Mucosal correlates of isolated HIV semen shedding during effective antiretroviral therapy

Sheth, Prameet M.; Yi, Tae Joon; Kovacs, Colin; Kemal, Kimdar Sherefa; Jones, R. Brad; Osborne, B.; Pilon, Richard; Porte, Charles la; Ostrowski, Mario; Mazzulli, Tony; Burger, Harold; Weiser, Barbara; Kaul, Rupert

doi:10.1038/mi.2012.1

Cited by 26 publications

(23 citation statements)

References 42 publications

(66 reference statements)

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“…However, in HIV-infected men who have sex with men (MSM) on suppressive antiretroviral therapy (ART), T cell activation in the semen has been associated with transient bursts of semen viral replication, in the absence of classical sexually transmitted infections and independent of cytomegalovirus reactivation or herpes infection [6]. There is also evidence that increased proinflammatory cytokine and chemokine in the semen might enhance local HIV replication and evolution in the male genital tract [15].…”

Section: Introductionmentioning

confidence: 99%

The Semen Microbiome and Its Relationship with Local Immunology and Viral Load in HIV Infection

et al. 2014

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Semen is a major vector for HIV transmission, but the semen HIV RNA viral load (VL) only correlates moderately with the blood VL. Viral shedding can be enhanced by genital infections and associated inflammation, but it can also occur in the absence of classical pathogens. Thus, we hypothesized that a dysregulated semen microbiome correlates with local HIV shedding. We analyzed semen samples from 49 men who have sex with men (MSM), including 22 HIV-uninfected and 27 HIV-infected men, at baseline and after starting antiretroviral therapy (ART) using 16S rRNA gene-based pyrosequencing and quantitative PCR. We studied the relationship of semen bacteria with HIV infection, semen cytokine levels, and semen VL by linear regression, non-metric multidimensional scaling, and goodness-of-fit test. Streptococcus, Corynebacterium, and Staphylococcus were common semen bacteria, irrespective of HIV status. While Ureaplasma was the more abundant Mollicutes in HIV-uninfected men, Mycoplasma dominated after HIV infection. HIV infection was associated with decreased semen microbiome diversity and richness, which were restored after six months of ART. In HIV-infected men, semen bacterial load correlated with seven pro-inflammatory semen cytokines, including IL-6 (p = 0.024), TNF-α (p = 0.009), and IL-1b (p = 0.002). IL-1b in particular was associated with semen VL (r2 = 0.18, p = 0.02). Semen bacterial load was also directly linked to the semen HIV VL (r2 = 0.15, p = 0.02). HIV infection reshapes the relationship between semen bacteria and pro-inflammatory cytokines, and both are linked to semen VL, which supports a role of the semen microbiome in HIV sexual transmission.

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Section: Introductionmentioning

confidence: 99%

The Semen Microbiome and Its Relationship with Local Immunology and Viral Load in HIV Infection

et al. 2014

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“…Although anti-retroviral therapy (ART) effectively suppresses viral replication in all three compartments [9], [12], [13], [14], approximately10–40% of ART-treated subjects have detectable HIV in the genital tract fluid but not in blood plasma [6], [7], [8], [9], [15], [16], [17], [18], [19], [20], [21], [22]. Such discordances suggest a compartment-specific milieu for viral replication in blood and non-blood compartments [23], [24], which could lead to an erroneous perception of genital viral suppression and persistent potential for HIV transmission despite suppression of HIV in the blood compartment.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 RNA Levels and Antiretroviral Drug Resistance in Blood and Non-Blood Compartments from HIV-1–Infected Men and Women enrolled in AIDS Clinical Trials Group Study A5077

