Receptor For Human Immunodeficiency Virus Research Articles

What is the influence of preeclampsia on vertical transmission of HIV?

In a temporal perspective, the first studies regarding the influence of human immunodeficiency virus (HIV) on the occurrence of preeclampsia (PE) indicated that in HIV-infected pregnant women, PE would be reduced due to the immunological and endothelial changes subsequent to viral infection. However, with the advent of highly active antiretroviral therapy (HAART) and the possibility of minimizing or eliminating immunological and inflammatory changes, the risk of developing PE in HIV-infected pregnant women would be expected to increase (Machado. J Infect 2014;68:572–80). Even though a meta-analysis did not confirm this association (Brown. J Acquir Immune Defic Syndr 2015;70:91–8), a more recent publication supported this assertion (Sansone. Obstet Gynecol 2016;127:1027–32). There are a great number of studies on HIV infection in pregnant women in association with PE; however, only a few evaluated the influence of PE on the rate of HIV vertical transmission (VT). It is known that PE is a systemic disorder with abnormal activation of immune and inflammatory responses including in the placenta. These changes resemble the response to HIV infection and impact placental expression of tissue receptors involved in VT of HIV. Ultimately, knowledge of the influence of PE on expression of these receptors could influence strategies to prevent and control PE and strengthen measures to reduce the VT of HIV. Dorsamy et al. precisely assessed whether PE alters the expression of receptors in the placenta and umbilical cord that are linked to intrauterine transmission of HIV. They detected markers of HIV infection (p. 24, CD4 lymphocytes, CCR5 and ICAM-2) in trophoblast and umbilical cord tissue from both normotensive and preeclamptic HIV-infected pregnant women. The expression of CCR5 was significantly increased in both preeclamptic and normotensive HIV-infected women, showing that PE can increase the risk of VT of HIV. Increased expression of CCR5 on trophoblastic membrane coupled with the expression of CD4 receptor can also increase vulnerability to HIV infection. It was further observed that ICAM-2 had a significantly higher expression in placental tissue of HIV-negative preeclamptic women when compared with the HIV-positive groups under HAART, supporting that HAART protects against the VT of HIV. Conversely, improvements in immunological parameters in HIV-infected pregnant women and the high levels of HIV receptors in syncytiotrophoblast of normotensive pregnant women possibly exacerbate the risk of PE. These findings justify the need to continue use of antiretroviral drugs for the mother during her prenatal care, and during labour, delivery and the postpartum period (Luzuriaga, Mofenson. N Engl J Med 2016;374:761–70). Furthermore, it also indicates the need for special monitoring of pregnant women on HAART, including blood pressure evaluations at short intervals, to optimize specific screening and prophylactic care for PE (O'Gorman. BMJ Open 2016;6:e011801). None declared. Completed disclosure of interests form available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The Selective Serotonin Reuptake Inhibitor Citalopram Decreases Human Immunodeficiency Virus Receptor and Coreceptor Expression in Immune Cells

BackgroundThis study investigated whether the selective serotonin reuptake inhibitor (SSRI) citalopram downregulates the expression of the human immunodeficiency virus (HIV) receptor cluster of differentiation 4 (CD4) and coreceptors chemokine receptor type 5 and chemokine-related receptor type 4 (CCR5 and CXCR4) on peripheral blood mononuclear cells (PBMCs) and macrophages ex vivo as a potential mechanism of reducing susceptibility to HIV infection. MethodsThe sample included 150 participants 18–58 years old (59% women, 65% African American, 61% with depression). Monocyte-depleted PBMCs were treated with phytohemagglutinin for 72 hours and then cultured in the presence of interleukin-2 with vehicle control or the SSRI (10−6 mol/L) for 2 hours. To generate monocyte-derived macrophages, monocytes were cultured for 7 days, after which either vehicle control or SSRI (10−6 mol/L) was added for 2 hours. RNA was collected from both cell types, and messenger RNA expression of CD4, CCR5, and CXCR4 was measured by real-time polymerase chain reaction. ResultsIn PBMCs, SSRI treatment decreased expression of CD4 (p = .009), CCR5 (p = .008), and CXCR4 (p < .0001). In monocyte-derived macrophages, SSRI treatment decreased expression of CD4 (p < .0001) and CXCR4 (p = .0003), but not CCR5 (p = .71). The suppressive effects of the SSRI on receptor expression did not differ as a function of depression diagnosis or depressive symptom severity. ConclusionsTreatment with the SSRI at a physiologic dose decreased CD4, CCR5, and CXCR4 expression on PBMCs and macrophages ex vivo. These findings suggest that SSRI treatment, independent of depression status, downregulates HIV receptor and coreceptor expression and may reduce susceptibility of immune cells to HIV infection and decrease inflammation. If clinical trials confirm the present findings, ultimately there may be a role for using SSRI treatment adjunctively in HIV and acquired immunodeficiency syndrome.

