Impact of CMV Therapy With Valganciclovir on Immune Activation and the HIV Viral Load in Semen and Blood

Shin, Lucy Y.; Sheth, Prameet M.; Persad, Desmond; Kovacs, Colin; Kain, Taylor; Diong, Christina; Su, DeSheng; Ostrowski, Mario; Raboud, Janet; Kaul, Rupert

doi:10.1097/01.qai.0000435256.34306.c1

Cited by 12 publications

(11 citation statements)

References 54 publications

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“…Valgancyclovir treatment resulted in the reduction not only of CMV but also of HIV-1 viral load (VL) in blood and in semen. The decrease in the semen HIV VL was not associated with immune parameters (activated T cells and inflammatory cytokines), suggesting that the reduced HIV VL in semen could not be solely explained by the suppression of immune activation but rather by alternative mechanisms, as hypothesized by the authors [22]. Here, we describe such a mechanism: we showed that GCV has a direct suppressive effect on HIV-1 replication in human lymphoid and cervical tissues ex vivo .…”

Section: Introductionmentioning

confidence: 49%

“…Towards this goal, Shin et al (2014) assessed the effect of CMV therapy on HIV genital levels by evaluating the impact of valganciclovir (a valine ester prodrug of gancyclovir, GCV) on HIV-infected, ART-naïve men in an open label observational study [22]. Valgancyclovir treatment resulted in the reduction not only of CMV but also of HIV-1 viral load (VL) in blood and in semen.…”

Section: Introductionmentioning

confidence: 99%

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A common anti-cytomegalovirus drug, ganciclovir, inhibits HIV-1 replication in human tissues ex vivo

Vanpouille

Bernatchez

Lisco

et al. 2017

Aids

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Cytomegalovirus (CMV) is a common HIV-1 copathogen. Since CMV infection is an important contributor to immune activation, the driving force of HIV disease, an anti-CMV strategy might be beneficial to HIV-infected patients. Shin et al. reported that anti-CMV therapy with valganciclovir in coinfected individuals results in a decrease of HIV viral load that is not accompanied by a decrease of immune activation. This suggests an alternative mechanism for HIV inhibition other than suppression of CMV-mediated inflammation. Here, we show that ganciclovir, the active form of valganciclovir, has a direct suppressive activity on HIV replication in human tissues ex vivo, including HIV-1 of laboratory strains, drug-resistant and primate isolates. We deciphered the mechanism of this inhibition and showed that GCV-TP is incorporated in the nascent DNA chain and acts as a delayed chain terminator.

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Section: Introductionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

A common anti-cytomegalovirus drug, ganciclovir, inhibits HIV-1 replication in human tissues ex vivo

Vanpouille

Bernatchez

Lisco

et al. 2017

Aids

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“…Local reactivation of CMV has been previously associated with the sVL [9, 30], and increased semen cytokines have been associated with semen levels of both CMV and HIV [8, 34, 35]. The absolute number of HIV-specific T cells in semen has also been associated with the sVL [8], although this was not seen in studies where a substantial proportion of men were on ART [34].…”

Section: Discussionmentioning

confidence: 99%

“…Compartmentalized reactivation of asymptomatic, persistent human herpesviruses (HHVs), such as CMV and Epstein-Barr virus (EBV), have been linked with an elevated sVL [5–9], and the association of a disproportionately high sVL with increased unprotected insertive (but not receptive) sex suggests that nonclassic STI may also be involved [10]. Associations are also seen between the sVL of ART-naive men and total semen bacterial levels (one aspect of the semen microbiome) [11, 12], several semen proinflammatory cytokines [9, 13–15], and the presence of various immune cell subsets [15–17]. …”

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confidence: 99%

Clinical and Mucosal Immune Correlates of HIV-1 Semen Levels in Antiretroviral-Naive Men

