CD4+ T-Cells Are Required for the Establishment of Maedi-visna Virus Infection in Macrophages but Not Dendritic Cells in Vivo

Abstract

The role of CD4(+) lymphocytes in the establishment of lentivirus infection in macrophages has been studied in an in vivo system of lentivirus infection where CD4(+) lymphocytes are not the targets for infection. Using the non-T-cell-tropic lentivirus, maedi-visna virus (MVV), in CD4-depleted sheep, we have found that CD4(+) T cells were required for MVV infection in macrophages but not dendritic cells. CD4-depleted sheep had significantly lower levels of MVV-infected cells in lymph nodes and efferent lymph after MVV challenge in the drainage area of the lymph node. Due to the absence of virus in combination with the lack of CD4(+) T helper cells, virus-specific immune responses were reduced. There was delayed induction of cytotoxic T cell precursors, a marked reduction in virus-specific in vitro proliferative responses, and a delay in the appearance of MVV-specific antibodies. By contrast, CD4 depletion had no effect on the establishment of MVV infection in afferent lymph dendritic cells migrating from the skin infection site to the lymph node.

Systemic DNA immunization against ovine lentivirus using particle-mediated epidermal delivery and modified vaccinia Ankara encoding the gag and/or env genes

“…It is conceivable that two types of immune response are operating concomitantly: one that stimulates virus replication, and one that recognises and eliminates productively infected cells. VMV--specific CD4+ T cells have been shown to enhance virus replication in target cells [10] and such cells could have played a role in enhancing provirus loads in the PMED and mucosal [24] studies. As noted above, CTL precursors were observed in blood the present study, and it is possible that they could have reduced the levels of productively infected cells in the lung.…”

“…Thus, the lesions in the lungs could have been due to immune complex formation or to binding of these antibodies to virus--infected cells and activation of antibody--dependent cell--mediated cytotoxicity. Another possibility is that anti--ENV T cell responses were responsible for the lesion enhancement [10].…”

“…Similarly, immunization of sheep with an immunodominant T--helper peptide derived from the CAEV GAG protein in adjuvant resulted in increased virus load after intravenous challenge [8]. The lesions in SRLV infections are thought to be immune mediated, since immunosuppression reduces tissue inflammation [9], and depletion of CD4+ T cells causes a reduction in the number of virus--infected macrophages in vivo [10]. The results of the vaccine studies were thus interpreted to mean that immunization simply resulted in immune responses that stimulated virus replication and caused tissue damage.…”

Immune Response to Individual Maedi-Visna VirusgagAntigens

“…However, the role of the antiviral T-cell response is unclear. So far no one has been able to show whether T cells are protective against MVV infection (17,18). Similar vaccination attempts against the small-ruminant lentiviruses (MVV and CAEV) have been unsuccessful at producing sterile immunity (10,11,13,22,37,41,46,53) and often make the pathology seen after infection worse (37,41,53).…”

“…ϩ T lymphocytes are necessary to see an efficient infection of sheep by MVV (17). After infection the level of expression of MHC is increased on microglial cells in the central nervous system in sheep (3) and is increased in the infected lung (32) and synovium (1).…”