Progesterone-based intrauterine device use is associated with a thinner apical layer of the human ectocervical epithelium and a lower ZO-1 mRNA expression.

Currently, whether hormonal contraceptives affect male to female human immunodeficiency virus (HIV) transmission is being debated. In this study, we investigated whether the use of progesterone-based intrauterine devices (pIUDs) is associated with a thinning effect on the ectocervical squamous epithelium, down-regulation of epithelial junction proteins, and/or alteration of HIV target cell distribution in the human ectocervix. Ectocervical tissue biopsies from healthy premenopausal volunteers using pIUDs were collected and compared to biopsies obtained from two control groups, namely women using combined oral contraceptives (COCs) or who do not use hormonal contraceptives. In situ staining and image analysis were used to measure epithelial thickness and the presence of HIV receptors in tissue biopsies. Messenger RNA levels of epithelial junction markers were measured by quantitative PCR. The epithelial thickness displayed by women in the pIUD group was similar to those in the COC group, but significantly thinner as compared to women in the no hormonal contraceptive group. The thinner epithelial layer of the pIUD group was specific to the apical layer of the ectocervix. Furthermore, the pIUD group expressed significantly lower levels of the tight junction marker ZO-1 within the epithelium as compared to the COC group. Similar expression levels of HIV receptors and coreceptors CD4, CCR5, DC-SIGN, and Langerin were observed in the three study groups. Thus, women using pIUD displayed a thinner apical layer of the ectocervical epithelium and reduced ZO-1 expression as compared to control groups. These data suggest that pIUD use may weaken the ectocervical epithelial barrier against invading pathogens, including HIV.

Preferential HIV Infection of CCR6 + Th17 Cells Is Associated with Higher Levels of Virus Receptor Expression and Lack of CCR5 Ligands

Th17 cells are enriched in the gut mucosa and play a critical role in maintenance of the mucosal barrier and host defense against extracellular bacteria and fungal infections. During chronic human immunodeficiency virus (HIV) infection, Th17 cells were more depleted compared to Th1 cells, even when the patients had low or undetectable viremia. To investigate the differential effects of HIV infection on Th17 and Th1 cells, a culture system was used in which CCR6(+) CD4(+) T cells were sorted from healthy human peripheral blood and activated in the presence of interleukin 1β (IL-1β) and IL-23 to drive expansion of Th17 cells while maintaining Th1 cells. HIV infection of these cultures had minimal effects on Th1 cells but caused depletion of Th17 cells. Th17 loss correlated with greater levels of virus-infected cells and cell death. In identifying cellular factors contributing to higher susceptibility of Th17 cells to HIV, we compared Th17-enriched CCR6(+) and Th17-depleted CCR6(-) CD4 T cell cultures and noted that Th17-enriched CCR6(+) cells expressed higher levels of α4β7 and bound HIV envelope in an α4β7-dependent manner. The cells also had greater expression of CD4 and CXCR4, but not CCR5, than CCR6(-) cells. Moreover, unlike Th1 cells, Th17 cells produced little CCR5 ligand, and transfection with one of the CCR5 ligands, MIP-1β (CCL4), increased their resistance against HIV. These results indicate that features unique to Th17 cells, including higher expression of HIV receptors and lack of autocrine CCR5 ligands, are associated with enhanced permissiveness of these cells to HIV.

