Circulating proviral HIV DNA and HIV-associated dementia

Shiramizu, Bruce; Gartner, Suzanne; Williams, Andrew E.; Shikuma, Cecilia; Ratto‐Kim, Silvia; Watters, Michael R.; Aguon, Joleen; Valcour, Victor

doi:10.1097/00002030-200501030-00005

Cited by 105 publications

(132 citation statements)

References 51 publications

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“…Cells of the monocyte and macrophage lineage may represent another mechanism for viral persistence. These cells are among the cells infected early upon exposure to HIV (11), and the presence of CCR5-utilizing "macrophage-tropic" forms of HIV in the plasma of essentially all newly infected individuals is consistent with the notion that macrophages represent an early target for HIV infection (12)(13)(14)(15). In contrast to CD4 T cells which die with effective HIV replication, macrophages are resistant to the cytopathic effect of the virus.…”

supporting

confidence: 75%

Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone

Jin

McGrath

2015

J Virol

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Macrophages are a target for infection with HIV and represent one of the viral reservoirs that are relatively resistant to current antiretroviral drugs. Here we demonstrate that methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine analog and potent S-adenosylmethionine decarboxylase inhibitor, decreases HIV expression in monocytes and macrophages. MGBG is selectively concentrated by these cells through a mechanism consistent with active transport by the polyamine transporter. Using a macrophage-tropic reporter virus tagged with the enhanced green fluorescent protein, we demonstrate that MGBG decreases the frequency of HIV-infected cells. The effect is dose dependent and correlates with the production of HIV p24 in culture supernatants. This anti-HIV effect was further confirmed using three macrophage-tropic primary HIV isolates. Viral life cycle mapping studies show that MGBG inhibits HIV DNA integration into the cellular DNA in both monocytes and macrophages. O ne of the major remaining obstacles in treating human immunodeficiency type 1 (HIV-1)-related diseases is the elimination of viral reservoirs that contribute to persistent infection and chronic immune activation. Although highly active antiretroviral therapy (HAART) is effective at reducing the plasma viral load and slowing down the decline of CD4 ϩ T lymphocytes and dendritic cells, it has failed to eradicate the residual long-lived HIV-infected cellular reservoirs (1-3). At the molecular level, HAART successfully suppresses HIV RNA replication and decreases total viral DNA load in treated individuals. However, it fails to eliminate the integrated proviral DNA (4, 5). Even in HAART-treated patients with an undetectable plasma viral load, discontinuation of treatment is routinely associated with the reappearance of HIV RNA in circulation, confirming the presence of significant HIV proviral reservoirs in HAART-treated individuals (6, 7).HIV-1 cellular reservoirs include resting CD4 ϩ T lymphocytes and cells of the monocyte and macrophage lineage (1, 8, 9). Research on the HIV reservoirs has largely focused on T cells and more specifically a rare subset of resting memory CD4 T cells that has been reproducibly identified in the blood of patients with low or no detectible plasma viral loads (10). Cells of the monocyte and macrophage lineage may represent another mechanism for viral persistence. These cells are among the cells infected early upon exposure to HIV (11), and the presence of CCR5-utilizing "macrophage-tropic" forms of HIV in the plasma of essentially all newly infected individuals is consistent with the notion that macrophages represent an early target for HIV infection (12)(13)(14)(15). In contrast to CD4 T cells which die with effective HIV replication, macrophages are resistant to the cytopathic effect of the virus. Furthermore, macrophages and dendritic cells are capable of transmitting HIV to T cells or other macrophages via cell-cell contact (16). Depending on the origins of the virus, both cis-infection and trans-infection modes h...