et al. 2014

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BackgroundDetectable HIV-1 in body compartments can lead to transmission and antiretroviral resistance. Although sex differences in viral shedding have been demonstrated, mechanisms and magnitude are unclear. We compared RNA levels in blood, genital-secretions and saliva; and drug resistance in plasma and genital-secretions of men and women starting/changing antiretroviral therapy (ART) in the AIDS Clinical Trials Group (ACTG) 5077 study.MethodsBlood, saliva and genital-secretions (compartment fluids) were collected from HIV-infected adults (≥13 years) at 14 United-States sites, who were initiating or changing ART with plasma viral load (VL) ≥2,000 copies/mL. VL testing was performed on all compartment fluids and HIV resistance genotyping on plasma and genital-secretions. Spearman rank correlations were used to evaluate concordance and Fisher’s and McNemar’s exact tests to compare VL between sexes and among compartments.ResultsSamples were available for 143 subjects; 36% treated (23 men, 29 women) and 64% ‘untreated’ (40 men, 51 women). RNA detection was significantly more frequent in plasma (100%) than genital-secretions (57%) and saliva (64%) (P<0.001). A higher proportion of men had genital shedding versus women (78% versus 41%), and RNA detection was more frequent in saliva versus genital-secretions in women when adjusted for censoring at the limit of assay detection. Inter-compartment fluid VL concordance was low in both sexes. In 22 (13 men, 9 women) paired plasma-genital-secretion genotypes from treated subjects, most had detectable resistance in both plasma (77%) and genital-secretions (68%). Resistance discordance was observed between compartments in 14% of subjects.ConclusionsHIV shedding and drug resistance detection prior to initiation/change of ART in ACTG 5077 subjects differed among tissues and between sexes, making the gold standard blood-plasma compartment assessment not fully representative of HIV at other tissue sites. Mechanisms of potential sex-dependent tissue compartmentalization should be further characterized to aid in optimizing treatment and prevention of HIV transmission.Trial RegistrationClinicalTrials.gov NCT00007488

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“…Future studies, in persons on ART with suppressed plasma HIV-1 RNA, could also assess whether high-dose anti-HSV therapy could reduce genital HIV-1 RNA shedding, which may be a potential transmission risk in persons with suppressed plasma viral load. 46 …”

Section: Discussionmentioning

confidence: 99%

High-Dose Valacyclovir Decreases Plasma HIV-1 RNA More Than Standard-Dose Acyclovir in Persons Coinfected with HIV-1 and HSV-2

Perti¹,

Saracino²,

Baeten

et al. 2013

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Standard doses of HSV suppressive therapy reduce plasma HIV-1 RNA levels (0.25-0.53 log10 copies/mL) among HIV-1/HSV-2 co-infected persons. Postulated mechanisms for this effect include direct inhibition of HIV-1 by acyclovir or indirect reduction by decreasing HSV-associated inflammation. We hypothesized that high-dose valacyclovir would further reduce plasma HIV-1 RNA, and that the effect would be mediated by greater suppression of HSV shedding. Methods 34 participants with HIV-1 and HSV-2 not on antiretroviral therapy were enrolled into a randomized, open-label cross-over trial of valacyclovir 1000 mg twice daily or acyclovir 400 mg twice daily for 12 weeks, followed by a two week washout, and then the alternate treatment arm for 12 weeks. HSV DNA was measured from daily self-collected genital swabs for the initial 4 weeks of each arm and HIV-1 RNA was quantified from weekly plasma samples. Results 28 participants provided plasma samples and genital swabs on both acyclovir and valacyclovir. The genital HSV-2 shedding rate was the same on valacyclovir and acyclovir (7.8% vs. 8.2% of days; RR, 0.95; 95% CI, 0.66-1.37; p=0.78). Plasma HIV-1 RNA was 0.27 log10 copies/mL lower on valacyclovir compared with acyclovir (95% CI, −0.41 to −0.14 log10 copies/mL; p<0.001); this was unchanged after adjustment for genital HSV-2 shedding. Conclusions High-dose valacyclovir reduces plasma HIV-1 RNA levels more than standard-dose acyclovir in HIV-1/HSV-2 seropositive persons not receiving antiretroviral therapy. The incremental reduction in plasma HIV-1 RNA achieved is not mediated by greater genital HSV-2 suppression.

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Mucosal correlates of isolated HIV semen shedding during effective antiretroviral therapy

Cited by 26 publications

References 42 publications

The Semen Microbiome and Its Relationship with Local Immunology and Viral Load in HIV Infection

The Semen Microbiome and Its Relationship with Local Immunology and Viral Load in HIV Infection

HIV-1 RNA Levels and Antiretroviral Drug Resistance in Blood and Non-Blood Compartments from HIV-1–Infected Men and Women enrolled in AIDS Clinical Trials Group Study A5077

High-Dose Valacyclovir Decreases Plasma HIV-1 RNA More Than Standard-Dose Acyclovir in Persons Coinfected with HIV-1 and HSV-2

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