Immunological Mechanisms Mediating Hantavirus Persistence in Rodent Reservoirs

Hantaviruses, similar to several emerging zoonotic viruses, persistently infect their natural reservoir hosts, without causing overt signs of disease. Spillover to incidental human hosts results in morbidity and mortality mediated by excessive proinflammatory and cellular immune responses. The mechanisms mediating the persistence of hantaviruses and the absence of clinical symptoms in rodent reservoirs are only starting to be uncovered. Recent studies indicate that during hantavirus infection, proinflammatory and antiviral responses are reduced and regulatory responses are elevated at sites of increased virus replication in rodents. The recent discovery of structural and non-structural proteins that suppress type I interferon responses in humans suggests that immune responses in rodent hosts could be mediated directly by the virus. Alternatively, several host factors, including sex steroids, glucocorticoids, and genetic factors, are reported to alter host susceptibility and may contribute to persistence of hantaviruses in rodents. Humans and reservoir hosts differ in infection outcomes and in immune responses to hantavirus infection; thus, understanding the mechanisms mediating viral persistence and the absence of disease in rodents may provide insight into the prevention and treatment of disease in humans. Consideration of the coevolutionary mechanisms mediating hantaviral persistence and rodent host survival is providing insight into the mechanisms by which zoonotic viruses have remained in the environment for millions of years and continue to be transmitted to humans

Changes in Mycobacterium tuberculosis Genotype Families Over 20 Years in a Population-Based Study in Northern Malawi

BACKGROUND: Despite increasing interest in possible differences in virulence and transmissibility between different genotypes of M. tuberculosis, very little is known about how genotypes within a population change over decades, or about relationships to HIV infection. METHODS AND PRINCIPAL FINDINGS: In a population-based study in rural Malawi we have examined smears and cultures from tuberculosis patients over a 20-year period using spoligotyping. Isolates were grouped into spoligotype families and lineages following previously published criteria. Time trends, HIV status, drug resistance and outcome were examined by spoligotype family and lineage. In addition, transmissibility was examined among pairs of cases with known epidemiological contact by assessing the proportion of transmissions confirmed for each lineage, on the basis of IS6110 RFLP similarity of the M tuberculosis strains. 760 spoligotypes were obtained from smears from 518 patients from 1986-2002, and 377 spoligotypes from cultures from 347 patients from 2005-2008. There was good consistency in patients with multiple specimens. Among 781 patients with first episode tuberculosis, the majority (76%) had Lineage 4 ("European/American") strains; 9% had Lineage 3 ("East-African/Indian"); 8% Lineage 1 ("Indo-Oceanic"); and 2% Lineage 2 ("East-Asian"); others unclassifiable. Over time the proportion of Lineage 4 decreased from >90% to 60%, with an increase in the other 3 lineages (p<0.001). Lineage 1 strains were more common in those with HIV infection, even after adjusting for age, sex and year. There were no associations with drug resistance or outcome, and no differences by lineage in the proportion of pairs in which transmission was confirmed. CONCLUSIONS: This is the first study to describe long term trends in the four M. tuberculosis lineages in a population. Lineage 4 has probably been longstanding in this population, with relatively recent introductions and spread of Lineages1-3, perhaps influenced by the HIV epidemic

Summary of Immune Responses in Humans during Hantavirus Infection.

a<p>SNV, Sin Nombre virus; NY-1V, New York-1 virus; PUUV, Puumala virus; PHV, Prospect Hill virus; ANDV, Andes virus; TULV, Tula virus; HTNV, Hantaan virus; DOBV, Dobrava virus.</p>b<p>HUVEC, human umbilical vascular endothelial cells; HSVEC, human saphenous vein endothelial cells; HMVEC-L, human lung microvascular endothelial cells; COS-7, African green monkey kidney fibroblasts transformed with Simian virus 40; MRC5, human fetal lung fibroblasts; MФ, macrophages; DCs, dendritic cells; BAL, bronchoalveolar lavage, PBMC, human peripheral blood mononuclear cells.</p>c<p>Acute infection is during symptomatic disease in patients.</p>d<p>Suppressor T cells likely represent cells currently referred to as regulatory T cells.</p

Summary of Immune Responses in Rodents during Hantavirus Infection.

a<p>SEOV, Seoul virus; HTNV, Hantaan virus, PUUV, Puumala virus; SNV, Sin Nombre virus; PUUV, Puumala virus; BCCV, Black Creek Canal virus.</p>b<p>MФ, macrophages.</p>c<p>Acute infection is <30 days p.i. and persistent infection is ≥30 days p.i.</p>d<p><i>Mus musculus</i>, non-natural reservoir host for hantaviruses.</p

Kinetics of Hantavirus Infection in Rodents.

<p>Adapted from Lee et al. <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000172#ppat.1000172-Lee1" target="_blank">[15]</a> and others <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000172#ppat.1000172-Botten1" target="_blank">[12]</a>–<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000172#ppat.1000172-Yanagihara1" target="_blank">[14]</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000172#ppat.1000172-Lee2" target="_blank">[16]</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000172#ppat.1000172-Hutchinson1" target="_blank">[18]</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000172#ppat.1000172-Klein3" target="_blank">[20]</a>, the kinetics of relative hantaviral load in blood (red), saliva (green), and lung tissue (blue) and antibody responses (black) during the acute and persistent phases of infection are represented. The amount of genomic viral RNA, infectious virus titer, and/or relative amount of viral antigen have been incorporated as relative hantaviral load. The antibody response is integrated as the relative amount of anti-hantavirus IgG and/or neutralizing antibody titers.</p

Common genetic variation and the control of HIV-1 in humans

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians