The interplay between host genetic variation, viral replication and microbial translocation in untreated HIV-infected individuals.

Systemic immune activation, a major determinant of HIV disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. While human genetic variants influencing HIV viral load have been identified, it is unknown to what extent the host genetic background contributes to inter-individual differences in other determinants of HIV pathogenesis like gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty-acid binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble sCD14 (sCD14), a marker of LPS bioactivity and microbial translocation. We also assessed the correlations between HIV viral load, sCD14 and I-FABP. While we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV viral load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infection

The Interplay Between Host Genetic Variation, Viral Replication, and Microbial Translocation in Untreated HIV-Infected Individuals

Systemic immune activation, a major determinant of human immunodeficiency virus (HIV) disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. Although human genetic variants influencing HIV load have been identified, it is unknown how much the host genetic background contributes to interindividual differences in other determinants of HIV pathogenesis such as gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty acid-binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble CD14 (sCD14), a marker of lipopolysaccharide bioactivity and microbial translocation. We also assessed the correlations between HIV load, sCD14, and I-FABP. Although we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infectio

MRSA Infections in HIV-Infected People Are Associated with Decreased MRSA-Specific Th1 Immunity

<div><p>People with HIV infection are at increased risk for community-acquired methicillin-resistant <i>Staphylococcus aureus</i> (CA-MRSA) skin and soft tissue infections (SSTIs). Lower CD4 T-cell counts, higher peak HIV RNA levels and epidemiological factors may be associated with increased risk but no specific immune defect has been identified. We aimed to determine the immunologic perturbations that predispose HIV-infected people to MRSA SSTIs. Participants with or without HIV infection and with MRSA SSTI, MRSA colonization or negative for MRSA were enrolled. Peripheral blood and skin biopsies from study participants were collected. Flow cytometry, flow cytometry with microscopy, multiplex assays of cell culture supernatants and immunohistochemistry were used to evaluate the nature of the immune defect predisposing HIV-infected people to MRSA infections. We found deficient MRSA-specific IFNγ⁺ CD4 T-cell responses in HIV-infected people with MRSA SSTIs compared to MRSA-colonized participants and HIV-uninfected participants with MRSA SSTIs. These IFNγ⁺ CD4 T cells were less polyfunctional in HIV-infected participants with SSTIs compared to those without SSTIs. However, IFNγ responses to cytomegalovirus and <i>Mycobacterium avium</i> antigens and MRSA-specific IL-17 responses by CD4 T cells were intact. Upon stimulation with MRSA, peripheral blood mononuclear cells from HIV-infected participants produced less IL-12 and IL-15, key drivers of IFNγ production. There were no defects in CD8 T-cell responses, monocyte responses, opsonization, or phagocytosis of <i>Staphylococcus aureus</i>. Accumulation of CD3 T cells, CD4 T cells, IL-17⁺ cells, myeloperoxidase⁺ neutrophils and macrophage/myeloid cells to the skin lesions were similar between HIV-infected and HIV-uninfected participants based on immunohistochemistry. Together, these results indicate that MRSA-specific IFNγ⁺ CD4 T-cell responses are essential for the control of initial and recurrent MRSA infections in HIV-infected people.</p></div

Histological evaluation of skin biopsies.

<p>Skin biopsies were obtained from MRSA SSTI participants at the infection site (SSTI lesion) or a distant site (SSTI Not Lesion), or MRSA-negative participants (-). (A) Abundance of CD3. (B) Abundance of CD4. (C) Abundance of IL-17. (D) Abundance of neutrophils (myeloperoxidase⁺ [MPO]). (E) Abundance of macrophage/myeloid cells (CD68⁺ and/or CD163⁺). <i>P</i>-values were calculated using the Mann-Whitney <i>U</i> test.</p

MRSA-specific memory CD4 T cells.

<p>Flow cytometry analysis of MRSA-specific memory (CD27⁺CD45RO⁺ or CD27^-) CD4 T-cell responses in HIV-infected or HIV-uninfected participants with MRSA SSTI, colonization or neither. Frequency of memory CD4 T cells producing (A) IFNγ, (B) IL-17, (C) TNF and (D) CD40L. For all figures, horizontal lines indicate medians. <i>P</i>-values were calculated using the Mann-Whitney <i>U</i> test.</p

Baseline characteristics.

<p>Baseline characteristics.</p

Cytokine concentrations released into supernatant.

<p>Supernatant concentrations of IFNγ (A) and drivers of IFNγ production, IL-12 (B) and IL-15 (C), after MRSA stimulation of PBMCs were assayed using the Luminex platform. <i>P</i>-values were calculated using the Mann-Whitney <i>U</i> test.</p

CD4 T follicular helper cell dynamics during SIV infection

CD4 T follicular helper (TFH) cells interact with and stimulate the generation of antigen-specific B cells. TFH cell interaction with B cells correlates with production of SIV-specific immunoglobulins. However, the fate of TFH cells and their participation in SIV-induced antibody production is not well understood. We investigated the phenotype, function, location, and molecular signature of TFH cells in rhesus macaques. Similar to their human counterparts, TFH cells in rhesus macaques represented a heterogeneous population with respect to cytokine function. In a highly differentiated subpopulation of TFH cells, characterized by CD150lo expression, production of Th1 cytokines was compromised while IL-4 production was augmented, and cells exhibited decreased survival, cycling, and trafficking capacity. TFH cells exhibited a distinct gene profile that was markedly altered by SIV infection. TFH cells were infected by SIV; yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH cells was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. Therefore, chronic SIV does not disturb the ability of TFH cells to help B cell maturation and production of SIV-specific immunoglobulins