NEUTROPHILS FROM HUMAN-IMMUNODEFICIENCY-VIRUS (HIV)-SERONEGATIVE DONORS INDUCE HIV REPLICATION FROM HIV-INFECTED PATIENTS MONONUCLEAR-CELLSAND CELL-LINES - AN IN-VITRO MODEL OF HIV TRANSMISSION FACILITATED BYCHLAMYDIA-TRACHOMATIS

Infection with a sexually transmitted disease (STD) increases the risk for human immunodeficiency virus (HIV) infection. Polymorphonuclear l eukocytes (PMNs) are recruited into the genital tract by STD pathogens , such as Chlamydia trachomatis. Semen of HIV-infected men contains HI V associated with mononuclear cells. This study investigated the inter action among PMNs from HIV-uninfected persons, C, trachomatis, and HIV -infected cells and examined the mechanisms for enhanced HIV replicati on. We demonstrated that PMNs from HIV-seronegative donors induced HIV replication in mononuclear cells from 17 HIV-infected patients in med ium without exogenous IL-2. HIV in the cell-free supernatants from coc ultures of PMNs and patients' peripheral blood mononuclear cells (PBMC s) was replication competent, as indicated by their capacity to propag ate HIV in a second round of culture using PBMCs from HIV-seronegative individuals and by the fact that proviral DNA was found in these cell s. PMNs from HIV-seronegative donors increased HIV replication over 10 0-fold in chronically HIV-infected cell lines of the monocytic, T, and B cell lineages, Moreover, PMNs increased U1 cells' production of p24 antigen by as much as ninefold when compared with U1 cells cocultured with PBMCs. The addition of C. trachomatis to PMN and U1 coculture in creased HIV replication by an additional ninefold at 24 h, whereas C, trachomatis alone had no effect on p24 antigen production by U1 cells. Thus, C, trachomatis serves not only to recruit PMNs, but also to int eract with PMNs to increase HIV replication, HIV replication is trigge red by contact of HIV-infected cells with PMNs, by the generation of r eactive oxygen intermediates (ROIs), and by soluble factors such as TN F-alpha and IL-6, This is based on the findings that production of p24 antigen, IL-6, and TNF-alpha induced by PMNs is abrogated by disrupti ng or partitioning PMNs from HIV-infected cells; is inhibited by super oxide dismutase and catalase, enzymes that destroy ROIs; is enhanced b y differentiated HL60 cells capable of producing ROIs; and is induced by PMNs tested negative for CMV. Furthermore, the production of ROIs i s independent of HIV infection of mononuclear cells, since PMNs cocult ured with HIV-uninfected parental monocytic and T cell lines generated ROIs. Therefore, the increased risk for acquiring HIV infection assoc iated with chlamydia cervicitis may be related to the local recruitmen t of PMNs by C. trachomatis and the induction of infectious virus from mononuclear cells present in semen, These observations provide a rati onale for strategies to reduce HIV transmission by control of STD.