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Clinical Trial
. 2014 Jul 24;10(7):e1004262.
doi: 10.1371/journal.ppat.1004262. eCollection 2014 Jul.

The semen microbiome and its relationship with local immunology and viral load in HIV infection

Cindy M Liu  1 , Brendan J W Osborne  2 , Bruce A Hungate  3 , Kamnoosh Shahabi  2 , Sanja Huibner  2 , Richard Lester  4 , Michael G Dwan  4 , Colin Kovacs  5 , Tania L Contente-Cuomo  4 , Erika Benko  6 , Maliha Aziz  7 , Lance B Price  7 , Rupert Kaul  8
Affiliations
Clinical Trial

The semen microbiome and its relationship with local immunology and viral load in HIV infection

Cindy M Liu et al. PLoS Pathog. .

Abstract

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 (r(2) = 0.18, p = 0.02). Semen bacterial load was also directly linked to the semen HIV VL (r(2) = 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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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Rank abundance and the five most abundant semen bacteria in uninfected versus HIV-infected men over the course of antiretroviral treatment.
In this rank abundance plot, richness is the distance the plot extends along the x-axis, and evenness is low slope. Extreme dominance is a high y-intercept. HIV uninfected is both richer and more even than the ART- naïve, but by 6 months ART, the relationship converges onto the HIV uninfected. The five top-ranked semen bacteria from each group are listed, with its respective group-level proportional abundance in parenthesis.
Figure 2
Figure 2. Semen microbiome biodiversity in uninfected versus HIV-infected men over the course of antiretroviral treatment.
In this set of two plots (Panels A–B), the solid circles represent HIV-uninfected men, whereas open circles represent HIV-infected men. Panel A depicts the higher richness (i.e., greater number of unique bacterial types) of the semen microbiome in HIV-uninfected men, as well as the restoration of richness over the period of six months on ART. A similar trend was seen in semen microbiome diversity, as shown in Panel B.
Figure 3
Figure 3. Correlation of semen bacterial load with CD4+ T-cell counts and viral loads in the semen and blood of HIV-infected men prior to antiretroviral treatment.
Our data showed multiple correlations between HIV loads and CD4+ counts, including the correlation of semen and blood viral loads and of blood CD4+ T-cell counts and viral load (Figure S1). However, we found that the significant correlation between semen bacterial load with semen viral load was unique (Panel A), and the semen bacterial load showed no such correlation with either the blood viral load (Panel B) or CD4+ T-cell counts (Panel C), suggesting that the correlation between bacterial and viral loads in the semen might be caused by localized mechanisms.
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