HIV-1 Nef in Macrophage-Mediated Disease Pathogenesis

Lamers, Susanna L.; Fogel, Gary B.; Singer, Elyse J.; Salemi, Marco; Nolan, David J.; Huysentruyt, Leanne C.; McGrath, Michael S.

doi:10.3109/08830185.2012.737073

Cited by 33 publications

(29 citation statements)

References 160 publications

(199 reference statements)

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“…Plaque is macrophage rich and could harbor replication-competent HIV or even protect infected cells from cART targeting (86). In the cases where residual HIV was identified in cancer participants, it may likewise be the case that alternatively activated and anti-inflammatory macrophages, which are linked to certain metastatic processes (87, 88), harbored a low-level HIV infection that migrated to other sites.…”

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

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138

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%

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

Self Cite

138

125

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“…In this aging population, the pathogenic effects of HIV, especially in those with a long duration of infection, may intersect with those of age-related illnesses and the effects of long-term use of cART. Several broad categories of pathologies associated with HIV infection, aging, and long-term cART exist, including lipid disorders, B-cell lymphomas, and neurocognitive disorders (Lamers et al 2012; Herndier et al 1994; Bandaru et al 2013). As such, it is now important that the unique medical challenges posed by the aging HIV+ population be delineated.…”

Section: Introductionmentioning

confidence: 99%

Factors related to HIV-associated neurocognitive impairment differ with age

Fogel

Lamers²,

Levine

et al. 2014

J. Neurovirol.

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Over 50% of HIV-infected (HIV+) persons are expected to be over age 50 by 2015. The pathogenic effects of HIV, particularly in cases of long-term infection, may intersect with those of age-related illnesses and prolonged exposure to combined antiretroviral therapy (cART). One potential outcome is an increased prevalence of neurocognitive impairment in older HIV+ individuals, as well as an altered presentation of HIV-associated neurocognitive disorders (HAND). METHODS In this study, we employed stepwise regression to examine 24 features sometimes associated with HAND in forty older (55–73 years of age) and thirty younger (32–50 years of age) HIV+, cART-treated participants without significant central nervous system confounds. RESULTS The features most effective in generating a true assessment of the likelihood of HAND diagnosis differed between older and younger cohorts, with the younger cohort containing features associated with drug abuse that were correlated to HAND, and the older cohort containing features that were associated with lipid disorders mildly associated with HAND. CONCLUSION As the HIV-infected population grows and the demographics of the epidemic change, it is increasingly important to re-evaluate features associated with neurocognitive impairment. Here we have identified features, routinely collected in primary care settings that provide more accurate diagnostic value than a neurocognitive screening measure among younger and older HIV-individuals.

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“…In addition, recent work has demonstrated that nef can enhance macrophage tissue infiltration by altering its migratory mode (13), which may play a central role in the accumulation of macrophages residing in the CNS, the establishment of viral reservoirs, and neuropathogenesis (14). However, very few studies have focused on Nef evolution and disease progression in vivo (9,15,16).…”

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confidence: 99%

Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques

Lamers¹,

Nolan

Rife

et al. 2015

J Virol

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While a clear understanding of the events leading to successful establishment of host-specific viral populations and productive infection in the central nervous system (CNS) has not yet been reached, the simian immunodeficiency virus (SIV)-infected rhesus macaque provides a powerful model for the study of human immunodeficiency virus (HIV) intrahost evolution and neuropathogenesis. The evolution of the gp120 and nef genes, which encode two key proteins required for the establishment and maintenance of infection, was assessed in macaques that were intravenously inoculated with the same viral swarm and allowed to naturally progress to simian AIDS and potential SIV-associated encephalitis (SIVE). Longitudinal plasma samples and immune markers were monitored until terminal illness. Single-genome sequencing was employed to amplify full-length env through nef transcripts from plasma over time and from brain tissues at necropsy. nef sequences diverged from the founder virus faster than gp120 diverged. Host-specific sequence populations were detected in nef (ϳ92 days) before they were detected in gp120 (ϳ182 days). At necropsy, similar brain nef sequences were found in different macaques, indicating convergent evolution, while gp120 brain sequences remained largely host specific. Molecular clock and selection analyses showed weaker clock-like behavior and stronger selection pressure in nef than in gp120, with the strongest nef selection in the macaque with SIVE. Rapid nef diversification, occurring prior to gp120 diversification, indicates that early adaptation of nef in the new host is essential for successful infection. Moreover, the convergent evolution of nef sequences in the CNS suggests a significant role for nef in establishing neurotropic strains. IMPORTANCEThe SIV-infected rhesus macaque model closely resembles HIV-1 immunopathogenesis, neuropathogenesis, and disease progression in humans. Macaques were intravenously infected with identical viral swarms to investigate evolutionary patterns in the gp120 and nef genes leading to the emergence of host-specific viral populations and potentially linked to disease progression. Although each macaque exhibited unique immune profiles, macaque-specific nef sequences evolving under selection were consistently detected in plasma samples at 3 months postinfection, significantly earlier than in gp120 macaque-specific sequences. On the other hand, nef sequences in brain tissues, collected at necropsy of two animals with detectable infection in the central nervous system (CNS), revealed convergent evolution. The results not only indicate that early adaptation of nef in the new host may be essential for successful infection, but also suggest that specific nef variants may be required for SIV to efficiently invade CNS macrophages and/or enhance macrophage migration, resulting in HIV neuropathology. Aclear understanding of the events leading to the establishment of human immunodeficiency virus type 1 (HIV-1) infection in a new host, including the central nervous system (C...

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HIV-1 Nef in Macrophage-Mediated Disease Pathogenesis

Cited by 33 publications

References 160 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

Factors related to HIV-associated neurocognitive impairment differ with age

Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques

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