It has been demonstrated that CD8 ؉ T cells produce a soluble factor(s) that suppresses human immunodeficiency virus (HIV) replication in CD4؉ T cells. The role of soluble factors in the suppression of HIV replication in monocyte͞macrophages (M͞M) has not been fully delineated. To investigate whether a CD8؉ T-cell-derived soluble factor(s) can also suppress HIV infection in the M͞M system, primary macrophages were infected with the macrophage tropic HIV-1 strain Ba-L. CD8؉ T-cell-depleted peripheral blood mononuclear cells were also infected with HIV-1 IIIB or Ba-L. HIV expression from the chronically infected macrophage cell line U1 was also determined in the presence of CD8 ؉ T-cell supernatants or ␤-chemokines. We demonstrate that: (i) CD8؉ T-cell supernatants did, but ␤-chemokines did not, suppress HIV replication in the M͞M system; (ii) antibodies to regulated on activation normal T-cell expressed and Secreted (RANTES), macrophage inf lammatory protein 1␣ (MIP-1␣) and MIP-1␤ did not, whereas antibodies to interleukin 10, interleukin 13, interferon ␣, or interferon ␥ modestly reduced anti-HIV activity of the CD8 ؉ T-cell supernatants; and (iii) the CD8 ؉ T-cell supernatants did, but ␤-chemokines did not, suppress HIV-1 IIIB replication in peripheral blood mononuclear cells as well as HIV expression in U1 cells. These results suggest that HIV-suppressor activity of CD8 ؉ T cells is a multifactorial phenomenon, and that RANTES, MIP-1␣, and MIP-1␤ do not account for the entire scope of CD8 ؉ T-cell-derived HIV-suppressor factors.

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Microbial coinfections variably influence HIV-1 infection through immune activation or direct interaction of microorganisms with HIV-1 or its target cells. In this study, we investigated whether exposure of macrophages to bacterial products impacts the susceptibility of these cells to HIV-1 of different cellular tropisms.We demonstrate that (1) macrophages exposed to bacterial cell wall components such as lipopolysaccharide (

It remains controversial whether human T lymphotropic virus type I (HTLV-I) coinfection leads to more rapid progression of human immunodeficiency virus (HIV) disease in dually infected individuals. To investigate whether HTLV-I infection of certain cells can modulate HIV-1 infection of surrounding cells, primary CD4+ T cells were treated with cell-free supernatants from HTLV-I–infected MT-2 cell cultures. The primary CD4+ T cells became resistant to macrophage (M)-tropic HIV-1 but highly susceptible to T cell (T)-tropic HIV-1. The CC chemokines RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1α, and MIP-1β in the MT-2 cell supernatants were identified as the major suppressive factors for M-tropic HIV-1 as well as the enhancers of T-tropic HIV-1 infection, whereas soluble Tax protein increased susceptibility to both M- and T-tropic HIV-1. The effect of Tax or CC chemokines on T-tropic HIV-1 was mediated, at least in part, by increasing HIV Env-mediated fusogenicity. Our data suggest that the net effect of HTLV-I coinfection in HIV-infected individuals favors the transition from M- to T-tropic HIV phenotype, which is generally indicative of progressive HIV disease.

Genital herpes has been associated with increased efficiency of the sexual transmission and enhanced replication of human immunodeficiency virus type 1 (HIV-1). In this study we demonstrate that exposure to infectious or heat-inactivated herpes simplex virus (HSV) type 1 or 2 virions increases HIV-1 expression in macrophages at least in part by inducing NF-kappaB activity. Neutralizing antibodies to the HSV glycoprotein gB or gD markedly attenuated these virion-mediated effects on HIV-1 expression in macrophages. Thus HSV infection of macrophages that reside in genital mucosal tissue induces HIV-1 replication in these cells. Our study may have implications for the management of patients who are coinfected with the two viruses.

Neutrophils dominate acute inflammatory responses that generally evolve into chronic inflammatory reactions mediated by monocyte/macrophages and lymphocytes. The latter cell types also serve as major targets for human immunodeficiency virus type 1 (HIV-1). In this study we have investigated the role of neutrophil products, particularly cathepsin G, in HIV infection. Cathepsin G induced chemotaxis and production of proinflammatory cytokines by macrophages but not CD4 ؉ T cells. Pretreatment with cathepsin G markedly increased susceptibility of macrophages but not CD4؉ T cells to acute HIV-1 infection. When macrophages were exposed to pertussis toxin prior to cathepsin G treatment, the cathepsin G-mediated effect was almost abrogated, suggesting that enhancement of HIV-1 replication by cathepsin G requires Gi protein-mediated signal transduction. Although prolonged exposure to cathepsin G suppressed HIV infection of macrophages, serine protease inhibitors, which are exuded from the bloodstream later during inflammatory processes, neutralized the inhibitory effect. Neutrophil extracts or supernatants from neutrophil cultures, which contain cathepsin G, had effects similar to purified cathepsin G. Thus, cathepsin G, and possibly other neutrophilderived serine proteases, may have multiple activities in HIV-1 infection of macrophages, including chemoattraction of monocyte/macrophages (HIV-1 targets) to inflamed tissue, activation of target cells, and increase in their susceptibility to acute HIV-1 infection.

