Herpesviruses, including herpes simplex (HSV) and varicella-zoster virus (VZV), establish lifelong latent infection in nerve cells. HSV-1 can reactivate to cause cold sores, and HSV-2 can reactivate to cause genital herpes. Although these infections are usually mild, they can cause encephalitis and severe disease in newborn infants. In addition, HSV-2 is a risk factor for transmission and acquisition of HIV. HIV can cause opportunistic infections and is associated with increased rates of several cancers. HSV-1, HSV-2, and VZV establish a latent infection in the neurons in the ganglia (a group of nerve cells outside the central nervous system). The mechanism by which these viruses establish latency is not understood. A better understanding of latency might result in novel ways to prevent latent infections or prevent the virus from reactivation once it establishes latency. HSV expresses a predominant viral RNA, termed the latency-associated transcript (LAT), when the virus is latent in nerve cells. Animal models, using viruses deleted for HSV LAT, indicate that LAT is important for regulating HSV reactivation. While the function of the HSV LAT in reactivation is uncertain, LAT has been postulated to increase the ability of the virus to establish or maintain latency, likely by increasing the survival of latently infected nerve cells. We have been studying other mechanisms whereby the LAT might affect latency or reactivation. We have collaborated with Philip Krause at the FDA and Bryan Cullen at Duke University to look for HSV-2 microRNAs in latently infected guinea pig and human ganglia. microRNAs are short (22 nucleotide) pieces of nucleic acid (RNA) that recognize mRNA and inhibit their translation into proteins enhance mRNA degradation. We previously identified an HSV-2 LAT-related microRNA termed miR-I in HSV-2 latently infected ganglia of guinea pigs and humans. This year we performed additional analysis of HSV-2 latently infected human sacral ganglia and identified five distinct HSV-2 miRNA species, three of which had not been reported previously. Two of these, miR-H7 and miR-H9, are derived from the LAT and are located antisense to the viral transcript encoding the HSV-2 transactivator ICP0. A third novel HSV-2 miRNA, miR-H10, is located 3'to the UL15 gene of HSV-2, and is presumably excised from a novel, latent HSV-2 transcript distinct from LAT. This year we also collaborated with Todd Margolis at the University of California at San Francisco studying herpesvirus ocular infections. Human herpesvirus 6 and 7 (HHV-6, HHV-7) cause roseola and have been associated with several neurologic syndromes and have been detected in nervous tissue from healthy persons;however, only two cases of HHV-6A have been reported to be associated with eye inflammatory disease. Intaocular fluid was tested from 101 patients, including 69 samples from patients with eye inflammation including CMV retinitis, idiopathic retinitis, iritis, and vitritis, for HHV-6A, HHV-6B, and HHV-7 DNA by PCR. HHV-6A DNA (at 4,950 copies per ml) was detected in ocular fluid from one patient with CMV retinitis, HHV-6B DNA (10,140 copies per ml) was detected in ocular fluid from one patient with unexplained ocular inflammation in the absence of CMV DNA, and HHV-7 was not detected in any of the ocular samples. We concluded that HHV-6A, HHV-6B, and HHV-7 DNA are detectable in less than 2% of ocular fluid samples in patients with eye inflammation.
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