Failure to clear intra-monocyte HIV infection linked to persistent neuropsychological testing impairment after first-line combined antiretroviral therapy

Shiramizu, Bruce; Ananworanich, Jintanat; Chalermchai, Thep; Siangphoe, Umaporn; Troelstrup, David; Shikuma, Cecilia; Grutolla, V. De; Sithinamsuwan, Pasiri; Praihirunkit, Pairoa; Rattanamanee, Somprartthana; Valcour, Victor

doi:10.1007/s13365-011-0068-8

Cited by 38 publications

(35 citation statements)

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“…16,17 We previously described HIV DNA as an important factor in HIV disease progression. [5][6][7][8] The significance of HIV DNA in disease pathogenesis lies in the fact that monocytes harboring HIV DNA persist in patients on cART in spite of having undetectable HIV RNA levels. 5,7,8 The current study was limited to assessing HIV DNA from the pool of cells from anal cytology specimens.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8] The significance of HIV DNA in disease pathogenesis lies in the fact that monocytes harboring HIV DNA persist in patients on cART in spite of having undetectable HIV RNA levels. 5,7,8 The current study was limited to assessing HIV DNA from the pool of cells from anal cytology specimens. Since monocyte subsets may possibly be key players in the disease process, plans to measure HIV DNA from isolated cellular subsets will be considered for the future.…”

Section: Discussionmentioning

confidence: 99%

“…Recent data suggest that the continued persistence of HIV DNA in circulating monocytes in patients treated with combined antiretroviral therapy (cART) leads to progression of HIV disease itself and other HIV-associated complications, which may include HPV infection and associated anal neoplasia. [5][6][7][8] The objective of the present study was to evaluate anal cytology specimens for HIV DNA copy numbers and HPV genotypes in relationship to anal lowgrade and high-grade squamous intraepithelial lesions (LGSIL/HGSIL) from patients participating in an anal cancer screening study. We hypothesized that a relationship between high-risk HPV genotypes and the presence of HIV DNA would be associated with anal LGSIL/HGSIL.…”

Section: Introductionmentioning

confidence: 99%

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Presence of High-Risk Human Papillomavirus Genotype and Human Immunodeficiency Virus DNA in Anal High-Grade and Low-Grade Squamous Intraepithelial Lesions

Shiramizu

Liang²,

Agsalda-Garcia³

et al. 2013

AIDS Research and Human Retroviruses

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Human immunodeficiency virus type 1 (HIV)-infected individuals are at risk for anal cancer, which is caused by human papillomavirus (HPV). The relationship between HIV and HPV that leads to anal cancer remains unclear. Recent data, however, suggest that the continued persistence of HIV DNA in patients treated with combined antiretroviral therapy leads to progression of HIV disease and other HIV-associated complications. Therefore, we investigated the relationship among anal low-and high-grade squamous intraepithelial lesions (LGSIL/ HGSIL), high-risk HPV genotypes, and high HIV DNA copy numbers. Anal cytology specimens were assayed for HPV genotype and HIV DNA copy number. High-risk HPV genotypes (odds ratio OR: 3.73; 95% confidence interval CI: 1.08-12.91; p = 0.04) and high HIV DNA copy numbers (OR per 100 HIV DNA copies : 1.13; 95% CI: 1.01-1.27, p = 0.04) were both associated with LGSIL/HGSIL. When considering both high-risk HPV genotypes and HIV DNA copy numbers in predicting LGSIL/HGSIL, HIV DNA copy number was significant (OR per 100 HIV DNA copies : 1.09; 95% CI: 0.96-1.23, p = 0.04) but not high-risk HPV genotypes (OR: 2.30, p = 0.28), which did not change when adjusted for nadir CD4 cell count and HIV RNA levels. The findings warrant further investigation of HIV DNA and its relationship with HPV in LGSIL/HGSIL pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Presence of High-Risk Human Papillomavirus Genotype and Human Immunodeficiency Virus DNA in Anal High-Grade and Low-Grade Squamous Intraepithelial Lesions

Shiramizu

Liang²,

Agsalda-Garcia³

et al. 2013

AIDS Research and Human Retroviruses

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“…For quantitative PCR (qPCR) assays, the primers and TaqMan probes were synthesized according to previously published sequences for the HIV gag region gene and ␤-globin gene, a single-copy conserved gene that serves as the control (51). Each 20-l qPCR mixture contained 10 l of the PerfeCTa qPCR master mix (Quant BioSciences, Gaithersburg, MD), 10 ng of total DNA or 4 l of the HMW genomic DNA as the template, 0.05 M globin primers, 0.1 M Gag primers, and 0.025 M VIC-or 6-carboxyfluorescein (FAM)-labeled probes.…”

