDS and Cancer Specimen Resource, San Francisco, California, USA University of California, San Francisco, Department of Medicine, San Francisco, California, USA.
authors.forename: Paige
authors.initials: P
authors.lastname: Bracci
authors.affiliation: National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA David Geffen School of Medicine and Olive View-UCLA Medical Center, Department of Pathology and Laboratory Medicine, Los Angeles, California, USA.
authors.forename: William
authors.initials: W
authors.lastname: Yong
authors.affiliation: University of Southern California Keck School of Medicine, Los Angeles, California, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Commins
authors.affiliation: National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA David Geffen School of Medicine and Olive View-UCLA Medical Center, Department of Pathology and Laboratory Medicine, Los Angeles, California, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Said
authors.affiliation: National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA David Geffen School of Medicine and Olive View-UCLA Medical Center, Department of Pathology and Laboratory Medicine, Los Angeles, California, USA.
authors.forename: Negar
authors.initials: N
authors.lastname: Khanlou
authors.affiliation: National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA UCLA School of Medicine, Department of Psychiatry & Biobehavioral Sciences, Los Angeles, California, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Hinkin
authors.affiliation: National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA David Geffen School of Medicine and Olive View-UCLA Medical Center, Department of Neurology, Los Angeles, California, USA.
authors.forename: Miguel Valdes
authors.initials: MV
authors.lastname: Sueiras
authors.affiliation: National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Mathisen
authors.affiliation: National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Donovan
authors.affiliation: The University of Hawaii, Department of Tropical Medicine, Medical Microbiology & Pharmacology and Hawaii Center for AIDS, Honolulu, Hawaii, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Shiramizu
authors.affiliation: Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Stoddart
authors.affiliation: The AIDS and Cancer Specimen Resource, San Francisco, California, USA University of California, San Francisco, Department of Medicine, San Francisco, California, USA MMcGrath@php.ucsf.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: McGrath
authors.affiliation: National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA David Geffen School of Medicine and Olive View-UCLA Medical Center, Department of Neurology, Los Angeles, California, USA.
authors.forename: Elyse J
authors.initials: EJ
authors.lastname: Singer
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D001344:Autopsy; D004279:DNA, Viral / Q000032:analysis*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D008137:Longitudinal Studies; D060888:Real-Time Polymerase Chain Reaction; D019562:Viral Load
chemical_list: D044966:Anti-Retroviral Agents; D004279:DNA, Viral