Osborne

Marsh

Huibner

et al. 2017

Open Forum Infectious Diseases

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Background.This study was done to characterize parameters associated with semen human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) viral load (VL) variability in HIV-infected, therapy-naive men.Methods.Paired blood and semen samples were collected from 30 HIV-infected, therapy-naive men who have sex with men, and 13 participants were observed longitudinally for up to 1 year. Human immunodeficiency virus RNA, bacterial load by 16S RNA, herpesvirus (Epstein-Barr virus and cytomegalovirus [CMV]) shedding, and semen cytokines/chemokines were quantified, and semen T-cell subsets were assessed by multiparameter flow cytometry.Results.Semen HIV RNA was detected at 93% of visits, with >50% of men shedding high levels of virus (defined as >5000 copies/mL). In the baseline cross-sectional analysis, an increased semen HIV VL correlated with local CMV reactivation, the semen bacterial load, and semen inflammatory cytokines, particularly interleukin (IL)-8. T cells in semen were more activated than blood, and there was an increased frequency of Th17 cells and γδ-T-cells. Subsequent prospective analysis demonstrated striking interindividual variability in HIV and CMV shedding patterns, and only semen IL-8 levels and the blood VL were independently associated with semen HIV levels.Conclusions.Several clinical and immune parameters were associated with increased HIV semen levels in antiretroviral therapy-naive men, with induction of local proinflammatory cytokines potentially acting as a common pathway.

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“…HIV disease progression is associated with increased adaptive and innate immune activation (IA) [6], which is multi-factorial including increased expansion of CMV-specific T cells [7] and persistent HIV RNA at low levels [8]. However, a major contributing factor to immune activation is the depletion of CD4+ T cells in gut-associated lymphoid tissue (GALT) during the acute HIV infection [9–11] leading to increased microbial translocation (MT).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the CD14 and TLR4 genes independently predict CD4+ T-cell recovery in HIV-infected individuals on antiretroviral therapy

Yong

Shankar

Solomon

et al. 2016

Aids

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Background Chronic HIV infection leads to marked depletion of CD4+ T cells in the gastrointestinal (GI) tract and increased microbial translocation measured by an increase in circulating lipopolysaccharide (LPS) levels. Here, we hypothesised that single-nucleotide polymorphisms (SNPs) in genes encoding the Toll-like receptor 4 (TLR4) and CD14, the principal receptors for LPS, were associated with CD4+ T-cell recovery post-antiretroviral therapy (ART). Methods Prospective study of predominantly Caucasian HIV-infected subjects receiving suppressive ART for at least 12 months. We analysed the CD14 SNPs C-260T and the TLR4 SNPs A+896G, C+1196T. We also determined the levels of LPS and soluble CD14 (sCD14) in plasma samples collected pre- and post-ART initiation. CD4+ T-cell recovery was assessed by linear mixed models. Results Following ART, individuals with a TT genotype compared to a CT or CC genotype for CD14 C-260T SNP showed higher levels of sCD14 (p=0.008 and 0.003 respectively). The CC genotype for the CD14 C-260T SNP, compared to CT or TT and the TLR4 SNP (AC/GT) compared to the homozygous genotype (AA/CC) were both independently associated with enhanced long-term CD4+ T-cell recovery (>3 months; p<0.001). Conclusions Polymorphisms in CD14 and TLR4 are independently associated with long-term CD4+ T-cell recovery in HIV-infected individuals post-ART.

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Impact of CMV Therapy With Valganciclovir on Immune Activation and the HIV Viral Load in Semen and Blood

Abstract: Although valganciclovir therapy was associated with reduced HIV and semen CMV levels, these results suggest that the reduced HIV VL was a direct drug effect rather than a CMV antiviral effect or CMV-associated immune alterations.

Cited by 12 publications

References 54 publications

A common anti-cytomegalovirus drug, ganciclovir, inhibits HIV-1 replication in human tissues ex vivo

A common anti-cytomegalovirus drug, ganciclovir, inhibits HIV-1 replication in human tissues ex vivo

Clinical and Mucosal Immune Correlates of HIV-1 Semen Levels in Antiretroviral-Naive Men

Polymorphisms in the CD14 and TLR4 genes independently predict CD4+ T-cell recovery in HIV-infected individuals on antiretroviral therapy

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