Section: Flow Cytometry Analysis (I) Studies With Egfp-tagged Hivmentioning

confidence: 99%

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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“…Direkt virusassoziierte Kofaktoren sind: lange Dauer der HIV-Positivität, niedriger CD4 + -Zell-Nadir, niedrige aktuelle CD4 + -Zellzahlen [16], eine hohe Plasma-Viruslast [17] und zerebrale, opportunistische Infektionen in der Vorgeschichte [18]. Shiramizu et al fanden eine gute Korrelation zwischen HAND und der Virus-DNA in infizierten Monozyten [19], therapieassoziierte Kofaktoren sind: niedrige Therapietreue, suboptimale Behandlung mit im Blut und/oder Liquor nachweisbarer Viruslast bzw. Therapieunterbrechungen [20], ein geringer "CNS-Penetration-Effectiveness"-Score [21] sowie die potenzielle Neurotoxizität der antiretroviralen Therapie [22].…”

Section: Kofaktorenunclassified

Neues bei HIV und Neuro-Aids

et al. 2015

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Zusammenfassung Trotz sehr effektiver Behandlungsoptionen f?r die systemische HIV-Infektion sind Neuro-Aids und die HIV-assoziierte neurokognitive St?rung ein klinisches und alltagsrelevantes Problem. Man unterscheidet 3 Stufen, das HIV-assoziierte, neuropsychologische Defizit (ANPD), das milde, HIV-assoziierte neurokognitive Defizit (MNCD) und die HIV-assoziierte Demenz (HAD). Die Behandlungsm?glichkeiten HIV-assoziierter neuro-kognitiver St?rungen umfasst die antiretrovirale Therapie (cART), die den CPE-Score zur Penetration der Medikamente ins ZNS ber?cksichtigen sollte. Es ist sinnvoll, bei Auftreten multiresistenter Virusvarianten im Blut auch im Liquor entsprechende Untersuchungen durchzuf?hren. Im peripheren Nervensystems treten neben der klassischen, distal-symmetrischen, HIV-assoziierten Polyneuropathie immunogen vermittelte Neuropathien oder Myopathien auf (CIDP, AIDP). Durch die antiretrovirale Therapie (cART) verursachte Polyneuropathien sind differenzialdiagnostisch zu ber?cksichtigen. Erworbene mitochondrial toxische Myopathien treten h?ufiger auf, da nun eine cART durchaus ?ber 10???20 Jahre durchgef?hrt wird. Bei Patienten mit schweren depressiven Episoden zeigte sich eine 6-mal h?here Wahrscheinlichkeit, die Einnahme der cART mindestens einmal zu vergessen. Depressive Episoden sind oft ein Grund f?r mangelhafte Adh?renz, korrelieren mit einer h?heren Viruslast und sind dringend zu behandeln. In den letzten Jahren kam es infolge der verbesserten cART zu einem R?ckgang der opportunistischen Infektionen (OI) des ZNS. Die h?ufigsten OI stellen die progressive multifokale Leukoenzephalopathie (PML), die Toxoplasma-Enzephalitis und die Kryptokokken-Meningitis dar. Bei rasch progredientem Verlauf einer OI muss an ein Immunrekonstitutionssyndrom (IRIS) gedacht werden. Es gibt momentan keine sichere Methode, z.?B. die Verschlechterung einer PML durch den nat?rlichen Krankheitsverlauf von der Verschlechterung durch ein IRIS zu unterscheiden. Infolge der deutlich zunehmenden Lebenserwartung treten Komorbidit?ten mehr in den Vordergrund. Zu den viralen Biomarkern f?r die Krankheitsaktivit?t im ZNS z?hlen Neopterin als Marker der Makrophagenaktivierung, das Neurofilament-Leichtprotein und das Gesamt-Tau-Protein.

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Failure to clear intra-monocyte HIV infection linked to persistent neuropsychological testing impairment after first-line combined antiretroviral therapy

Cited by 38 publications

References 12 publications

Presence of High-Risk Human Papillomavirus Genotype and Human Immunodeficiency Virus DNA in Anal High-Grade and Low-Grade Squamous Intraepithelial Lesions

Presence of High-Risk Human Papillomavirus Genotype and Human Immunodeficiency Virus DNA in Anal High-Grade and Low-Grade Squamous Intraepithelial Lesions

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

Neues bei HIV und Neuro-Aids

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