Thirty years on: HIV receptor gymnastics and the prevention of infection

During 30 years of research on human immunodeficiency virus (HIV), our knowledge of its cellular receptors - CD4, CCR5 and CXCR4 - has illuminated aspects of the pathogenesis of the acquired immune deficiency syndrome (AIDS). Studying how the HIV envelope glycoproteins interact with the receptors led to anti-retroviral drugs based on blocking the docking or fusion of virus to the host cell. Genetic polymorphisms of CCR5 determine resistance to HIV infection and the rate of progression to AIDS. Eliciting neutralizing antibodies to the sites of receptor interaction on HIV glycoproteins is a promising approach to HIV vaccine development.

Antiviral Activity of Cardiospermum Halicacabum L. Extract against Coinfecting Agents HIV and HBV

Current inadequate and inefficient market drugs used for the control and management of human immunodeficiency virus (HIV) coinfection with hepatitis viruses (HBV) poses serious threats to public health. The medicinal plant Cardiospermum halicacabum, having known anticancer and immunostimulatory activity was explored for their control in this study. The plant active principles extracted using five solvents were identified, and tested for antiHIV, antiHBV and phytochemical constituents. Methanol extract inhibited both HIV-RT (91%) and HBsAg (79%) and has 11 compounds. Among the compounds, Benzene dicarboxylic acid yielded a dock score −4.85 against HIV receptor and −4.71 against HBV receptor. The obtained results indicated C. halicacabum bioactive principles potentiality as HIV and HBV co-infection controlling novel therapeutics lead compounds.

Innate Molecular and Anatomic Mucosal Barriers against HIV Infection in the Genital Tract of HIV‐Exposed Seronegative Individuals

Sexual transmission is the single most common mechanism for acquiring infection with human immunodeficiency virus (HIV), and the efficiency of transmission reflects the biology of the mucosal site. The localization and phenotypic characterization of HIV target cells and receptors and the presence of immune molecules are therefore important to define at sites of HIV exposure. To complicate the picture, HIV&#x2010;binding receptors and antiviral immune molecules can be protective under certain circumstances but can exert an opposite effect at other mucosal sites, concentrations, and time points. Considering the additional physiological changes induced by inflammation, hormones, and semen deposition, it is an enormous challenge to design relevant experimental models for evaluating prophylactic compounds or biological events. Studies in mucosal samples of HIV&#x2010;exposed seronegative individuals are among the many opportunities to explore the biological events of HIV transmission under physiological circumstances.

The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities

The existence of drug-resistant human immunodeficiency virus (HIV) viruses in patients receiving antiretroviral treatment urgently requires the characterization and development of new antiretroviral drugs designed to inhibit resistant viruses and to complement the existing antiretroviral strategies against AIDS. We assayed several natural or semi-synthetic lupane-type pentacyclic triterpenes in their ability to inhibit HIV-1 infection in permissive cells. We observed that the 30-oxo-calenduladiol triterpene, compound 1, specifically impaired R5-tropic HIV-1 envelope-mediated viral infection and cell fusion in permissive cells, without affecting X4-tropic virus. This lupane derivative competed for the binding of a specific anti-CCR5 monoclonal antibody or the natural CCL5 chemokine to the CCR5 viral coreceptor with high affinity. 30-oxo-calenduladiol seems not to interact with the CD4 antigen, the main HIV receptor, or the CXCR4 viral coreceptor. Our results suggest that compound 1 is a specific CCR5 antagonist, because it binds to the CCR5 receptor without triggering cell signaling or receptor internalization, and inhibits RANTES (regulated on activation normal T cell expressed and secreted)-mediated CCR5 internalization, intracellular calcium mobilization, and cell chemotaxis. Furthermore, compound 1 appeared not to interact with beta-chemokine receptors CCR1, CCR2b, CCR3, or CCR4. Thereby, the 30-oxo-calenduladiol-associated anti-HIV-1 activity against R5-tropic virus appears to rely on the selective occupancy of the CCR5 receptor to inhibit CCR5-mediated HIV-1 infection. Therefore, it is plausible that the chemical structure of 30-oxo-calenduladiol or other related dihydroxylated lupane-type triterpenes could represent a good model to develop more potent anti-HIV-1 molecules to inhibit viral infection by interfering with early fusion and entry steps in the HIV life cycle.

