West Nile virus (WNV) is a re-emerging pathogen that can cause fatal encephalitis. In mice, susceptibility to WNV has been reported to result from a single point mutation in oas1b, which encodes 2′–5′ oligoadenylate synthetase 1b, a member of the type I interferon-regulated OAS gene family involved in viral RNA degradation. In man, the human ortholog of oas1b appears to be OAS1. The ‘A’ allele at SNP rs10774671 of OAS1 has previously been shown to alter splicing of OAS1 and to be associated with reduced OAS activity in PBMCs. Here we show that the frequency of this hypofunctional allele is increased in both symptomatic and asymptomatic WNV seroconverters (Caucasians from five US centers; total n = 501; OR = 1.6 [95% CI 1.2–2.0], P = 0.0002 in a recessive genetic model). We then directly tested the effect of this SNP on viral replication in a novel ex vivo model of WNV infection in primary human lymphoid tissue. Virus accumulation varied markedly among donors, and was highest for individuals homozygous for the ‘A’ allele (P<0.0001). Together, these data identify OAS1 SNP rs10774671 as a host genetic risk factor for initial infection with WNV in humans.

There is growing recognition that HIV-1 infection leads to an activation of the immune system that includes perturbations of cytokine expression, redistribution of lymphocyte subpopulations, cell dysfunction, and cell death. Here, we explored the relationships between HIV-1 infection and immune activation in chronically HIV-1-infected human lymph nodes. In addition to CD4 T-cell depletion, we found increased effector T-cell frequencies associated with profound up-regulation of an activation marker

Infection and dissemination of HIV-1 through the female body after vaginal intercourse depends on the activation/differentiation status of mucosal CD4 T cells. Here, we investigated this status and the susceptibility to HIV-1 infection of human cervico-vaginal tissue ex vivo. We found that virtually all T cells are of the effector memory phenotype with broad CCR5 expression. As it does in vivo, human cervico-vaginal tissue ex vivo preferentially supports the productive infection of R5 HIV-1 rather than that of X4 HIV-1 in spite of broad expression of CXCR4. X4 HIV-1 replicated only in the few tissues that were enriched in CD27+CD28+ effector memory CD4 T cells. Productive infection of R5 HIV-1 occurred preferentially in activated CD38+CD4 T cells and was followed by a similar activation of HIV-1-uninfected (bystander) CD4 T cells that may amplify viral infection. These results provide new insights into the dependence of HIV-1 infection and dissemination on the activation/differentiation of cervico-vaginal lymphocytes.

SUMMARY For most viruses, including HIV, there is a need for antimicrobials that target unique viral molecular properties. Acyclovir (ACV) is such a drug for human herpesviruses (HHVs): it is activated into a HHV-DNA polymerase inhibitor exclusively by HHV-kinases and thus does not suppress other viruses. Here, we report on the direct inhibition of HIV-1 reverse transcriptase (RT) by phosphorylated ACV, which terminates DNA chain elongation and can trap RT at the site of termination. Consequently, ACV suppresses HIV-1 in HHV-coinfected human tissues but not in a HHV-free tissue or cell lines. However, addition of HHV-6-infected cells or administration of ACV monophosphorylated prodrugs (not requiring activation by HHV-kinases) renders HIV sensitive to ACV in these cells. These data suggest that ACV is active against HIV-1 in tissues coinfected with various HHVs, provide new insights in ACV activity into HIV/HSV-2-coinfected patients, and provide strategies for the development of new HIV-1 RT inhibitors.

Summary A patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound. We had previously found a dominant interleukin-23–interleukin-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder. Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition. We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23–dependent production of interleukin-17. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

SUMMARY The HIV reverse transcriptase inhibitor tenofovir, was recently formulated into a vaginal gel for use as a microbicide. In human trials, a 1% tenofovir gel inhibited HIV sexual transmission by 39% and surprisingly herpes simplex virus-2 (HSV-2) transmission by 51%. We demonstrate that the concentration achieved intravaginally with a 1% tenofovir topical gel has direct anti-herpetic activity. Tenofovir inhibits the replication of HSV clinical isolates in human embryonic fibroblasts, keratinocytes, and organotypic epithelial 3D-rafts, decreases HSV replication in human lymphoid and cervical tissues ex vivo, and delays HSV-induced lesions and death of topically treated HSV-infected mice. The active tenofovir metabolite inhibits HSV DNA-polymerase and HIV reverse transcriptase. Tenofovir must be topically administered to achieve concentrations, which are higher than systemic levels after oral treatment, that exert these dual antiviral effects. These findings indicate that a single topical treatment, like tenofovir, can inhibit the transmission of HIV and its co-pathogens.

Background West Nile virus (WNV) is a neurotropic flavivirus transmitted to humans by mosquito vectors. Homozygosity for CCR5Δ32, a complete loss-of-function mutation in the chemokine receptor CCR5, has been previously associated with severe symptomatic WNV infection in patients presenting with clinical disease, however whether it acts at the level of initial infection or in promoting clinical progression is unknown. Methods Here we address this gap in knowledge by comparing CCR5Δ32 distribution in US blood donors identified through a comprehensive blood supply screening program (n=34,766,863 donations from 2003–2008) as either WNV true positive (WNV+ cases; n=634) or false positive (WNV− controls; n=422). Results No difference was observed in CCR5Δ32 homozygous frequency between the WNV+ cases and WNV− controls, suggesting that CCR5 deficiency is not a risk factor for initial infection. However, CCR5Δ32 homozygosity was associated with worse clinical outcome, with these individuals developing more clinical symptoms as determined by a standardized questionnaire (P=0.0016). Conclusions Thus CCR5 deficiency is not a risk factor for WNV infection per se, but is a risk factor for both early and late clinical manifestations after infection. Our study also illustrates the power of large scale databases to answer important clinical questions in man.

HIV-1 infection results in an aberrant production of cytokines and reactivation of EBV and CMV that further changes the seminal cytokine network. The altered seminal milieu in HIV-1 infection may be a determinant of HIV-1 sexual transmission.