This review describes the various viruses identified in the semen and reproductive tracts of mammals (including humans), their distribution in tissues and fluids, their possible cell targets, and the functional consequences of their infectivity on the reproductive and endocrine systems. The consequences of these viral infections on the reproductive tract and semen can be extremely serious in terms of organ integrity, development of pathological and cancerous processes, and transmission of diseases. Furthermore, of essential importance is the fact that viral infection of the testicular cells may result not only in changes in testicular function, a serious risk for the fertility and general health of the individual (such as a fall in testosteronemia leading to cachexia), but also in the possible transmission of virus-induced mutations to subsequent generations. In addition to providing an exhaustive account of the data available in these domains, this review focuses attention on the fact that the interface between endocrinology and virology has so far been poorly explored, particularly when major health, social and economical problems are posed. Our conclusions highlight the research strategies that need to be developed. Progress in all these domains is essential for the development of new treatment strategies to eradicate viruses and to correct the virus-induced dysfunction of the endocrine system

The chemokine receptors CCR5 and CXCR4 are the major coreceptors for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). At least 12 other chemokine receptors or close relatives support infection by particular HIV and SIV strains on CD4؉ transformed indicator cell lines in vitro. However, the role of these alternative coreceptors in vivo is presently thought to be insignificant. Infection of cell lines expressing high levels of recombinant CD4 and coreceptors thus does not provide a true indication of coreceptor use in vivo. We therefore tested primary untransformed cell cultures that lack CCR5 and CXCR4, including astrocytes and brain microvascular endothelial cells (BMVECs), for naturally expressed alternative coreceptors functional for HIV and SIV infection. An adenovirus vector (Ad-CD4) was used to express CD4 in CD4 ؊ astrocytes and thus confer efficient infection if a functional coreceptor is present. Using a large panel of viruses with well-defined coreceptor usage, we identified a subset of HIV and SIV strains able to infect two astrocyte cultures derived from adult brain tissue. Astrocyte infection was partially inhibited by several chemokines, indicating a role for the chemokine receptor family in the observed infection. BMVECs were weakly positive for CD4 but negative for CCR5 and CXCR4 and were susceptible to infection by the same subset of isolates that infected astrocytes. BMVEC infection was efficiently inhibited by the chemokine vMIP-I, implicating one of its receptors as an alternative coreceptor for HIV and SIV infection. Furthermore, we tested whether the HIV type 1 and type 2 strains identified were able to infect peripheral blood mononuclear cells (PBMCs) via an alternative coreceptor. Several strains replicated in ⌬32/⌬32 CCR5 PBMCs with CXCR4 blocked by AMD3100. This AMD3100-resistant replication was also sensitive to vMIP-I inhibition. The nature and potential role of this alternative coreceptor(s) in HIV infection in vivo is discussed.

The coreceptors used by primary syncytium-inducing (SI) human immunodeficiency virus type 1 isolates for infection of primary macrophages were investigated. SI strains using only CXCR4 replicated equally well in macrophages with or without CCR5 and were inhibited by several different ligands for CXCR4 including SDF-1 and bicyclam derivative AMD3100. SI strains that used a broad range of coreceptors including CCR3, CCR5, CCR8, CXCR4, and BONZO infected CCR5-deficient macrophages about 10-fold less efficiently than CCR5+macrophages. Moreover, AMD3100 blocked infection of CCR5-negative macrophages by these strains. Our results therefore demonstrate that CXCR4, as well as CCR5, is used for infection of primary macrophages but provide no evidence for the use of alternative coreceptors.

The testis is divided into two compartments: the seminiferous tubules and the interstitial tissue. The latter essentially consists of the blood and lymphatic vessels, testosterone-producing Leydig cells, and testicular macrophages. In the exploration of the testicular antiviral defense system, we initially searched for interferon (IFN) production by the seminiferous tubule cells. The site of virus entry into the testis is probably the interstitial compartment; thus, it is important to know whether and how the cells in this compartment are protected against viral infection. In addition, as germ cell precursors (spermatogonia) are only partially protected by the blood-testis barrier, it was important to explore the antiviral capability of these cells. In this study we searched for IFN production by Leydig cells, testicular macrophages, and spermatogonia after exposure to Sendai virus. We also investigated the effect of viral exposure on testosterone production by Leydig cells. Our results show that spermatogonia do not constitutively express IFNs and give a very poor response to the virus. In contrast, testicular macrophages constitutively produced type I IFNs, and this production was markedly stimulated by Sendai virus. Leydig cells produced twice as much type I IFNs as testicular macrophages after viral exposure, and they were the only cells producing both IFNalpha and -gamma, with these IFNs being dramatically induced/ increased in response to exposure to the virus. Furthermore, incubation of Leydig cells with the Sendai virus stimulated testosterone production. In conclusion, this study further establishes the topography of IFN expression within the testis. This allows us to hypothesize that the potential antiviral system represented by Leydig cells and, to a lesser extent, by macrophages plays a key role in protecting both androgen production and spermatogenesis.