The Gastrointestinal Tract and AIDS Pathogenesis

Gastrointestinal disease has been recognized as a major manifestation of human immunodeficiency virus infection since the earliest recognition of acquired immunodeficiency syndrome (AIDS). Originally, these disease manifestations were considered to be sequelae of the immune destruction that characterizes AIDS rather than being central to the pathogenesis of AIDS. Over time, it has become clear that the mucosal immune system in general and the intestinal immune system in particular are central to the pathogenesis of AIDS, with most of the critical events (eg, transmission, viral amplification, CD4+ T-cell destruction) occurring in the gastrointestinal tract. Compared with peripheral blood, these tissues are not easily accessible for analysis and have only begun to be examined in detail recently. In addition, although the resulting disease can progress over years, many critical events happen within the first few weeks of infection, when most patients are unaware that they are infected. Moreover, breakdown of the mucosal barrier and resulting microbial translocation are believed to be major drivers of AIDS progression. In this review, we focus on the interaction between primate lentiviruses and the gastrointestinal tract and discuss how this interaction promotes the pathogenesis of AIDS and drives immune dysfunction and progression to AIDS. This article draws extensively on work done in the nonhuman primate model of AIDS to fill gaps in our understanding of AIDS in humans.

Introducción. Una breve historia del sida

Human immunodeficiency virus (HIV) infection shows that knowledge of the molecular mechanisms involved in the pathogenesis can lead to the rapid development of new drugs to treat infected patients. Since the description of acquired immunodeficiency syndrome (AIDS) in 1981 and the identification of its causal agent in 1983, twenty-three antiretrovirals, belonging to 5 families, have been marketed. The viral entry point is one of the preferred therapeutic treatment targets, but the development of antagonists against the different HIV receptors has been a long process and fraught with difficulties. Maraviroc is the first CCR5 antagonist drug approved for clinical use and represents a milestone in the development of new treatments against HIV infection. Maraviroc is a novel drug and different from the rest of the antiretrovirals due to the special characteristics of its mechanism of action and is also the first antiretroviral directed towards a cell target. The different aspects of treatment with Maraviroc are analysed in this article; mechanism of action, toxicity, efficacy, resistance mechanisms, and its role in the context of antiretroviral treatment of the HIV infected patient.

Susceptibility of Human Testis to Human Immunodeficiency Virus-1 Infection in Situ and in Vitro

Semen represents the main vector for human immunodeficiency virus (HIV) dissemination worldwide and has been shown to harbor replication-competent virus despite otherwise effective highly active anti-retroviral therapy, which achieves undetectable viral load in plasma. Despite this, the origin of seminal HIV particles remains unclear, as does the question of whether the male genital tract organs contribute virus to semen. Here we investigated the presence of HIV receptors within the human testis using immunohistochemistry and quantitative real-time polymerase chain reaction. We also analyzed the infectivity of a dual tropic HIV-1 strain in an organotypic culture, as well as the impact of viral exposure on testosterone production. Our study establishes that CXCR4+, CCR5+, CD4+, and DC-SIGN+ cells are present within the interstitial tissue of human testis and that these molecules persist throughout our organotypic culture. Our data also reveal that the human testis is permissive to HIV-1 and supports productive infection, leaving testosterone production apparently unaffected. Infected cells appeared to be testicular macrophages located within the interstitial tissue. That the testis itself represents a potential source of virus in semen could play a role in preventing viral eradication from semen because this organ constitutes a pharmacological sanctuary for many current antiretrovirals.

