HIV Insertions Within and Proximal to Host Cell Genes Are a Common Finding in Tissues Containing High Levels of HIV DNA and Macrophage-Associated p24 Antigen Expression

Kd, Mack; X, Jin; Yu, Shaohua; Wei, Ronghua; Kapp, Linda M.; Green, C; Herndier, Brian; Nw, Abbey; Elbaggari, Ahmed; Y, Liu; Ms, McGrath

doi:10.1097/00126334-200307010-00004

Cited by 60 publications

(52 citation statements)

References 18 publications

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“…In these earlier studies, we identified an abundance of HIV recombinants (80), which could arise due to superinfection of long-lived HIV-infected macrophages. Furthermore, Mack et al (96) found that a large variety of diseased tissues derived from cART-negative autopsy tissues from patients who died with AIDS lymphoma or AIDS dementia contained amplifiable amounts of HIV DNA. In these tissues, p24 antigen staining was localized predominantly to macrophages in-terspersed in a background of p24-negative lymphocytes; this type of staining was not seen in nondiseased tissues (96).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, Mack et al (96) found that a large variety of diseased tissues derived from cART-negative autopsy tissues from patients who died with AIDS lymphoma or AIDS dementia contained amplifiable amounts of HIV DNA. In these tissues, p24 antigen staining was localized predominantly to macrophages in-terspersed in a background of p24-negative lymphocytes; this type of staining was not seen in nondiseased tissues (96). These macrophage p24-rich tissues contained HIV integrated within genetic activation loci.…”

Section: Discussionmentioning

confidence: 99%

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HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads

Lamers¹,

Rose²,

Maidji

et al. 2016

J Virol

135

125

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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. IMPORTANCEIt 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 tissueassociated HIV is present despite cART and can inform future studies into HIV persistence.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads

Lamers¹,

Rose²,

Maidji

et al. 2016

J Virol

135

125

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“…However, non-AIDS-defining malignancies have been on the increase since the availability of combination antiretroviral therapy, and the underlying cause of these additional malignancies is poorly understood (25)(26)(27). Although the activation of protooncogenes due to normal HIV-1 integration seems to be extremely rare, which is one of the reasons lentiviral vectors are being tested for gene therapy, there is a report suggesting that HIV integration can cause oncogene activation (28). The fact that the treatment with INSTIs leads to aberrant insertions that are accompanied by rearrangements of the host genome could increase the potential for the insertional activation of oncogenes and/or the inactivation of genes encoding tumor suppressors.…”

Section: Discussionmentioning

confidence: 99%

Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations

Varadarajan

McWilliams

Hughes

2013

Proc. Natl. Acad. Sci. U.S.A.

