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.

Interferon-alpha (IFN alpha), -beta, and -gamma are well known for their antiviral, antiproliferative, and immunoregulatory activities. Although several studies suggest an involvement of IFNs in the spermatogenic process, nothing is known about the possible production of these molecules within the testis. Moreover, the antiviral capabilities of testicular cells have not yet been explored despite their importance in the context of sexually transmissible diseases. Using reverse transcription-polymerase chain reaction, a cytopathic inhibition micromethod assay, and an enzyme-linked immunosorbent assay, the present study demonstrates for the first time that IFN alpha and -gamma are produced by testicular cells. IFN alpha protein and corresponding messenger RNA are expressed by peritubular, Sertoli, and germ cells. In vitro, IFN alpha production by Sertoli cells, peritubular cells, and early spermatids was inducible by the Sendai virus, whereas pachytene spermatocyte IFN alpha production was not triggered by this virus. Of all the testicular cell types tested, Sertoli cells by far produced the highest concentrations of IFN alpha/beta, followed by peritubular cells. Both IFN gamma messenger RNA and IFN gamma protein were found in early spermatids, but, in contrast, were not produced by peritubular cells, Sertoli cells, or pachytene spermatocytes. In conclusion, our study establishes the cellular distribution of IFNs within the seminiferous tubules and provides the basis for research into the possible involvement of IFNs in regulation of the spermatogenic process. To the best of our knowledge, our results afford the first insight on how the testicular antiviral defense system is organized.

Changes in co-receptor-use by human immunodeficiency virus type 1 (HIV-1) strains are relatively rare in vivo. Here we describe two variants derived from the CCR5-using strain SF162, selected for replication in the C8166 T-cell line. Amino acid substitutions in the V3 loop conferred CXCR4-use ; however, the loss of macrophage-tropism by one variant was due to a single mutation in the start codon of vpu. We discuss how V3 loop and vpu mutations acquired by replication in T-cell lines in vitro correlate with similar changes reported for primary isolates and HIV-1 sequences in vivo.

HIV is a persistent virus that survives and replicates despite an onslaught by the host's immune system. A strategy for cell entry, requiring the use of two receptors, has evolved that may help evade neutralizing antibodies. HIV and SIV usually require both CD4 and a seven transmembrane (7TM) coreceptor for infection. At least eleven different 7TM coreceptors have been identified that confer HIV and/or SIV entry. For HIV-1, the major coreceptors are CCR5 and CXCR4, while the role of other coreceptors for replication and cell tropism in vivo is currently unclear. Polymorphisms in the CCR5 gene that reduce CCR5 expression levels, protect against disease progression, suggesting that drugs targeted to CCR5 could be effective. Such therapies however will not work if HIV simply adapts to use alternative coreceptors. In the light of these themes, this review will discuss the following topics: (i) the coreceptors used by primary HIV-1 and HIV-2 viruses, (ii) the properties and coreceptors of HIV-2 strains that infect cells without CD4, (iii) the role of coreceptors in HIV cell tropism and particularly macrophage infection and (iv) the properties of chemokine receptor ligands that block HIV infection.

Although the involvement of viruses in alterations of testicular function and in sexually transmitted diseases is well known, paradoxically, the testicular antiviral defense system has virtually not been studied. The well known antiviral activity of interferons (IFNs) occurs via the action of several IFN-induced proteins, among which the 2′5′ oligoadenylate synthetase (2′5′ A synthetase), the double-stranded RNA-activated protein kinase (PKR), and the Mx proteins are the best known. To explore the antiviral capacity of the testis and to study the testicular action of IFNs, we looked for the presence and regulation of these three proteins in isolated seminiferous tubule cells, cultured in the presence or in the absence of IFN α, IFN γ, or Sendai virus. In all conditions tested, the meiotic pachytene spermatocytes and the post-meiotic early spermatids lacked 2′5′ A synthetase, PKR, and Mx mRNAs and proteins. In contrast, Sertoli cells constitutively expressed these mRNAs and proteins, and their levels were greatly increased after IFN α or Sendai virus exposure. While peritubular cells were also able to markedly express 2′5′ A synthetase, PKR, and Mx mRNA and proteins after IFN α or viral exposure, only PKR was constitutively present in these cells. Interestingly, IFN γ had no effect on peritubular cells' 2′5′ A synthetase and Mx production but it enhanced Mx proteins in Sertoli cells. In conclusion, this study reveals that the seminiferous tubules are particularly well equipped to react to a virus attack. The fact that the two key tubular elements of the blood–testis barrier, namely, Sertoli and peritubular cells, were found to assume this protection allows the extension of the concept of blood–testis barrier to the testicular antiviral defense.