The Nef Protein of Human Immunodeficiency Virus Establishes Superinfection Immunity by a Dual Strategy to Downregulate Cell-Surface CCR5 and CD4

Viruses frequently render cells refractory to subsequent infection with the same virus. This state of superinfection immunity counteracts potentially detrimental consequences for the infected cell and facilitates high-level replication and viral spread in the host. Here, we show that human immunodeficiency virus (HIV) employs its early gene product Nef to efficiently interfere with superinfection at the viral-entry step. In this context, we identify the downregulation of cell-surface CCR5, the major HIV coreceptor, as a novel and highly conserved activity of Nef. Nef targets the CCR5 coreceptor and the HIV binding receptor CD4 via distinct cellular machineries to enhance the endocytosis rate of both HIV receptor components and to accelerate their degradation. Functionally, these genetically separable actions by Nef synergized to efficiently protect cells from HIV superinfection at the level of fusion of the viral envelope with the plasma membrane. HIV has evolved two independent activities for Nef to downregulate the receptor complex and to facilitate its efficient replication and spread. This evasion strategy likely represents a mechanism by which the pathogenicity factor Nef elevates viral replication in vivo and thus promotes AIDS pathogenesis.

DC-SIGN–mediated Infectious Synapse Formation Enhances X4 HIV-1 Transmission from Dendritic Cells to T Cells

Dendritic cells (DCs) are essential for the early events of human immunodeficiency virus (HIV) infection. Model systems of HIV sexual transmission have shown that DCs expressing the DC-specific C-type lectin DC-SIGN capture and internalize HIV at mucosal surfaces and efficiently transfer HIV to CD4+ T cells in lymph nodes, where viral replication occurs. Upon DC–T cell clustering, internalized HIV accumulates on the DC side at the contact zone (infectious synapse), between DCs and T cells, whereas HIV receptors and coreceptors are enriched on the T cell side. Viral concentration at the infectious synapse may explain, at least in part, why DC transmission of HIV to T cells is so efficient.Here, we have investigated the role of DC-SIGN on primary DCs in X4 HIV-1 capture and transmission using small interfering RNA–expressing lentiviral vectors to specifically knockdown DC-SIGN. We demonstrate that DC-SIGN− DCs internalize X4 HIV-1 as well as DC-SIGN+ DCs, although binding of virions is reduced. Strikingly, DC-SIGN knockdown in DCs selectively impairs infectious synapse formation between DCs and resting CD4+ T cells, but does not prevent the formation of DC–T cells conjugates.Our results demonstrate that DC-SIGN is required downstream from viral capture for the formation of the infectious synapse between DCs and T cells. These findings provide a novel explanation for the role of DC-SIGN in the transfer and enhancement of HIV infection from DCs to T cells, a crucial step for HIV transmission and pathogenesis.

Pharmacogenomics of antiretroviral therapy

AbstractEffective therapy for human immunodeficiency virus (HIV) infection requires long‐term administration of multiple antiretroviral drugs. This has markedly reduced morbidity and mortality due to AIDS, but drug toxicities often limit the success of treatment. Using candidate gene approaches, pharmacogenomic studies have begun to identify associations between host allelic variants and increased risk of adverse reactions to antiretroviral medications. Of note are associations between abacavir hypersensitivity reactions and specific HLA and hsp70‐hom genotypes, and between CYP2B6 polymorphisms, efavirenz pharmacokinetics, and central nervous system side effects. Pharmacogenomics also has the long‐term potential to reveal new drug targets. The observation that a naturally occurring, nonfunctional deletion mutant of the HIV receptor gene CCR5 protected against HIV infection and slowed disease progression encouraged the development of drugs that target CCR5. Pharmacogenomics promises to improve the lives of persons living with HIV by identifying new therapeutic targets and by fostering rational drug prescribing that optimizes efficacy while minimizing toxicity. Drug Dev. Res. 62:213–220, 2004. © 2004 Wiley‐Liss, Inc.

Identification of CD4-independent HIV receptors on spermatozoa.

