Susan Jackson

Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults

A safety and immunogenicity trial was conducted in vaccinia-immune and vaccinia-naive human immunodeficiency virus (HIV)-uninfected adults who were randomized to receive 10(6) or 10(7) TCID50 of canarypox (ALVAC) vector expressing HIV-1MN gp160 or 10(5.5) TCID50 of ALVAC-rabies virus glycoprotein control at 0 and 1 or 2 months and ALVAC-gp160 or 50 microg of HIV-1SF2 recombinant (r) gp120 in microfluidized emulsion at 9 and 12 months; others received rgp120 at 0, 1, 6, and 12 months. All vaccines were well-tolerated. Neither vaccinia-immune status before vaccination nor ALVAC dose affected HIV immune responses. HIV-1MN and HIV-1SF2 neutralizing antibodies were detected more often (100%) in ALVAC-gp160/rgp120 recipients than in recipients of ALVAC-gp160 (<65%) or rgp120 (89%) alone. ALVAC-gp160/rgp120 also elicited more frequent HIV V3-specific and fusion-inhibition antibodies, antibody-dependent cellular cytotoxicity, lymphoproliferation, and cytotoxic CD8+ T cell activity than did either vaccine alone. Trials with ALVAC expressing additional HIV components and rgp120 are underway.

The human IgA system: A reassessment☆

In healthy adults the total daily production of secretory and serum IgA exceeds that of other immunoglobulin classes. Secretory and serum IgA display features of mutual independence: they are represented by molecules with different physiochemical and immunochemical properties and antibody activities and are produced by cells with different organ distributions. Secretory and serum IgA also exhibit different effector functions: interaction of secretory IgA with environmental antigens results in prevention of the penetration of such antigens by a variety of mechanisms. Although the function of polymeric serum IgA antibodies in certain animal species involves elimination of antigenic substances by noninflammatory means, the primary function of serum IgA remains unknown. It is proposed that in humans monomeric serum IgA (which prevents activation of the complement systems, inhibits phagocytosis and antibody-dependent cellular cytotoxicity) may protect endogenous antigens expressed on various cells and tissues by preventing their interaction with humoral and cellular immune mechanisms that may lead to tissue damage.

Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies.

Circulating immune complexes (CIC) containing IgA and C3 were elevated in 48% of IgA nephropathy patients; IgA1 was the predominant subclass. IgA1-IgG CIC were detected in 44%, IgA2-IgG CIC in 7%, and IgM-IgA1 CIC in 16% of the patients. No IgM-IgA2 CIC were detectable. Sucrose gradient ultracentrifugation indicated that IgG-IgA1 CIC were predominantly of intermediate (13-19S) size whereas IgA1-C3 CIC sedimented from 11S to 19S. At acid pH, isolated CIC revealed the presence of substantial amounts of 7S IgA. One third of the patients had elevated serum IgA rheumatoid factor (RF) of both polymeric and monomeric forms despite normal levels of IgM-RF; 87% of patients with elevated IgA-RF had IgA1-IgG CIC. These results indicate that the IgA1 component of CIC in patients with IgA nephropathy is not necessarily of mucosal origin and suggest that a portion of these CIC consists of IgA RF immunologically complexed with autologous IgG.

Advances in Mucosal Immunology

The proceedings of the August 1992 congress comprise 354 papers grouped within ten sections: B and T cells of the mucosal immune system; non-lymphoid cells of the mucosal immune system; development of mucosal immunity; gnotobiology, environmental, nutritional, and intrinsic factors in mucosal immuno

Oral epithelial cells are susceptible to cell-free and cell-associated HIV-1 infection in vitro

Epithelial cells lining the oral cavity are exposed to HIV-1 through breast-feeding and oral-genital contact. Genital secretions and breast milk of HIV-1-infected subjects contain both cell-free and cell-associated virus. To determine if oral epithelial cells can be infected with HIV-1 we exposed gingival keratinocytes and adenoid epithelial cells to cell-free virus and HIV-1-infected peripheral blood mononuclear cells and monocytes. Using primary isolates we determined that gingival keratinocytes are susceptible to HIV-1 infection via cell-free CD4-independent infection only. R5 but not X4 viral strains were capable of infecting the keratinocytes. Further, infected cells were able to release infectious virus. In addition, primary epithelial cells isolated from adenoids were also susceptible to infection; both cell-free and cell-associated virus infected these cells. These data have potential implications in the transmission of HIV-1 in the oral cavity.

Reassessment of the impact of mucosal immunity in infection with the human immunodeficiency virus (HIV) and design of relevant vaccines.