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Integration of the DNA copy of the HIV-1 genome into a host chromosome is required for viral replication and is thus an important target for antiviral therapy. The HIV-encoded enzyme integrase (IN) catalyzes two essential steps: 3′ processing of the viral DNA ends, followed by the strand transfer reaction, which inserts the viral DNA into host DNA. Raltegravir binds to IN and blocks the integration of the viral DNA. Using the Rous sarcoma virus-derived vector RCAS, we previously showed that mutations that cause one viral DNA end to be defective for IN-mediated integration led to abnormal integrations in which the provirus had one normal and one aberrant end, accompanied by rearrangements in the host genome. On the basis of these results, we expected that suboptimal concentrations of IN inhibitors, which could block one of the ends of viral integration, would lead to similar aberrant integrations. In contrast to the proviruses from untreated cells, which were all normal, ∼10-15% of the proviruses isolated after treatment with a suboptimal dose of raltegravir were aberrant. The aberrant integrations were similar to those seen in the RCAS experiments. Most of the aberrant proviruses had one normal end and one aberrant end and were accompanied by significant rearrangements in the host genome, including duplications, inversions, deletions and, occasionally, acquisition of sequences from other chromosomes. The rearrangements of the host DNA raise concerns that these aberrant integrations might have unintended consequences in HIV-1-infected patients who are not consistent in following a raltegravir-containing treatment regimen.strand transfer inhibitor | chromosomal rearrangements | integrase inhibitors H IV-1 integration is a two-step process: first, in the cytoplasm, an integrase (IN) dimer binds to each end of the newly synthesized linear viral DNA and removes two nucleotides from each of the 3′ ends, exposing the conserved CA dinucleotide. The preintegration complex (PIC) is translocated from the cytoplasm into the nucleus, where the viral DNA is integrated into the host genome. In the strand transfer (ST) reaction, the two exposed 3′ hydroxyl groups on the newly processed viral DNA ends attack phosphodiester bonds on the opposite strands of the target DNA at positions that lie across the major groove, 4-6 bp apart. This reaction is carried out by a tetramer of IN; each of the viral DNA ends is associated with an IN dimer. This transesterification reaction generates an intermediate in which the 3′ ends of the viral DNA are covalently joined to the host DNA and there are 4-to 6-bp gaps in the host DNA associated with both of the 5′ ends of the viral DNA. Cellular machinery repairs these gaps, creating a 4-to 6-bp duplication (the size of the duplication varies for different retroviruses) of the host DNA flanking the integrated viral DNA (1-4). HIV-1 integration generates a 5-bp duplication of the host DNA at the integration site (5, 6).Raltegravir (RAL) and all of the potent IN inhibitors thus far discovered bind to...

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“…Control sequences were obtained from both a lymphocyte-depleted iliac lymph node and seminal vesicles. DNA was prepared, and the HIV copy number/genomic equivalent within specimens was quantitated as previously described (19). Immunohistochemistry on tissues to evaluate the sites of HIV expression was also performed as previously described (19).…”

Section: Methodsmentioning

confidence: 99%

Phylodynamic Analysis of Human Immunodeficiency Virus Type 1 in Distinct Brain Compartments Provides a Model for the Neuropathogenesis of AIDS

Salemi

Lamers²,

Yu³

et al. 2005

J Virol

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"Phylodynamic" analysis combines various statistical procedures that can be used to correlate the epidemiological and evolutionary behavior of viral pathogens with the immune system of the host. We utilized this approach to examine human immunodeficiency virus type 1 (HIV-1) gp120 envelope DNA sequences (V1, V2, and V3) isolated from different brain compartments of a T-cell-depleted patient diagnosed with severe HIVassociated dementia at the time of death. In agreement with previous reports, phylogenetic analysis showed distinct virodemes but also revealed a significant amount of viral gene flow among different brain compartments. Local-molecular-clock analysis showed that HIV-1 meninges and temporal lobe subpopulations evolve about 30 and 100 times faster, respectively, than the other viral populations in the brain. However, maximum likelihood codon-based substitution models did not detect any site under significant positive selective pressure, and the main cause of HIV-1 genetic variation appeared to be random genetic drift. Therefore, the higher evolutionary rate in the meninges and temporal lobe could be due to an enhanced infection/expansion rate of macrophages as a consequence of the immune system failure. In conclusion, in this case study, viral infection in the brain progressed with a nonspecific genetic evolution, recurrent migration events, and an expansion of macrophage-tropic sequences. The data suggest that after immune failure newly produced viral variants, which would be rapidly cleared under normal conditions, begin to productively infect macrophages in a "selfamplifying" cycle of infection/inflammatory response that could be at the origin of HIV-associated dementia.

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HIV Insertions Within and Proximal to Host Cell Genes Are a Common Finding in Tissues Containing High Levels of HIV DNA and Macrophage-Associated p24 Antigen Expression

Cited by 60 publications

References 18 publications

HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads

HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads

Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations

Phylodynamic Analysis of Human Immunodeficiency Virus Type 1 in Distinct Brain Compartments Provides a Model for the Neuropathogenesis of AIDS

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