Human immunodeficiency virus (HIV) has been demonstrated to bind and enter into the spermatozoa facilitating the transmission into urogenital cells. However, spermatozoa has been reported to be devoid of the conventional CD4 receptors for HIV. This suggests that there exists an alternate modality of HIV entry into spermatozoa using receptors other than CD4. Present communication describes the identification of HIV receptors on the spermatozoa. The sperm proteins were solubilized using Triton X-100 and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Western blot analysis, using cell-free HIV or gp120 envelope glycoprotein as a probe. HIV or gp120 bound protein band was then visualized by using alkaline phosphatase (AP) labeled anti-gp120 antibody as well as by using anti-gp120 antibody and subsequently by AP-labeled anti-rabbit gamma globulin. The results obtained demonstrate for the first time that cell-free HIV and gp120 protein bind specifically to 160 kDa sperm protein that could be the receptor for HIV entry into spermatozoa. A 160 kDa sperm protein could be the CD4-independent HIV receptor for HIV to bind and enter into the spermatozoa. Further characterization of this 160 kDa HIV receptor on sperm will provide an insight in understanding the mechanism and probable mode of intervention or prevention of HIV transmission at the initial stage of infection.

Infectious Synapse

Dendritic cells (DCs) may play a role in host-pathogen interactions. For example, certain proteins expressed on DCs, such as DC-SIGN, can stimulate the efficiency of infection of target cells by the human immunodeficiency virus (HIV). McDonald et al. visualized individual particles of HIV in living cells and found that DC-associated HIV was recruited to the site of contact with target cells such as T cells. Simultaneously, the HIV receptor and coreceptor were recruited to the contact site. This recruitment effectively concentrates HIV, its receptor, and its coreceptor and presumably facilitates infection. D. McDonald, L. Wu, S. M. Bohks, V. N. KewalRamani, D. Unutmaz, T. J. Hope, Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science 300 , 1295-1297 (2003). [Abstract] [Full Text]

Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR.

DC-SIGN and DC-SIGNR are two closely related membrane-associated C-type lectins that bind human immunodeficiency virus (HIV) envelope glycoprotein with high affinity. Binding of HIV to cells expressing DC-SIGN or DC-SIGNR can enhance the efficiency of infection of cells coexpressing the specific HIV receptors. DC-SIGN is expressed on some dendritic cells, while DC-SIGNR is localized to certain endothelial cell populations, including hepatic sinusoidal endothelial cells. We found that soluble versions of the hepatitis C virus (HCV) E2 glycoprotein and retrovirus pseudotypes expressing chimeric forms of both HCV E1 and E2 glycoproteins bound efficiently to DC-SIGN and DC-SIGNR expressed on cell lines and primary human endothelial cells but not to other C-type lectins tested. Soluble E2 bound to immature and mature human monocyte-derived dendritic cells (MDDCs). Binding of E2 to immature MDDCs was dependent on DC-SIGN interactions, while binding to mature MDDCs was partly independent of DC-SIGN, suggesting that other cell surface molecules may mediate HCV glycoprotein interactions. HCV interactions with DC-SIGN and DC-SIGNR may contribute to the establishment or persistence of infection both by the capture and delivery of virus to the liver and by modulating dendritic cell function.

T-tropic human immunodeficiency virus (HIV) type 1 Nef protein enters human monocyte-macrophages and induces resistance to HIV replication: a possible mechanism of HIV T-tropic emergence in AIDS.