ConclusionsThe development of vaccines that would induce specific immune responses in the genital tract secretions would have far-reaching implications for not only the prevention of AIDS and sexually transmitted diseases but also the immunological control of fertility (4, 76, 88, 89, 123, 124, 149). Most of the currently studied vaccines utilize systemic routes of immunization which are of limited value for the prevention of mucosa-contracted diseases. The relative contribution of antigensensitized cells from PP or other inductive sites (e.g., rectal tonsils) to remote or adjacent effector sites (e.g., genital tract) as manifested by the appearance of corresponding S-IgA antibodies has not been studied extensively in humans despite its unquestionable practical importance. Exploration of immunization routes that are effective for induction of mucosal immune responses and that are based primarily on current knowledge of the origin of antibodies and of specific antibody-forming cells in mucosal tissues, together with novel antigen delivery systems (1, 76, 89, 130), is likely to reduce the incidence of many infectious diseases including AIDS and also reduce the cost of administration of such vaccines.

A POLARIZED HUMAN ENDOMETRIAL CELL LINE THAT BINDS AND TRANSPORTS POLYMERIC IgA

SummaryWe have demonstrated that a human endometrial cell line, HEC-1, maintains a high transepithelial electrical resistance, directionally transports fluids across the cell monolayer, and releases enveloped viruses at distinct plasma membrane domains: influenza virus is released at the apical surfaces and vesicular stomatitis virus (VSV) at the basolateral surfaces. In addition, we have examined the expression of domain-specific endogenous proteins, including the polyimmunoglobulin receptor. Multiple endogenous polypeptides were found to be secreted into the culture medium at basolateral surfaces, whereas no secretion of specific polypeptides was observed from apical cell surfaces. Distinct patterns of endogenous proteins were also observed on apical and basolateral cell surfaces, with a much more complex polypeptide pattern on the basolateral membranes. Using surface biotinylation and immunofluorescence, the polyimmunoglobulin receptor was found to be expressed on the basolateral surfaces of HEC-1 monolayers. The specific binding of poly-immunoglobulin A (pIgA) was found to occur on the basolateral surface, and was followed by transcytosis to the apical surface and release into the apical medium. The observed characteristics indicate that the endometrium-derived HEC-1 epithelial cell line can be employed as a model for studies of protein transport in polarized epithelial cells of human endometrial tissues, as well as for studies of the interaction of microorganisms with epithelial cells in the genital tract.

IgA1 is the major immunoglobulin component of immune complexes in the acquired immune deficiency syndrome

Compared to a panel of healthy controls, sera from 13 of 23 (57%) patients with the acquired immune deficiency syndrome (AIDS) were shown to have elevated levels of circulating immune complexes (CIC) containing IgA. Levels of IgG-containing CIC were increased in seven patients (30%); no patients had elevated levels of IgM-containing CIC. Additional experiments showed that in all instances in which IgG CIC were demonstrable, IgA was also present; however, IgA CIC could be found that did not contain IgG. The IgA in the CIC was restricted to the IgA1 subclass. These data suggest selective abnormalities of IgA regulation in AIDS and raise questions as to the role in this disease of the immunoglobulin isotype usually thought to possess different protective mechanisms from those attributed to other isotypes.

Immunization with Envelope MN rgp120 Vaccine in Human Immunodeficiency Virus-Infected Pregnant Women

Twenty-six human immunodeficiency virus (HIV)-infected pregnant women participated in a placebo-controlled study of immunogenicity and safety of multiple doses of MN rgp120 vaccine over the last half of pregnancy. The women had CD4 lymphocyte counts>400/mm3, no AIDS-defining illness and normal pregnancies. Vaccination was well tolerated, with no significant local or systemic reactions in the women and no adverse outcomes in the infants attributable to the vaccine. Vaccination did not alter plasma RNA reverse transcriptase-polymerase chain reaction copy number; moreover, immunization was not associated with changes in CD4 counts or HIV binding and neutralization antibody titers. Infants were followed up until 18 months of age. Five of 26 infants (19%) were HIV infected, with infection occurring in children of both vaccinated and placebo women. Analysis of factors that influence transmission did not disclose associations with immunization status, viral load, CD4 count, or maternal viral neutralization titers.

False positivity of enzyme-linked immunosorbent assay for measurement of secretory IgA antibodies directed at HIV type 1 antigens

We have determined that polymeric IgA in saliva of HIV-1-uninfected individuals binds in varying degrees to components of culture supernatants containing HIV-1 recombinant proteins when ELISA is used for the determination. This finding did not extend to salivary IgG antibodies. Further, such problems were not encountered in Western blot. Binding did not appear to be mediated by salivary proteins known to bind to IgA, including secretory component, amylase, lactoferrin, lysozyme, galactosyl transferase, or secretory leukocyte protease inhibitor, and was not influenced by blocking reagents or by changes in secondary anti-IgA antibodies. Although these findings will not likely impact on the use of saliva as a diagnostic fluid for HIV-1 infection (the HIV-1 response in saliva is mostly of the IgG isotype), they indicate that assessments of this secretion as an indicator of IgA mucosal immune responses to HIV-1 vaccines should be undertaken with caution.