The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection

Cordero

Cytometry Part B Clinical

et al. 2006

Background: HIV-1 infection has been associated with high expression of CD38 on peripheral blood (PB) CD81 and CD41 T-cells, which has been related with poor prognosis in untreated HIV-11 patients. In turn, CD38 expression on PB monocytes from HIV-11 individuals and its behavior after starting antiretroviral therapy (ART) have been poorly studied.Methods: CD38 expression on PB CD81 and CD41 T-lymphocytes and monocytes was prospectively analyzed in 30 ART-naive HIV-11 patients, using a quantitative multiparameter flow cytometry approach. Patients were tested prior to therapy, and at weeks 12, 14, 18, 112, and 152 after ART.Results: Prior to ART, CD38 expression was significantly increased on PB CD81 and CD41 T-cells and monocytes; despite a significant decrease after ART, CD38 expression remained abnormally high on PB CD81 T-cells and monocytes, even after one year of therapy, in the absence of detectable plasma viral load. The ART-induced early changes on CD38 expression by PB T-cells and monocytes differed among the cell subsets analyzed and patient groups, probably reflecting an interaction between the direct effects of therapy and a redistribution of the PB compartments of T-cells and monocytes. Hierarchical clustering analysis showed that the overall pattern of changes in CD38 expression observed early after starting ART was predictive of a better response to therapy, not only for PB CD81 T-cells, but also for CD41 T-cells and monocytes. Accordingly, those HIV-11 patients, who experienced a more pronounced increase in CD38 expression on both PB CD41 T-cells and monocytes after 2 weeks of ART, showed a more rapid viral clearance, which might reflect decreased HIV-1 replication in lymph nodes and other tissues, and a partial restoration of hematopoiesis.Conclusions: Combined quantitative measurement of CD38 expression on PB monocytes, and CD81 and CD41 T-cells is a more useful tool for monitoring HIV-11 patients under ART, rather than quantitation of CD38 expression on PB CD81 T-lymphocytes alone. q

Section: Discussionmentioning

confidence: 99%

Relationship between CD38 expression on peripheral blood T‐cells and monocytes, and response to antiretroviral therapy: A one‐year longitudinal study of a cohort of chronically infected ART‐naive HIV‐1+ patients

Cordero

Cytometry Part B Clinical

et al. 2006

“…Therefore, macrophages were proposed to be important for pathogenesis and dissemination. [16][17][18] In addition, HIV-1 infection has been reported to impair the functions of macrophages both in vivo and in vitro. Whereas macrophages from HIV-1-infected patients are deficient for phagocytosis of apoptotic neutrophils, 19 infected monocyte-derived macrophages are impaired in vitro in phagocytosis of Candida albicans and Toxoplasma gondii, 20,21 as well as phagocytosis mediated by FcR and CR3.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of phagocytosis in HIV-1–infected macrophages relies on Nef-dependent alteration of focal delivery of recycling compartments

Mazzolini

Herit

Bouchet

et al. 2010

Blood

Phagocytosis in macrophages is receptor mediated and relies on actin polymerization coordinated with the focal delivery of intracellular membranes that is necessary for optimal phagocytosis of large particles. Here we show that phagocytosis by various receptors was inhibited in primary human macrophages infected with wild-type HIV-1 but not with a nefdeleted virus. We observed no major perturbation of F-actin accumulation, but adaptor protein 1 (AP1)-positive endosome recruitment was inhibited in HIV-1-infected cells. Expression of negative factor (Nef) was sufficient to inhibit phagocytosis, and myristoylation as well as the LL and DD motifs involved in association of Nef with AP complexes were important for this inhibition. We observed that Nef interferes with AP1 in association with membranes and/or with a cleaved regulatory form of AP1. Finally, an alteration of the recruitment of vesicleassociated membrane protein (VAMP3)-and tumor necrosis factor-␣ (TNF␣)-positive recycling endosomes regulated by AP1, but not of VAMP7-positive late endosomes, was observed in phagocytic cups of HIV-1-infected macrophages. We conclude that HIV-1 impairs optimal phagosome formation through Nefdependent perturbation of the endosomal remodeling relying on AP1. We therefore identified a mechanism of macrophage function down-regulation in infected cells. IntroductionMacrophages play crucial functions at the interface between innate and adaptive immunity. They recognize, take up, and degrade microorganisms and are responsible for clearance of cell debris during developmental processes, elimination of dead red blood cells in the liver, as well as clearance of pathogenic microorganisms. They also participate in the generation of specific adaptive immune responses by presenting microbial-derived peptides associated with major histocompatibility complex class II (MHC II ) to T lymphocytes and by secreting proinflammatory cytokines. 1 Macrophages possess a wide variety of receptors that sense and bind microorganisms, including receptors for surface determinants such as the Toll-like receptors, and receptors for mannose or beta glucans (Dectin-1). Other receptors recognize opsonins, molecules of the immune system covering the surface of microorganisms. Some of these receptors, including receptors for the Fc portion of immunoglobulins (crystallizable fragment receptor [FcR]) and complement receptor 3 (CR3) receptors have strong phagocytic capacities; their stimulation induces the efficient uptake of the bound microorganism. Phagocytosis induced by FcRs is the best characterized pathway. It activates a signaling cascade that involves small guanosine-5Ј-triphosphate-binding proteins of the Rho and adenosine diphosphate-ribosylation factor families and eventually leads to actin polymerization, plasma membrane remodeling, and extension of pseudopods around the particle. [2][3][4][5] Extension of the plasma membrane around large particles is supported by a process of internal membrane delivery that involves the fusion machinery relying on ve...

The American Journal of Pathology

“…Chronically infected tissue macrophages are generally regarded as long-lived reservoirs in which reverse transcriptase inhibitors are ineffective and protease inhibitors demonstrate lower antiviral activity than in T lymphocytes. 44,45 That productively infected CD3…”

mentioning

confidence: 99%

Human Immunodeficiency Virus Infects Human Seminal Vesicles in Vitro and in Vivo

Deléage

Moreau

Rioux‐Leclercq

et al. 2011

1 the precise origins of the infected leukocytes and free viral particles contaminating the seminal plasma remain unclear. Phylogenetic studies have established that HIV in semen arises from local sources within the male genital tract and/or from passive diffusion via the blood 2-4 (previous references in Le Tortorec and Dejucq-Rainsford 5 ). The existence of productive sources in the male genital tract is further substantiated through observations of several differences between blood and semen, including i) detection of persistent infectious HIV in the semen of 5% to 30% of men with undetectable blood viral load receiving fully suppressive antiretroviral therapy [5][6][7][8][9] ; ii) higher viral load in semen in a subpopulation of treatment-naïve men 10 ; iii) different rates, kinetics of emergence, and diversity of drug-resistant strains 4,11,12 ; and iv) different ratio of infected versus noninfected leukocytes. 13At present, the nature of the sources of HIV in the male genital tract remains unclear. This knowledge is crucial to the understanding of the biology of HIV sexual transmission and to the design of targeted therapies for eradicating HIV from semen.Semen is composed of secretions and cells from the testes, epididymides, prostate, seminal vesicles, and bulbo urethral glands. Vasectomy has little effect on seminal shedding of HIV-1 RNA, 14 which suggests that the testes and epididymides are not the primary sources of HIV particles in semen. The seminal vesicles, the secretions of which represent more than 60% of the seminal fluid, could be an important source of seminal HIV. We recently demonstrated that the seminal vesicles of asymptomatic macaques are productively infected by simian immunodeficiency virus (SIV) in vivo and, together with the prostate, exhibit the highest level of infection among the male genital tract organs in this animal model. 15 To date, infection of human seminal vesicles by HIV has not been reported.