Increasing interest has been devoted to the role that monocyte-macrophages play in the pathogenesis of AIDS. The hypothesis of an involvement in AIDS pathogenesis of human/simian immunodeficiency virus (HIV/SIV) Nef also is currently under evaluation by many investigators. The original basis of this hypothesis came from evidence that monkeys infected with a nef-deleted SIV strain failed to develop simian AIDS. Here, we show that treatment of human monocyte-derived macrophages (MDM) with recombinant HIV-1 Nef protein (rNef) induces a strong inhibition of the replication of either macrophage (M-) or dual-tropic HIV-1 strains. Through cytofluorimetric analyses, we detected internalization of FITC-conjugated rNef in MDM as early as 6 h after treatment. Confocal microscope observations demonstrated that the intracellular distribution of internalized rNef was identical to that of endogenously produced Nef. Down-regulation of the CD4 HIV receptor detected upon rNef treatment of MDM suggested that the rNef-induced HIV inhibition occurred at the virus entry step. This deduction was strengthened by the observation that CD4-independent infection was totally insensitive to rNef treatment. The specificity of all observed effects was demonstrated by immunodepletion of rNef. Finally, we showed that the resistance to HIV replication induced by rNef treatment in MDM favours the spread of T-tropic over M-tropic HIV strains in doubly infected CD4(+) lymphocyte-MDM co-cultures. We propose that extracellular Nef contributes to AIDS pathogenesis by inducing resistance to M-tropic HIV replication in MDM, thereby facilitating the switching from M- to T-tropic HIV prevalence that correlates frequently with AIDS progression.

Interferon-γ Upregulates CCR5 Expression in Cord and Adult Blood Mononuclear Phagocytes

The C-C chemokine receptors CCR5 and CCR3 are fusion coreceptors for human immunodeficiency virus (HIV) entry into macrophages. The regulation of their expression influences infectivity by HIV. We report here that interferon-γ (IFN-γ) a cytokine that has bidirectional effects on HIV infection of macrophages, significantly upregulated CCR5 and CCR3 cell surface expression in human mononuclear phagocytes isolated from placental cord blood and adult peripheral blood. Monocytes treated with IFN-γ showed increased chemotaxis to the CCR5 ligands macrophage inflammatory protein-1 (MIP-1) and MIP-1β, confirming the functional relevance of IFN-γ–induced CCR5 expression. However, IFN-γ suppressed HIV entry into macrophages. Interestingly, we demonstrated that IFN-γ inhibited cell surface expression of CD4, the major receptor for HIV. This finding may explain the suppressive effect of IFN-γ on HIV entry into macrophages, despite its enhancing effect on the expression of CCR5 and CCR3 by these cells. In addition, IFN-γ–induced secretion of C-C chemokines (RANTES, MIP-1, and MIP-1β) by mononuclear phagocytes may also suppress HIV entry into macrophages. These data provide further evidence for cytokine-mediated regulation of CCR5 expression and are consistent with a novel paradigm in which cytokines regulate HIV infection and leukocyte migration by reciprocal and opposing effects on the expression of CD4 and chemokine receptors.

New insights into the interaction between the gp120 and the HIV receptor in human sperm (human.sperm/gp120/galactoglycerolipid/antigalactosylceramide/seminolipid/spermatogonia)

The human immunodeficiency virus (HIV) can infect some cell types which lack CD4. Galactosylceramide, a glycolipid present in the nervous system and colonic epithelial cells, has been implicated in the virus entry in these cells. Our data demonstrate that the HIV surface glycoprotein gp120 binds to the galactosyl-alkyl-acylglycerol (GalAAG), a glycolipid structurally related to galactosylceramide present on the surface membrane of the spermatozoa. In this paper, we review our previous data and further confirm the specificity of the interaction between this galactoglycerolipid and the gp120. Consistent with the structural similarity to galactosylceramide, the sperm GalAAG is capable of specifically binding the gp120. The specificity of the binding of antibodies anti-galactosylceramide and the gp120 to the sperm extract and to the purified GalAAG fraction prepared from the same extract has been demonstrated utilizing an ELISA assay which favors sensitivity and specificity. Immunofluorescence and immunoelectron microscopy data show a different localization for the GalAAG and its sulfated form the seminolipid (SGalAAG). The GalAAG is preferentially localized in the equatorial segment and the middle piece of the sperm tail, while the seminolipid is widely distributed on the membrane of the spermatozoa. These data indicate that human sperm express on their surface membrane a glycolipid similar in structure to galactosylceramide, the receptor for HIV identified in the CD4 − cells, that could function as a HIV receptor and possibly be implicated in its transmission.