Simian-human immunodeficiency virus (SHIV) containing the nef/long terminal repeat region of the highly virulent SIVsmmPBj14 causes PBj-like activation of cultured resting peripheral blood mononuclear cells, but the chimera showed No increase in virulence.

SIVsmmPBj14 is a highly pathogenic lentivirus which causes acute diarrhea, rash, massive lymphocyte proliferation predominantly in the gastrointestinal tract, and death within 7 to 14 days. In cell culture, the virus has mitogenic effects on resting macaque T lymphocytes. In contrast, SIVmac239 causes AIDS in rhesus macaques, generally within 2 years after inoculation. In a previous study, replacement of amino acid residues 17 and 18 of the Nef protein of SIVmac239 with the corresponding amino acid residues of the Nef protein of SIVsmmPBj14 yielded a PBj-like virus that caused extensive activation of resting T lymphocytes in cultures and acute PBj-like disease when inoculated into pig-tailed macaques. This study suggested that nef played a major role in both processes. In this study, we replaced the nef/long terminal repeat (LTR) region of a nonpathogenic simian-human immunodeficiency virus (SHIV), SHIVPPc, with the corresponding region from SIVsmmPBj14 and examined the biological properties of the resultant virus. Like SIVsmmPBj14, SHIVPPcPBjnef caused massive stimulation of resting peripheral blood mononuclear cells (PBMC), which then produced virus in the absence of extraneous interleukin 2. However, when inoculated into macaques, the virus failed to replicate productively or cause disease. Thus, while these results confirmed that the nef/LTR region of SIVsmmPBj14 played a major role in the activation of resting PBMC, duplication of the cellular activation process in macaques may require a further interaction between nef and the envelope glycoprotein of simian immunodeficiency virus because SHIV, containing the envelope of human immunodeficiency virus type 1, failed to cause activation in vivo.

Significance of macrophage tropism of SIV in the macaque model of HIV disease.

Microglia, alveolar macrophages, and Langerhans cells are representatives of cells of macrophage lineage that are susceptible to infection with HIV-1 and they play important roles in the pathogenesis of AIDS dementia, lymphoid interstitial pneumonia, and systemic viral invasion from mucosal surfaces, respectively. In contrast, elimination of CD4+ T cells with resultant development of immunosuppression and AIDS is thought to be reflective of the exclusive tropism of the virus for CD4+ T cells. Examination of these concepts in macaques infected with molecularly cloned strains of SIVmac suggested that all strains of the virus are both macrophage- and lymphocyte-tropic and that all aspects of pathogenesis including loss of CD4+ T cells are dependent on infection in both cell types. However, viral clones that caused productive lytic infection in macrophages were less virulent than those which caused persistent nonproductive infection. The former caused subclinical and even immunizing infections, whereas the latter caused activation and productive infection in CD4+ T cells, AIDS, and systemic infection, even after inoculation of the virus on mucosal surfaces. If these findings on SIVmac are relevant to HIV-1 disease, then demonstration that HIV-1 isolates are macrophage-tropic probably does not necessarily correlate with their pathogenic potential.

Induction of T-lymphocyte adhesion by histidine-proline-rich glycoprotein and concanavalin A.

Histidine-proline-rich glycoprotein (HPRG) is a plasma protein which binds to a specific receptor on T-lymphocytes and represses T-cell activation and proliferation. In the presence of Concanavalin A (Con A), HPRG causes human T-lymphoblastic MOLT-3 cells and a fraction of normal human peripheral blood lymphocytes to attach to the culture dish and significantly change morphology by either extending processes or becoming elongated at the poles, respectively. HPRG and Con A are just as effective at inducing MOLT-3 attachment in a soluble or an immobilized form. MOLT-3 cell attachment is specific for HPRG, dose-dependent, and reversible in 72 hr. Only certain T-cell mitogenic lectins, Con A and phytohemagglutinin, are effective at stimulating adherence. Mannose, glucose, fucose, and N-acetylglucosamine inhibit HPRG-induced MOLT-3 cell attachment to different degrees, with methyl alpha-D-mannopyranoside being the most potent inhibitor. We propose that in vivo HPRG together with a naturally expressed lectin induces T-lymphocyte adhesion to initiate cell migration to sites of inflammation.