Human Herpesvirus 8 in the Prostate Glands of Men with Kaposi’s Sarcoma

Abstract

The epidemiology of human immunodeficiency virus (HIV)-associated Kaposi’s sarcoma (KS) resembles that of a sexually transmitted pathogen. However, human herpesvirus 8 (HHV-8), the proposed cause of KS, is found in semen only infrequently and at low titers. To determine whether HHV-8 was present in the urogenital tract, transrectal ultrasound-guided prostate biopsies were obtained from six men with KS (five with concurrent HIV infection) and four without KS (three with concurrent HIV) and assayed for HHV-8 by PCR. Nine of the 10 men were seropositive for HHV-8. Five of nine HHV-8-seropositive men had HHV-8 DNA detected in prostate tissue by solution-based PCR. All five currently had KS or had it previously. In two subjects, prostate tissue was the only identified source of HHV-8. In situ PCR on serial sections of prostate indicated that HHV-8 infection was localized to discrete areas of the prostate. When detected, HHV-8 DNA was present in the nuclei of >90% of the glandular epithelial cells. In situ hybridization for HHV-8 mRNA revealed that between 1 and 5% of cells harboring HHV-8 DNA expressed viral transcripts associated with HHV-8 replication (T1.1 transcript), while >90% expressed gene products associated with viral latency (T0.7 transcript). Intermittent replication of HHV-8 in the prostate and subsequent shedding of virus in semen may be crucial factors for determining whether HHV-8 can be transmitted through sexual activity.

HHV‐8 infection: a model for reactivation and transmission

“…Unfortunately, contamination of the PCR reaction can occur and DNA PCR cannot distinguish between latent versus 'lytic' stage of the virus life cycle [58]. Demonstration of HHV-8 RNA by reverse transcription PCR, especially RNA to latent or structural gene transcripts appears at present to offer the most accurate reflection of viral replication [9,10,59].…”

“…In both cases (Figure 2 While this model helps to explain the link between latently infected B cells, oral epithelial cells and mucosal excretion of HHV-8 in saliva, it sheds little light on what controls this process. The focality of HHV-8 infection in many glandular tissues including lymphoid tissue [10,59] and the recent epidemiologic demonstration that only a few HHV-8 seropositive persons are frequent shedders suggest that there is an important quantitative aspect to mucosal sites of HHV-8 infection and replication [85]. All the other herpesviruses found in saliva are ubiquitous.…”

“…Prospective studies have indicated that seroconversion or loss of antibodies occurs in some persons over time [28,29]. HHV-8 DNA has been demonstrated in prostatic tissue and PBMC of seronegative persons, indicating that current serologic assays underestimate the frequency of HHV-8 [10,59,112]. It is possible that HHV-8 may encode proteins that inhibit antibody formation or long term memory.…”

Kaposi's sarcoma triggered by endogenous HHV‐8 reactivation after non‐myeloablative allogeneic haematopoietic transplantation

“…Latent infection determines a transient increase in IgM and a durable IgG response against latency associated nuclear antigen (LANA) and lytic antigens. CD19+ B cells appear to be the primary viral reservoir (12), but other potential reservoirs, such as the endothelium, CD68+ monocyte‐macrophage cells, salivary glands, and prostate epithelia have been proposed (7, 13, 14). Host immunosuppression is a key factor for HHV‐8 clinical manifestations.…”

Raman tweezers provide the fingerprint of cells supporting the late stages of KSHV reactivation

“…Successful KSHV infection is characterized by both virus entry and the ability of the virus to establish latency. The lytic infection is also critical for the spread of KSHV to different organs.KSHV infects a variety of target cells that includes human B cells, macrophages, keratinocytes, endothelial cells and epithelial cells [7][8][9][10][11]. However, all of these infections are either abortive and/or latent, which are characterized by the presence of circular latent viral DNA and by the expression of KSHV latency-associated nuclear antigen (LANA) encoded by ORF73 [12].…”