Human T-lymphotropic virus type 1 (HTLV-1), the etiologic agent of adult T-cell leukemia/lymphoma, is transmitted through breast milk and seminal fluid, which are rich in prostaglandins (PGs). We demonstrate that PGE 2 upregulates the HTLV-1 long terminal repeat promoter through the protein kinase A pathway, induces replication of HTLV-1 in peripheral blood mononuclear cells (PBMC) derived from asymptomatic carriers, and enhances transmission of HTLV-1 to cord blood mononuclear cells (CBMC). Furthermore, HTLV-1 Tax transactivates a promoter for cyclooxygenase 2, a PG synthetase, and induces PGE 2 expression in PBMC or CBMC. Thus, HTLV-1 interacts with and benefits from PGs, constituents of its own vehicle for transmission.Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma and is transmitted horizontally or vertically through blood, seminal fluid, or breast milk (reviewed in references 13 and 37).Prostaglandins (PGs) are synthesized and secreted by most human tissues and cell types; however, they are especially abundant in seminal fluid and breast milk (2, 7, 9, 10). PGs, particularly those of the E series, are widely regarded as pleiotropic immunomodulatory molecules, and regulation of their expression appears to be critical for a number of immune responses (reviewed in references 26 and 29). There are two isoforms of cyclooxygenase (COX) that catalyze the formation of PGs from arachidonic acid. While COX-1 is a housekeeping gene that is expressed constitutively, COX-2 is an immediateearly response gene that is highly inducible by mitogenic and inflammatory stimuli and is considered essential for the induction of the aforementioned immune responses (reviewed in reference 32).In this study we demonstrate that (i) PGE 2 upregulates the HTLV-1 long terminal repeat (LTR) promoter through the protein kinase A (PKA) pathway, induces viral replication in peripheral blood mononuclear cells (PBMC) derived from asymptomatic HTLV-1 carriers, and enhances transmission of HTLV-1 to cord blood mononuclear cells (CBMC) and that (ii) HTLV-1 Tax transactivates a COX-2 promoter and induces PGE 2 production in PBMC. These data suggest that HTLV-1 interacts with and benefits from PGs that are abundant in seminal fluid and breast milk, vehicles for virus transmission. MATERIALS AND METHODSReagents. PGE 2 , H7, HA-1004, mitomycin C (MMC), 3Ј-azido-3Ј-deoxythymidine (AZT), phorbol 12-myristate 13-acetate (PMA), and ionomycin were purchased from Sigma (St. Louis, Mo.). MMC treatment of cells was performed as described previously (1).Infectious HTLV-1 stock which was rendered devoid of cell culture supernatants by directly pelleting virions was obtained from Advanced Biotechnologies, Inc. (Columbia, Md.). Glutathione S-transferase (GST) and GST-Tax protein were propagated as described previously (23).Plasmids and transient-expression assays. pU3R-luc, a generous gift of K.-T. Jeang (National Institute of Allergy and Infectious Diseases [NIAID], Bethesda, Md.), carries the luciferase gene ...

Several studies have reported that postnatally acquired cytomegalovirus (CMV) infection can cause sepsis-like syndrome in premature infants. We here report a 622-gram birth weight male infant of 23 weeks’ gestation who had sepsis-like syndrome and pneumonia. Substantial CMV loads were detected in peripheral blood cells, plasma, and urine when the patient was in crisis, but was decreased in parallel to clinical improvement without using ganciclovir. CMV DNA was not detected from his umbilical cord or Guthrie card, even by highly sensitive real-time PCR. Molecular profiles were indistinguishable between the CMV strain isolated from his urine and that from maternal breast milk, indicating postnatal acquisition of CMV through breast milk. Although he had transient hearing impairment, his neurodevelopmental outcome of 30 months of corrected age was normal. Further accumulation of clinical and virological data in postnatal CMV infection is necessary for evaluating the severity and selecting patients requiring antiviral therapy.