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supporting

confidence: 75%

Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone

Jin

McGrath

2015

J Virol

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“…Shiramizu et al reported isolating CD14 high CD16 ϩ monocytes from the peripheral blood of five HIV-1 infected individuals, three of whom were clinically defined as having HIV-related dementia. These cells harbored HIV-1 DNA in all five donors, although the infection of CD14 high CD16 Ϫ monocytes was not examined (72).…”

Section: Discussionmentioning

confidence: 99%

The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo

Ellery

Tippett

Chiu

et al. 2007

The Journal of Immunology

300

276

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HIV-1 persists in peripheral blood monocytes in individuals receiving highly active antiretroviral therapy (HAART) with viral suppression, despite these cells being poorly susceptible to infection in vitro. Because very few monocytes harbor HIV-1 in vivo, we considered whether a subset of monocytes might be more permissive to infection. We show that a minor CD16+ monocyte subset preferentially harbors HIV-1 in infected individuals on HAART when compared with the majority of monocytes (CD14highCD16−). We confirmed this by in vitro experiments showing that CD16+ monocytes were more susceptible to CCR5-using strains of HIV-1, a finding that is associated with higher CCR5 expression on these cells. CD16+ monocytes were also more permissive to infection with a vesicular stomatitis virus G protein-pseudotyped reporter strain of HIV-1 than the majority of monocytes, suggesting that they are better able to support HIV-1 replication after entry. Consistent with this observation, high molecular mass complexes of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) were observed in CD16+ monocytes that were similar to those observed in highly permissive T cells. In contrast, CD14highCD16− monocytes contained low molecular mass active APOBEC3G, suggesting this is a mechanism of resistance to HIV-1 infection in these cells. Collectively, these data show that CD16+ monocytes are preferentially susceptible to HIV-1 entry, more permissive for replication, and constitute a continuing source of viral persistence during HAART.

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“…5,6 HIV DNA within the activated CD141 monocyte subset of PBMC correlates with neurocognitive decline. 5,7 We have linked elevated PBMC HIV DNA to cortical thinning 8 but the relationship of HIV DNA to brain structure has not otherwise been explored.…”

mentioning

confidence: 99%

“…HIV DNA assay was carried out as detailed elsewhere, with low intra-assay and interassay variability shown by mean coefficients of variation of 1.1% and 1.4%, respectively. 7 We analyzed copy numbers of each sample gene (HIV gag and b-globin) against standard curves, and determined the HIV DNA copy number per 1 3 10 6 cells. ).…”

mentioning

confidence: 99%

Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter

et al. 2013

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Objective: We evaluated regional brain volumes and cerebral metabolite levels as correlates of HIV DNA in peripheral blood mononuclear cells (PBMCs). Methods:In this cross-sectional study, 35 HIV1 subjects aged $40 years (25 with detectable PBMC HIV DNA; 10 with HIV DNA ,10 copies/10 6 cells, the threshold of detection) and 12 seronegative controls underwent structural brain MRI and magnetic resonance spectroscopy at 3 T. HIV1 subjects were on combination antiretroviral therapy $1 year; all but 1 had plasma HIV RNA ,50 copies/mL. We used logistic regression to evaluate relationships of likely predictor variables to the outcome of PBMC HIV DNA detectability in the HIV1 subjects. Effects of serostatus and HIV DNA on regional brain volumes (normalized to intracranial volume) and on metabolite ratios over creatine were evaluated by analyses of covariance, controlling for age.Results: Relative to the HIV1 group with undetectable HIV DNA, subjects with detectable HIV DNA demonstrated decreased volumes of cerebellar (214%, p 5 0.020) and total subcortical (210%, p 5 0.024) gray matter. Compared to healthy controls, only the detectable HIV DNA group showed significant (p , 0.05) enlargement of lateral ventricles and volumetric reductions of caudate, putamen, thalamus, hippocampus, nucleus accumbens, brainstem, total cortical gray matter, and cerebral white matter. Detectable HIV DNA was not associated with significantly altered cerebral metabolite levels. Glu 5 glutamate; HAND 5 HIV-associated neurocognitive disorders; ICV 5 intracranial volume; MI 5 myo-inositol; MRS 5 magnetic resonance spectroscopy; NAA 5 N-acetylaspartate; PBMC 5 peripheral blood mononuclear cell; PLSD 5 protected least significant difference; SN 5 seronegative; U-HIV 5 HIV1 infected subjects with undetectable peripheral blood mononuclear cells HIV DNA; VRS 5 Virchow-Robin spaces. Conclusion:

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Circulating proviral HIV DNA and HIV-associated dementia

Abstract: These findings suggest a potentially important association between circulating provirus and HAD.

Cited by 105 publications

References 51 publications

Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone

Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone

The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo

Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter

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